Pharmacy and Wellness Review

Drug Abuse Volume 7, Issue 3 Summer 2016

ISSN 2168-7382

2

Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections CE Included Katherine Elsass*, Austin Hilverding**, Steven Blake**, Brendan Rasor*, Steven N. Leonard+, PharmD

9

Pharmacologic and Nonpharmacologic Approaches to Palliative Care in Oncology CE Included

Daniel Powell*, Sunitha Johns**, Samia Alam**, Isabel E. Cwikla**, Brendan Rasor*, David W. Koh+, RPh, Ph.D. 18

26 34

Hormonal Therapy and Preventive Care of Transgender Patients

Angela Chu*, Jana Randolph**, Austin Hopkins**, Victoria Cho*, Sophocles Chrissobolis+, Ph.D.

Use of Botulinum Toxin in Central Nervous System Disorders

Julie Puvogel*, Paige Torbet++, Jourdan Ujlaki**, Rebecca Worden*, Lindsey Peters+, PharmD, RPh, BCPS

Comparison of Long-Term Oral Anticoagulation Therapies Including Newly Approved Reversal Agent for Dabigatran Mackenzie DeVine**, Natalie Lennartz*, Michaela Wolford**, Rebecca Worden*, Joelle Farano*, Erin Petersen+, PharmD, BCPS

46

Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach Morgan Homan**, Haval Norman**, Victoria Cho*, Yousif Rojeab+, Ph.D.

* PharmD candidate 2017, Ohio Northern University ** PharmD candidate 2018, Ohio Northern University + Faculty, Ohio Northern University, Raabe College of Pharmacy ++ BS exercise physiology 2016, Ohio Northern University

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Editorial Board: Editor-in-Chief

Hannah Granger

Formatting Editor

Cassandra Hacker

Managing Editors

Christina Ciccone Joelle Farano

Website Editor

Sabrina Hamman

Lead Editors

Victoria Cho Brian Heilbronner Brendan Rasor Rebecca Worden

Faculty Advisors:

Mary Ellen Hethcox, BSPh, PharmD, BCPS Karen L. Kier, BSPh, Ph.D., BCPS, BCACP Natalie DiPietro Mager, PharmD, MPH

Layout

Darlene Bowers

Summer 2016 Volume 7, Issue 3 The Pharmacy And Wellness Review

Drug Abuse Infectious Disease

Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections Katherine Elsass, Austin Hilverding, Steven Blake, Brendan Rasor, Steven N. Leonard, PharmD

This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions.

ACPE Universal Activity Number (UAN): 0048-0000-17-002-H04-P To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/.

Objectives After completion of this program, the reader should be able to: 1. Describe changes outlined in the new CDC/ACP Acute Respiratory Tract Infection in Adults guidelines.

2. Evaluate human factors contributing to the spread of antibiotic resistance.

3. Recognize inappropriate use of antimicrobial agents.

4. Apply IDSA recommendations for ideal antimicrobial stewardship.

5. Describe the role of the pharmacist in antimicrobial stewardship.

Abstract Antibiotic resistance has rapidly become one of the most significant challenges facing modern health care. Despite widespread public education efforts by the national government and health organizations worldwide, there remains a significant lack of public understanding of antibiotic resistance, how to prevent it and the implications if the science and health care communities fail to find a solution. The Centers for Disease Control and Prevention (CDC) and the American College of Physicians (ACP) recently published updated guidelines for appropriate antibiotic use in upper respiratory tract infections. These guidelines include several key recommendations for acute bronchitis, pharyngitis and acute rhinosinusitis (including the common cold). In the United States, at least 2 million antibiotic-resistant illnesses and 23,000 deaths occur each year. These illnesses and deaths result in a large cost to patients, payers and health care institutions. Recent research has shown that numerous human factors, such as patient satisfaction and pressure on prescribers, have an impact on inappropriate antibiotic prescribing.

The Infectious Diseases Society of America (IDSA) has published information on the key elements of a model antimicrobial stewardship program. Pharmacists can use this information to help reduce inappropriate use of antibiotics and reduce the spread of antimicrobial resistance.

2

Key Terms Anti-infective Agents; Drug Resistance; Microbial, Pharmacists; Respiratory Tract Infections Introduction Antibiotic resistance has rapidly become one of the most significant challenges facing modern health care. Patients and policy makers, as well as drug manufacturers and health care providers, all stand to be adversely impacted by resistance.

Despite widespread public education efforts by the national government and health organizations worldwide, there remains a significant lack of public understanding of antibiotic resistance, how to prevent it and the implications if the science and health care communities fail to find a solution. New antibiotics are being developed at record low rates, while inappropriate prescribing and excessive agricultural use continue to fuel the spread of drug-resistant species. As a follow up to the Spring 2015 article on resistance, this article further explores the topic with emphasis on recent guidelines, additional factors contributing to resistance and an expanded discussion on the pharmacist’s role in minimizing the development of resistance.

Guideline Update The Centers for Disease Control and Prevention (CDC) in concert with the American College of Physicians (ACP) recently published guidelines for appropriate antibiotic use in adults with acute respiratory tract infections. Inappropriate prescribing of antibiotics leads to thousands of adverse reactions, many deaths and billions of health care dollars spent each year.1 The publication updates guidelines from 2001 that stated, “Antibiotic treatment of adults with nonspecific upper respiratory tract infection does not enhance illness resolution and is not recommended.�2 The updated guidelines specifically describe appropriate antibiotic use in four acute upper respiratory tract infections.

Acute Bronchitis The vast majority of bronchitis cases are viral in nature, and the guidelines recommend against routine testing for nonviral causes.1 Treatment with antibiotics for patients with bronchitis is generally inappropriate unless pneumonia is suspected.1,3 Using antibiotics in patients with bronchitis is associated with higher incidence of adverse events and insignificant treatment results compared to control data.3,4 Pharyngitis The guidelines recommend against the use of antibiotics in most pharyngitis cases. Pharyngitis is typically of viral origin and self-limiting with a short presentation, so only minor benefits are noticed with antibiotic treatment.5,6 Antibiotics

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

may be useful for those patients with confirmed group A streptococcal infection.5 Confirmation of a group A streptococcal infection may be completed via traditional throat swab on a sheep blood agar plate, but this involves a delay. 7 Commercial rapid antigen detection tests are more expensive but allow swift identification of the microbe.7 In these patients, antibiotics may reduce duration of symptoms by up to two days and complications such as acute rheumatic fever may be avoided.6 Penicillin is the recommended antibiotic in patients fitting this criteria and without allergy.1 Discretionary use of antibiotics is advised in this population.

Acute Rhinosinusitis Viruses are normally the cause of acute rhinosinusitis, but acute bacterial rhinosinusitis may be a secondary complication. Therefore, antibiotic treatment is recommended in patients with persistent symptoms. This includes patients displaying greater than 10 days of symptoms, the onset of severe symptoms and cases of “double sickening” where patients initially improve then remit with worsening symptoms. Amoxicillin-clavulanate is the recommended treatment for acute bacterial rhinosinusitis with doxycycline or respiratory fluoroquinolones as alternative options.1,8 Other guidelines may recommend amoxicillin as the drug of choice, but the current practice guidelines advise the need for clavulanate due to growing resistance concerns.1 Common Cold The updated guidelines caution providers against prescribing antibiotics in cases of the common cold. Only symptomatic therapy is recommended in these patients. In addition to inefficacy, antibiotics are associated with increased risks of adverse drug events in patients with the common cold.1,2

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Antibiotic Resistance The CDC defines antibiotic resistance as “the ability of microbes to resist the effects of drugs.” Resistance most often occurs due to the elimination of both harmful and beneficial bacteria, resulting in an optimal environment for the remaining drug resistant bacteria to develop and grow.9 In the medical community, antibiotic resistance has become an increasing concern. Not only is the quality of care affected, but the cost of sequential care escalates for the patient. In 2009, $20 billion in health care were spent on antibiotic resistance, with an additional $8,000 in hospital stays per patient and $35 billion spent in societal costs from loss of productivity due to hospitalization or death.10,11 A study conducted by Robert et al. found that a single patient with an antibiotic resistant infection could result in $29,069 in added costs.

However, this dollar value was based on 2008 data, meaning there are even greater costs in present day dollar value.11 In the United States, at least 2 million antibiotic-resistant illnesses and 23,000 deaths occur each year. Based on 2013 data from the CDC, invasive methicillin-resistant Staphylococcus aureus (MRSA) infections account for the largest number of antibiotic resistant deaths annually, totaling around 11,000 fatalities. Antibiotics are improperly prescribed approximately half of the time, including inappropriate duration of treatment and indication.9 A retrospective cohort study conducted by Gill et al. evaluated 52,135 cases of upper respiratory tract infections using electronic health records, and found that 65 percent of patients received antibiotics. Broad-spectrum antibiotics for upper respiratory infections were prescribed for over half of the cases, with 68 percent of broad-spectrum antibiotics being prescribed for acute bronchitis.12 This contradicts the general guideline rec-

Table 1. Summary of CDC/ACP Recommendations for Appropriate Antibiotic Use in Select Acute Respiratory Tract Infections.1

Acute Respiratory Tract Infection

Acute Bronchitis

Pharyngitis

Acute Rhinosinusitis

Common Cold

Appropriate Antibiotic Use Recommendation

Only if pneumonia is suspected.

Discretionary use in group A streptococcal infections.

Patients with persistent symptoms indicative of acute bacterial rhinosinusitis.

Not recommended.

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

ommendations for upper respiratory infections, which advise the year 2020.15 Although the 10 X ’20 Initiative has been reagainst the use of broad-spectrum antibiotics.2 leased, along with an initiative developed by the White House to bring new antibiotics to the market by 2020, the funding Physicians and health care professionals often feel pressured for new antibiotic development is often not available. On Jan. to prescribe an antibiotic for upper respiratory infections 20, 2016, more than 80 drug and medical device manufactureven when antibiotic use is not indicated. In a follow-up tele- ers requested governments along with industry leaders to phone survey of 959 patients, conducted by Stearns et al., declare a fight against antibiotic resistance by funding the visit satisfaction scores for treatment of upper respiratory research and development of new antibiotics. The Declaratract infections at both Veterans Administration (VA) hospital tion on Combating Antimicrobial Resistance represents a emergency departments and nonVA hospitals were studied. It monumental step in the fight against antibiotic resistance as was found that in the nonVA settings, an overall visit satisfac- commercial drug manufacturers, diagnostic developers and tion score based on a five point Likert scale was significantly global governments unite to conserve antibiotics by focusing increased with an antibiotic prescription, while there was no on three broad areas: reducing the development of drug restatistical difference in scores for VA hospitals. 13 Cordelia et sistance, increasing investment in research and development al. evaluated patient satisfaction as a driving factor for health that meets global public health needs and improving access to professionals when prescribing antibiotics for acute respira- high-quality antibiotics for all.16 tory tract infections. Overall, 33.7 million antibiotic prescriptions were prescribed to a population of 53.8 million patients, Antimicrobial Stewardship with antibiotic prescriptions showing a direct correlation to In order to meet the growing demands placed upon patient higher doctor and practice satisfaction scores based on pa- care by antibiotic resistance and a slowdown in introduction tient general practice surveys.14 of new antimicrobial drug classes to market, pharmacists and other health care professionals must strive toward improved In 2010, the IDSA announced the 10 X ’20 Initiative, bringing stewardship of current antimicrobials.17 Model guidelines set together interdisciplinary leaders to stimulate new antibacte- forth by the IDSA in 2007 detail components of an idealized rial research and development to create 10 new antibiotics by stewardship program for implementation in various health

Table 2. Summary of 2007 IDSA Model Antimicrobial Stewardship Program. 18

Guideline Measure

4

Purpose

Prospective audits with feedback

Review prescribing trends, provide one-on-one pharmacistprescriber feedback.

Formulary restriction/drug preauthorization

Curtail unnecessary antimicrobial agent prescribing, cut costs, improve outcomes.

Provider education/guidelines

Provide awareness of current antimicrobial agent prescribing recommendations.

Antimicrobial agent order forms

Require prescriber justification for antimicrobial agent use.

Dose-optimized therapy

Causative organism-specific therapy to curtail antimicrobial resistance development.

Parenteral to oral conversion

Decrease hospital stay length, decrease overall cost.

Computer-based clinical decision support

Provide real-time therapy recommendations to improve adherence to antimicrobial prescribing guidelines.

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

care settings.18 Components include utilization of prospective, ongoing audits with provider intervention and feedback; formulary restrictions and/or antimicrobial agent preauthorization; provider education and guidelines; use of antimicrobial agent order forms; streamlined, dose-optimized therapy; parenteral to oral conversion as appropriate; and computerbased clinical decision support, surveillance and feedback.

In the IDSA model, prospective audits with intervention and feedback involve direct interaction between an infectiousdiseases trained physician or pharmacist and the prescriber.18 In addition to this consult, the use of clinical guidelines and other modes of health care professional education have been met with mixed results.19 Potential provider education measures include educational pamphlets, outreach events and one-on-one consultations with prescribers. However, education must be coupled with active intervention or the educational interventions will have only a marginal impact on prescribing practices.18 Formulary restrictions and/or antimicrobial agent preauthorization can involve obtaining special approval from an advisory board before initiation of a restricted antimicrobial. Via such methods, the use of otherwise potentially unnecessary or redundant antimicrobials can be curtailed leading to significant cost reductions and improvements in overall patient health. Additionally, an appeals process and constant monitoring must be available to ensure judicious execution of a preauthorization program.

Other components of a model stewardship program include the use of antimicrobial ordering forms to improve patient outcomes and decrease antimicrobial usage.18 Such forms require prescribers to justify drug choice when initiating or continuing therapy. Antimicrobial ordering forms must be coordinated with appropriate, streamlined antimicrobial use.

Therapy must be specific to the causative organism, as unnecessary use of broad-spectrum or combination therapy can contribute to the development of antimicrobial-resistant pathogens.20 Additionally, antimicrobials must be dosed appropriately to ensure adequate antimicrobial action without facilitating the development of resistance.18 In addition to appropriate drug selection and dosage, the route of administration also plays an important role in infection treatment, as converting antimicrobials from parenteral to oral administration when clinically appropriate can decrease hospital stay length and overall costs.

A final component of a model stewardship program includes the use of computerized monitoring and clinical decision support.18 In this model, real-time recommendations are displayed in the electronic medical records system when a prescriber inputs an order. These recommendations can require immediate prescriber attention before allowing completion of the order or may appear as optional advice. Such programs have demonstrated improved adherence to and physician acceptance of antimicrobial prescribing guidelines.21,22 Overall, the use of model stewardship guidelines decreases overall antimicrobial usage, health care cost, and hospital stay length and improves patient outcomes.

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Update on New IDSA Guidelines The IDSA published updated stewardship guidelines in April 2016.23 This update provides further guidance on how to implement a stewardship program while stressing the importance of individualizing programs according to each clinical site’s characteristics, resources and needs. Table 3 provides a review of the new recommendations found in the updated guidelines.

Role of the Pharmacist Pharmacists play a key role in the promotion of antimicrobial stewardship. In the institutional setting, pharmacists often work closely with hospital staff to monitor patient therapy and ensure the correct drug selection, dosage and route of administration. More significantly, pharmacists are frequently responsible for the daily implementation of stewardship programs in clinical settings, including management and policy development. In the community setting, pharmacists can counsel patients, educating them on the importance of antimicrobial medication adherence.24 Additionally, they can immunize patients and lead other public health initiatives.

However, where pharmacists currently have the greatest potential to impact antimicrobial resistance is through collaborative practice with other health care professionals.

An important role for pharmacists in collaborative practice includes triage, where pharmacists assess the severity of a patient’s symptoms including the appropriateness of self-treatment with over-the-counter medications or if the condition requires a physician’s visit.24 Other collaborative practice examples include community pharmacists outside the United States (such as in Canada, the United Kingdom and New Zealand) who have entered into practice agreements with physicians where they can directly monitor and prescribe limited antimicrobials. Generally, these programs have been met with success and exemplify the potential of such agreements in the United States. In the hospital setting, pharmacists can lead antimicrobial stewardship teams, heading the fight against growing antimicrobial resistance by implementing model stewardship programs. Significantly, recent initiatives from the President’s Council of Advisors on Science and Technology and the Centers for Medicare and Medicaid Services indicate a regulatory requirement for Antimicrobial Stewardship Programs (ASPs) in clinical settings, with projected implementation by 2017, and represent a potential role for pharmacists.25 Overall, pharmacists play an instrumental role in leading and working with other health care professionals in the fight against antimicrobial resistance.

Conclusion While antimicrobial resistance remains an urgent challenge to modern health care, significant steps have been taken in an effort to curtail the spread of resistant organisms. New treatment guidelines help prescribers to better utilize current antimicrobials and to keep up with a rapidly changing field. The pharmaceutical industry has united to help provide new antibiotics and find new ways of treating infections.

Governments and health organizations continue to educate

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Table 3. Summary of the 28 Specific Recommendations from the 2016 IDSA Updates to Model Antimicrobial Stewardship Program (ASP).23 Guideline Measure

Evidence Strength

Guideline Measure

Moderate

Develop stratified antibiograms for empiric therapy guideline development

Low

Selective reporting of antimicrobial susceptibility test results

Yes

Specific infectious disease Yes syndrome-targeted interventions

Preauthorization/ Prospective Audit/Feedback Intervention*

Recommend

Yes

Do not Didactic education* use alone

Facility-specific practice guidelines

Reduce use of high risk Clostridium difficile infectionassociated antimicrobials Prescriber-led routine review of antibiotic usage*

Computerized clinical decision support*

Antibiotic cycling

Yes

Yes

Yes

No

ASP implementation in immunocompromised patients Yes to improve antifungal treatment

Evidence Strength

Guideline Measure

Recommend

Evidence Strength

Low

Aminoglycoside pharmacokinetic monitoring/ adjustment

Yes

Moderate

Low

Vancomycin pharmacokinetic monitoring/ adjustment

Yes

Low

Low

Rapid viral testing use to reduce inappropri- Yes ate antimicrobial use

Low

Alternative dosing strategies to avoid broad-spectrum Yes β-lactam dosing for cost concerns

Low

Low

Rapid diagnostic testing with routine testing

Moderate

Appropriate IV to oral antimicrobial Yes conversion*

Moderate

Moderate

Serial Procalcitonin Testing in Intensive Care Unit patients to Yes decrease antimicrobial use

Moderate

Allergy assessment and penicilYes lin skin testing for β-lactam allergy

Low

Low

Use nonculture-based fungal markers in hematologic maligYes nancy to optimize antifungal use

Low

Use shortest effective duration of Yes treatment*

Moderate

Moderate

Monitor antimicrobial use via Days of TheraYes py instead of Defined Daily Dose

Low

Consider goals and size for Yes syndrome-specific intervention

Good practice recommendation

Low

Antimicrobial cost measured by prescription/ Yes administration history instead of purchasing data

Develop facilityspecific guidelines for fever and Good practice neutropenia Yes recommendation management in hematologyoncology patients

Low

Low

ASP implementation in nursing/skilled nursing homes

ASP implementaGood practice tion in Neonatal recommendation Intensive Care Units

Yes

Good practice recommendation

ASP implementation in terminally Yes ill patients

Good practice recommendation

*Recommendation previously found in 2007 guidelines

6

Recommend

Yes

Yes

Yes

Yes

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

the public on how to do their part. Within health care practice, antimicrobial stewardship programs have become widespread and standardized. Through all of these changes, pharmacists remain at the forefront in each effort. Pharmacists are among the best prepared health care providers fighting to end the threat of widespread antimicrobial resistance.

References 1. Harris AM, Hicks LA, Qaseem A. Appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016;164(6):425-34.

2. Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods. Ann Intern Med. 2001 Mar 20;134(6):479-86.

3. Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev. Mar 2014;(3). Available from:onlineli brary.wiley.com/doi/10.1002/14651858.CD000245.pub3/full.

4. Llor C, Moragas A, Bayona C, Morros R, Pera H, Plana-Ripoll O, et al.

Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial. BMJ. 2013;347:f5762. Available from: www.bmj.com/content/347/bmj.f5762.

5. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al.

Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86-e102. Available from://cid.oxfordjournals.org/content/55/10/e86.full.

6. Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database Syst Rev. 2013;(11). Available from:onlinelibrary.wiley.com/ doi/10.1002/14651858.CD000023.pub4/full.

7. Gerber MA, Shulman ST. Rapid Diagnosis of Pharyngitis Caused by Group A Streptococci. Clin Microbiol Rev. 2004;17(3):571-80.

8. Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJC, Hicks LA, et al. Executive summary: IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012;54 (8):1041-5. Available from:cid.oxfordjournals.org/content/54/8/1041. long.

9. Centers for Disease Control and Prevention. [Internet]. Atlanta (GA): Centers for Disease Control and Prevention. About Antimicrobial Resistance; [Updated 2015 Sep 8; cited 2016 April 1]; [about 8 screens].

Available from:www.cdc.gov/drugresistance/about.html.

10. Bush K, Courvalin P, Dantas G, Davies J, Eisenstein B, Huovinen P, et al.

Tackling antibiotic resistance. Nat Rev Microbiol. 2011 Nov 2;9 (12):894-6.

11. Roberts RR, Hota B, Ahmad I, Scott D, Foster SD, Abbasi F, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009 Oct 15;49(8):1175-84.

12. Gill JM, Fleischut P, Haas S, Pellini B, Crawford A, Nash DB. Use of antibiotics for adult upper respiratory infections in outpatient settings: a national ambulatory network study. Fam Med. 2006 May;38(5):349-54.

13. Stearns CR, Gonzales R, Camargo CA Jr, Maelli J, Metlay JP. Antibiotic prescriptions are associated with increased patient satisfaction with emergency department visits for acute respiratory tract infections.

Acad Emerg Med. 2009 Oct;16(10):934-41.

14. Ashworth M, White P, Jongsma H, Schofield P, Armstrong D. Antibiotic prescribing and patient satisfaction in primary care in England: crosssectional analysis of national patient survey data and prescribing data.

British Journal of Gen Practice. 2016 Jan; 66(642): 40-6.

15. Infectious Diseases Society of America. The 10 x ’20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020.

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Clin Infect Dis. 2010 April 15; 50(8):1081-3.

16. Global pharmaceutical industry calls on governments to work with them to beat the rising threat of drug resistance [Internet]. London, England: HM Government; 2016 Jan 21 [cited 2016 April 1]. Available from:amr-review.org/sites/default/files/Press%20notice%20Jan%20 21%202016.pdf.

17. Bond CM. Antibiotic stewardship: an important pharmacy role? Can J Hosp Pharm. 2015 Nov-Dec;68(6):441-2.

18. Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein RA, Burke JP, et al. Infectious Diseases Society of America and the Society for Health care Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007 Jan 15;44:159-77.

19. Arnold AR, Strauss SE. Interventions to improve antibiotic prescribing practices in ambulatory care (review). Cochrane Database Syst Rev. 2005 July 31;4:1-78.

20. Paterson DL, Rice LB. Empirical antibiotic choice for the seriously ill patient: are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clin Infect Dis. 2003 Apr 15;36:1006-12.

21. Nachtigall I, Tafelski S, Deja M, Halle E, Grebe MC, Tamarkin A, et al.

Long-term effect of computer-assisted decision support for antibiotic treatment in critically ill patients: a prospective ‘before/after’ cohort study. BMJ Open. 2014 Dec 22;4(12):e005370.

22. Chow AL, Ang A, Chow CZ, Ng TM, Teng C, Ling LM, et al. Implementation hurdles of an interactive, integrated, point-of-care computerised decision support system for hospital antibiotic prescription. Int J Antimicrob Agents. 2016 Feb;47(2):132-9.

23. Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Health care Epidemiology of America. Clin Infect Dis. 2016 April 15;62:1-27.

24. International Pharmaceutical Federation. Fighting antimicrobial resistance: the contribution of pharmacists. The Hague: International Pharmaceutical Federation; 2015.

25. Goff D. NFID News [blog on the Internet]. Bethesda (MD): National Foundation for Infectious Diseases. Presidential order pushes mandatory antimicrobial stewardship: is your hospital prepared?; 2015 Apr 16 [2016 Apr 22]; [about 2 screens]. Available from:nfid.wordpress. com/2015/04/16/presidential-order-pushes-mandatory-antimicrobi al-stewardship-is-your-hospital-prepared/.

The authors have no conflict of interest or funding support to disclose.

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

Assessment Questions 1.

Antibiotics are never appropriate in patients with acute respiratory tract infections.

A. True B. False

2.

Which of the following statements about appropriate antibiotic use is correct?

A. Recent advances show minor usefulness of antibiotic treatment of patients with a common cold.

B. Inappropriate antibiotic use is not a concern in well-developed hospitals across the United States.

C. Inappropriate antibiotic use is often associated with insignificant treatment outcomes as well as higher rates of adverse reactions.

D. Inappropriate antibiotic use is not associated with antibiotic resistance although the two topics are often discussed in tandem.

3.

According to recent data, how much money is spent on antibiotic resistance annually?

A. $1 billion B. $2 billion C. $10 billion D. $20 billion

4.

Antibiotic prescribing is not relevant to a health care provider’s overall patient satisfaction scores.

A. True B. False

5.

According to the CDC, antibiotics are incorrectly prescribed what percent of the time?

A. 30% B. 20% C. 50% D. 60%

6.

Which of the following is NOT a part of a model stewardship program?

A. Computer-based decision support B. Prospective, ongoing audits with HCP intervention and feedback C. Formulary restrictions D. Antimicrobial agent postauthorizations E. Use of antimicrobial agent order forms

8

7.

Streamlined antimicrobial therapy should: A. Be targeted to the organism when such information is known.

B. Be wide-spectrum when the target organism is known.

C. Utilize the optimal dose for maximal antimicrobial action while minimizing chance of antibiotic resistance development.

D. Both A and B. E. Both A and C.

8.

Which of the following MOST ACCURATELY describes the role of the pharmacist in antibiotic stewardship?

A. The pharmacist plays a role in prescribing the appropriate antibiotic at the optimal dose.

B. The pharmacist plays a role in administering the antibiotic directly to the patient.

C. The pharmacist plays a role in overseeing all personnel in the hospital and ensuring their compliance with institutional stewardship guidelines.

D. The pharmacist plays a role in ensuring appropriate antibiotics are prescribed, including consulting with prescribers and patients to ensure best practices.

E. The pharmacist does not play any significant role in antibiotic stewardship.

9.

The IDSA recommends what action in order to maximize the impact of provider education regarding appropriate use of antimicrobials?

A. Active intervention B. Presentations and posters C. Informational pamphlets D. Use of the most recent prescribing guidelines

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 1/2/2020.

To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/ to enter the required information. Please allow two to three weeks for electronic distribution of your continuing education certificate, which will be sent to your valid email address in PDF format.

The Pharmacy And Wellness Review Summer 2016 Volume 7, Issue 3

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Pharmacologic and Nonpharmacologic Approaches to Palliative Care in Oncology Daniel Powell, Sunitha Johns, Samia Alam, Isabel E. Cwikla, Brendan Rasor, David W. Koh, RPh, Ph.D.

This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions.

ACPE Universal Activity Number (UAN): 0048-0000-17-001-H04-P To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/.

Objectives After completion of this program, the reader should be able to: 1. State the NCCN goals of palliative care.

2. Identify appropriate pharmacologic palliative care.

3. List several scientifically validated nonpharmacologic options of palliative care.

4. Assess clinical studies to implement effective palliative care options for patients.

Abstract In recent decades, few fields have changed as drastically as oncology. A wide variety of approaches must be taken in order to best care for cancer patients. With the globalization of health care and modern society, nontraditional management of cancer symptoms is once again increasing in popularity.

The National Comprehensive Cancer Network (NCCN) has also recently updated their palliative care guidelines. These guidelines provide a detailed approach for the care of a wide range of cancer patients but largely focus on traditional pharmacotherapy. An increasing number of studies are being conducted on nonpharmacologic approaches to care for patients with cancer. These strategies range from mindfulness-based stress reduction (MBSR) and acupuncture to massage and music therapy. As easily accessible and highly trusted health care professionals, pharmacists have a duty to know not only about appropriate pharmacologic palliative care but also appropriate nonpharmacologic alternatives to recommend to patients and providers.

Key Terms Alternative Medicine; Medicine; Complimentary; Oncology; Medical; Palliative Care; Pharmacists Introduction In recent decades, few fields have changed as drastically as oncology. However, with more numerous and effective treatment options, new challenges have appeared. In general, patients with cancer are living longer today than in years past.

Although many are surviving with few additional needs,

many patients still require care for advanced or terminal disease. Furthermore, the health care community has realized that each cancer patient responds differently to treatment. Therefore, a wide variety of approaches must be taken in order to best care for this population. With the globalization of health care and modern society, nontraditional management of cancer symptoms is once again increasing in popularity. This article will explore the most recent guidelines for pharmacologic palliative care as well as specific studies addressing nonpharmacologic options that patients and providers may encounter.

Practice Guidelines Palliative care is an integral part of cancer therapy. The goals of palliative care should be to “anticipate, prevent, and reduce suffering and to support the best possible quality of life for patients and their families,� according to the National Comprehensive Cancer Network (NCCN) Palliative Care Guidelines.1 Palliative care should be initiated at diagnosis and continued throughout treatment relative to the needs of the patient, whether treatment is curative or simply prolonging life. For the best patient outcomes, an interdisciplinary team consisting of board certified palliative care physicians, advanced practice nurses, physician assistants, pharmacists, social workers and chaplains should be utilized.

After diagnosis, every patient should be screened by their providers at each visit for the following: unmanaged symptoms, emotional distress due to therapy and diagnosis, comorbid conditions, decreasing life expectancy, metastatic tumors, or patient and/or family requests for palliative care.1 Patients should be continuously reevaluated at each subsequent visit, and palliative therapy should be adjusted as necessary according to the needs of the patient.

The goals of anticancer therapy should be set in relation to the estimated life expectancy of the patient, which will then help determine the best approach to palliative care.1 Anticancer therapy can be both physically and mentally taxing on the patient and family. The benefits and burdens of therapy must be properly communicated ensuring that the most effective course of therapy is selected according to the wishes of the patient. If it is determined that a patient has months to years in life expectancy, the patient should be made aware if treatment is palliative or curative and of the anticipated burdens associated with the selected therapy. Once the goals of the therapy are stated, the patient can begin to psychologically prepare for the disease progression and treatment regimen, an aspect unique to palliative care providers. If a patient has months to weeks or weeks to days, ensure the patient is aware of the incurability of their disease. Establish-

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Pharmacologic and Nonpharmacologic Approaches to Palliative Care in Oncology

ing updated goals as the disease progresses can help transition into providing extensive symptom relief during the dying process. This can include discontinuing inherently aggressive anticancer therapies and focusing on palliating physical and psychological symptoms to increase quality of life and comfort for the dying patient.

In cancer and cancer therapy, there is an overarching symptomatology associated with treatment and disease progression. 1 Pain, dyspnea and fatigue are among the more prevalent symptoms along with gastrointestinal complications such as constipation, diarrhea, and nausea and vomiting, which can exacerbate anorexia or cachexia.

Pain: Controlling pain in cancer is essential to maximizing patient outcomes and quality of life. Patients with longer life expectancies will follow the NCCN Cancer Pain Management guidelines while end stage patients will additionally follow the palliative care guidelines.1 The Cancer Pain Management Guidelines suggest titrating short acting opioids in both opioid naïve and tolerant patients either orally or intravenously using morphine or morphine equivalents.2 Titration should be to the patient’s acceptable pain intensity and opioid tolerability. If the patient’s pain is not adequately controlled, an increase of 50 to 100 percent of the opioid dose is indicated at the discretion of the provider. As the disease progresses or remits, it is imperative to constantly reassess pain intensity and goals in order to avoid supratherapeutic or subtherapeutic levels.

In patients with reduced life expectancies, the recommendations suggest a more aggressive approach to titration.1,3 Doses should not be reduced for decreasing blood pressure, respiratory rate or consciousness as long as pain is being managed to the patient’s preference. This aggressive approach can increase the risk of neurotoxicities such as myoclonus and hyperalgesia, so managing the symptoms with appropriate opioid rotation and rehydration is imperative for increased quality of life.1 In general, opioid dose reduction should be avoided to prevent acute withdrawal symptoms or reemergence of pain. If necessary, cautiously reduce opioid dose by 25 to 50 percent every 24 hours, while avoiding the use of opioid antagonists. Disease progression can also require changing routes of administration from oral to various different routes using the appropriate dosing conversions found in the corresponding package inserts.4 Dyspnea: Dyspnea is a common symptom in cancer because it is multifactorial and usually secondary to other symptoms.1 Lung cancer contributes considerably to the presence of dyspnea among all cancer patients. The intensity of discomfort during breathing should be assessed and underlying conditions or comorbidities should be treated according to life expectancy. For patients with longer life expectancies, interventional options include radiation and chemotherapy, removal of cardiac, pleural or abdominal fluids or bronchoscopic therapies.5 Continuous positive airway pressure and bi-level positive airway pressure can be used if the condition is reversible.1 Pharmacologic treatments of

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underlying conditions are also an option, which include the utilization of bronchodilators, diuretics, steroids, antibiotics, transfusions or anticoagulants if a pulmonary embolism develops. Morphine also has dual utilization as it can reduce dyspnea in the opioid naïve if dosed around the clock. If morphine is ineffective and dyspnea is rooted in anxiety associated with cancer, benzodiazepines are indicated but are not shown to reduce dyspnea unless anxiety-induced.6 Therapy for patients with a reduced life expectancy is less invasive with a focus on symptom alleviation.1 There are similarities in pharmacologic interventions such as morphine in the opioid naïve, benzodiazepines if anxiety-induced, and diuretics.

Additional options include a decrease in enteral or parenteral fluids to decrease fluid retention, a 25 percent increase in chronic opioid dose, or the use of anticholinergic agents to decrease excessive secretions. The preferred agents are scopolamine (subcutaneous or transdermal), ophthalmic atropine (sublingual) or glycopyrrolate (intravenous or subcutaneous). One of the last options when the disease is in its final stages, is a time-limited trial of mechanical ventilation, dependent upon the preference of the patient and family.

Cachexia or Weight Loss: Another series of symptoms in cancer patients is the physical deterioration of skeletal and muscle mass, known as cachexia. The development of anorexia, or the lost desire to eat, further exacerbates the cachectic state of the patient.1 To help prevent cachexia and anorexia, recognizing inducible factors such as distorted tastes, or dysgeusia, xerostomia, mucositis, gastroparesis, nausea and vomiting, constipation, pain, fatigue and a psychological distortion of one’s self appearance is key to improving patient outcomes. Also, providers must determine if there are comorbidities present in the patient that might be causing the anorexia or cachexia and treat these conditions appropriately. This could include hypogonadism, thyroid dysfunction or other metabolic anomalies. There are both pharmacologic and nonpharmacologic treatments available to help prevent anorexia and cachexia, but the following pharmacologic strategies can be employed to help treat underlying conditions and contributing factors. If an oral or pharyngeal candidiasis infection is contributing to the lost desire to eat, treat the infection appropriately with either oral or topical solutions. Sometimes, anorexia is attributable to depression associated with the cancer diagnosis or prognosis or a preexisting anorexic diagnosis. Mirtazapine can be prescribed to treat this depression and has the added benefit of stimulating appetite. Other appetite stimulants are also recommended for patients with a decreased life expectancy.

These include megestrol acetate, olanzapine, dexamethasone and cannabinoids.7 As the patients reach the end of life, providers must educate both patients and family members about the inevitable symptoms and decisions they will face.1 In the dying patient, anorexia and lack of thirst are quite common and should be palliated by proper mouth care and frequent, small amounts of fluids. Also, the patient may experience a complete metabolic shutdown even if they are given total parenteral nutrition (TPN). Withholding TPN from the dying patient is ethically sound and could prevent additional complications such as infection and refeeding syndrome.1,8

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Nausea and Vomiting: Nausea and vomiting are symptoms that present in many cancer patients receiving chemotherapeutic agents.1 Special care must be taken to properly premedicate these patients. First, check therapeutic levels of other agents known to induce nausea and vomiting such as phenytoin, digoxin, carbamazepine and tricyclic antidepressants. Determine if it is feasible to decrease the current dose, find a therapeutic equivalent or discontinue the medication.

Nausea and vomiting are also nonspecific symptoms associated with other disease states. Providers must diagnose and treat the following possible underlying conditions: gastroparesis, central nervous system involvement, gastritis/ gastroesophageal reflux and correcting metabolic abnormalities such as hypercalcemia, uremia or dehydration. Rotating or reducing chronic opioids and substituting them with coanalgesics without emetic or nauseating side effects can also reduce symptoms. If the cancer itself is the direct precipitating factor, consider palliative radiation, dexamethasone, proton pump inhibitors (PPIs), metoclopramide, endoscope stenting or a G-tube. For patients who have persistent nausea and vomiting, titrate dopamine receptor antagonists (prochlorperazine, haloperidol, metoclopramide, olanzapine) to the patient’s tolerability. If symptoms still persist, consider adding one or more of the following agents: 5-HT3 receptor antagonists (ondansetron), anticholinergics (scopolamine), antihistamines (meclizine) or cannabinoids. For refractory patients, add dexamethasone or olanzapine if the patient is not already receiving these medications. Patients might also experience psychological disorders that contribute to nausea and vomiting. If so, consider adding a dopamine receptor antagonist, lorazepam or a cannabinoid.

Constipation: Because of the heavy reliance on opioids for cancer pain management, opioid induced constipation is expected to be a symptom experienced almost universally among cancer patients.1 Comorbidities such as hypothyroidism, diabetes mellitus, hypokalemia and hypercalcemia can also contribute to constipation; so providers must treat these conditions as well. In the treatment of constipation, simple lifestyle or dietary modifications can help, but pharmacologic agents are often necessary to produce bowel movements.

Traditional agents such as sennosides and docusate can be titrated to maximum doses at intervals of two to three times a day to produce one bowel movement every one to two days. Bisacodyl up to three times a day may be added if the patient still cannot produce a bowel movement. For patients refractory to the above treatments, providers can add bisacodyl suppositories, polyethylene glycol, lactulose, sorbitol or magnesium-based solutions. Tap water enemas and metoclopramide are suggested if the patient remains refractory, but only as last line options. There are numerous medications that can induce constipation; so providers should consider the benefits of discontinuing nonessential agents that are known to constipate patients. If the patient is fecally impacted, utilize a glycerin suppository and/or a mineral oil. If necessary, manually disimpact after premedicating the patient with analgesics and anxiolytics. Newer agents specifically targeted to treat opioid induced constipation, like methylnaltrexone, can be injected subcutaneously to help produce bowel movements.

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Diarrhea: There are many causes that can contribute to diarrhea such as infection, antibiotics, anticancer treatment, impaction or changes in diet and exercise.1 Severity and grading of diarrhea is based upon the number of stools per day over the patient’s baseline. Grade 1 is less than four stools per day, grade 2 is between four and six stools per day, grade 3 is over seven stools per day requiring hospitalization and grade 4 is an urgent, life-threatening emergency situation. Grade 1 patients are initially treated with oral rehydration and electrolyte supplementation. Antidiarrheals such as loperamide or diphenoxylate-atropine are also recommended. Patients can adhere to the BRAT diet: bananas, rice, applesauce and toast. If the chemotherapy regimen is causing diarrhea, the chemotherapy dose can be reduced or withheld, although neither option is ideal. Grade 2 patients are continued on antidiarrheals, but intravenous (IV) fluids are initiated if the patient is unable to tolerate oral hydration.

Anticholinergics such as hyoscyamine and atropine can also be added in conjunction with antidiarrheals. Infections such as Clostridium difficile can occur in cancer patients due to chemotherapy and nosocomial acquisitions. Treat moderate C. difficile with oral metronidazole and severe C. difficile with oral vancomycin for 10 to 14 days.4 Patients receiving ipilimumab for metastatic melanoma can also experience grade 2 diarrhea, so it is recommended to consider either infliximab or corticosteroids as alternative therapy.1 Grades 2 through 4 also follow the above guidelines, with the addition of octreotide. However, recommendations are different for patients near death. These patients have the option of home infusion for IV rehydration, initiation of around the clock opioids or dose increase to induce constipation, octreotide or glycopyrrolate to help maximize comfort level in the final days of life.

Sleep Disturbances: Cancer patients often experience disturbances in sleep leading to insomnia and daytime drowsiness.1 Severity of the disturbances should be assessed using metrics such as the Epworth Sleepiness scale. After determining the severity of the disturbances, prescribers should attempt to determine the causative factors behind them. Anxiety and fears about the disease, as well as contemplation of death, often weigh heavily in these disturbances.

Providers should counsel their patients on proper sleep hygiene or refer them for cognitive behavioral therapy for treatment of depression and/or anxiety.

Medication withdrawal or side effects sometimes lead to disturbances. Corticosteroids, opioids, anticonvulsants, caffeine, hormones, herbals, barbiturates, benzodiazepines, alcohol and tricyclic antidepressants are all offending agents. Proper management and tapering should be performed to reduce discomfort. Underlying conditions such as obstructive sleep apnea or restless leg syndrome also prevent sleep for cancer patients. Proper continuous positive or bi-level airway pressure therapy should be used for sleep apnea, while ropinirole, pramipexole with pregabalin, and carbidopa-levodopa are options for restless leg syndrome. If the patient is still experiencing disturbances leading to insomnia, medications that induce somnolence can be prescribed. These include:

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Table 1. Summary of Pharmacologic Interventions for Symptoms Associated with Cancer Treatment. 1-8 Indication

Proposed Therapy

Longer life expectancy Short acting opioids, titrated up to 50-100% at the discretion of the provider -Years, years to months, months to weeks Pain

Dyspnea

Reduced life expectancy -Weeks to days

More aggressive dosing and titration, doses should not be reduced for decreasing blood pressure, respiratory rate or consciousness as long as pain is being managed to the patient’s preference, avoid opioid dose reduction, reduce opioid dose by 25-50% every 24 hours if necessary, avoid opioid antagonists

Radiation and chemotherapy, removal of cardiac, pleural, or abdominal fluids, Longer life expectancy bronchoscopic therapies, continuous positive airway pressure (CPAP) or bi-level -Years, years to months, months to weeks positive airway pressure (BiPAP) therapy if condition is reversible, morphine in opioid naïve, benzodiazepine if anxiety-induced Reduced life expectancy -Weeks to days

Morphine in opioid naïve, benzodiazepine if anxiety-induced, scopolamine (subQ or transdermal), ophthalmic atropine (sublingual), glycopyrrolate (subQ or IV), time-limited mechanical ventilation as one of the last options

Presence of oral or pharyngeal candidiaOral or topical antifungal regimens sis infection Cachexia or Depression associated with cancer diagWeight Loss nosis/ prognosis or preexisting anorexia Mirtazapine diagnosis

Nausea or Vomiting

Constipation

Patients with decreased life expectancy

Megestrol acetate, olanzapine, dexamethasone, cannabinoids

Cancer as precipitating factor

Palliative radiation, dexamethasone, PPIs, metoclopramide, endoscopic stenting, G-tube

Persistent nausea and vomiting

Prochlorperazine, haloperidol, metoclopramide, olanzapine titrated to patient’s tolerability

Ineffective treatment of persistent nausea and vomiting

Addition of ondansetron, scopolamine, meclizine or cannabinoids

Refractory patients

Addition of dexamethasone or olanzapine unless already included in treatment

Psychological disorders contributing to nausea and vomiting

Addition of dopamine receptor antagonist, lorazepam or cannabinoid

First-line treatment

Sennosides and docusate titrated to maximum doses 2-3 times per day

Patient unable to produce bowel movement after initial treatment

Bisacodyl up to 3 times per day

Refractory patients

Bisacodyl suppositories, polyethylene glycol, lactulose, sorbitol or magnesiumbased solutions

Refractory patients if above therapies fail Tap water enemas, metoclopramide

Diarrhea

Fecal impaction

Glycerin suppository and/or mineral oil

Grade 1 diarrhea

Oral rehydration and electrolyte supplementation, loperamide, diphenoxylateatropine

Grade 2 diarrhea

Antidiarrheals continued, addition of hyoscyamine or atropine

Grade 2 diarrhea in patient unable to tolerate oral hydration

Initiation of IV fluids

Grade 2 diarrhea in patients receiving ipilimumab for metastatic melanoma

Consider infliximab or corticosteroids as alternative therapy

Grade 2-4 diarrhea

Addition of octreotide

Grade 2-4 diarrhea in patients near death

Home infusion for IV rehydration, around the clock opioids or dose increase, octreotide, or glycopyrrolate

Clostridium difficile due to chemotherapy Metronidazole (oral) if moderate, vancomycin (oral) x 10-14 days if severe or nosocomial acquisition Sleep apnea

CPAP/BiPAP therapy

Restless leg syndrome

Ropinirole, pramipexole with pregabalin, carbidopa-levodopa

Sleep Continued sleep disturbances after initial Trazodone, olanzapine, zolpidem, mirtazapine, chlorpromazine, quetiapine, loDisturbances therapy razepam

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Daytime fatigue

Caffeine, methylphenidate, dextroamphetamine, modafinil

End of life patient

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trazodone, olanzapine, zolpidem, mirtazapine, chlorpromazine, quetiapine or lorazepam. Daytime fatigue may be treated with caffeine, methylphenidate, dextroamphetamine and modafinil. Finally, in the dying patient, sedation level should be determined according to the patient’s wishes and the wishes of the family. If required, chlorpromazine can be initiated at bedtime for insomnia.

Nonpharmacologic Intervention Nonpharmacologic interventions are important to consider as treatment options or adjuncts to traditional pharmacologic treatments for cancer patients. Sometimes pharmacologic treatments may not be sufficient alone or patients may want more natural options. Thus, it is important that pharmacists understand the nonpharmacologic treatment options that are available to patients attempting to manage their chronic pain. There are a variety of interventions that are being studied or have yet to be studied in cancer patients who are thought to have at least some potential to decrease pain and improve quality of life.

Massage therapy is becoming more frequently used in cancer patients to help relieve symptoms.9 Massage involves the manipulation of soft tissue areas of the body and has traditionally been used in multiple clinical settings to help patients sleep more easily, relax and to help relieve aches and pains in the muscles. The NCCN recommends that massage therapy be included in the treatment guidelines for refractory cancer pain.2 Several studies have been conducted that suggest massage therapy can be used to reduce pain for cancer patients in a variety of stages.10 A large study conducted at Memorial Sloan-Kettering Cancer Center over a three-year period included 1,290 patients.9 The patients reported how severe their symptoms were premassage therapy and postmassage therapy using 0 to 10 rating scales for symptoms including pain, fatigue, stress/anxiety, nausea and depression. After therapy, symptom scores decreased by nearly 50 percent. Three types of massage therapy were available including the standard Swedish massage, light touch massage and foot massage in order to determine if a specific type of massage provided superior benefits. The therapy sessions were about 20 minutes for inpatients and 60 minutes for outpatients. Before and after the session, the patients were given a card with each symptom and were instructed to rate the symptom on a scale from 0 to 10, with 0 being not at all bothersome and 10 being extremely bothersome. Overall, out of 1,131 patients, the average combined overall symptom baseline score was 7.3 and posttreatment was 3.5 leading to a 52 percent improvement after massage therapy. The following are the results for each of the symptoms specifically after massage therapy: pain, n=625, baseline=6.1, posttreatment=3.3, improvement=47.8 percent; fatigue, n=819, baseline=6.6, posttreatment=3.8, improvement=42.9 percent; anxiety, n=786, baseline=6.7, posttreatment=2.7, improvement=59.9 percent; nausea, n=222, baseline=6, posttreatment=3, improvement=51.4 percent; depression, n=378, baseline=6.2, posttreatment=3.2, improvement=48.9 percent. Table 2 provides a summary of

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the results for each of the symptoms after massage therapy.

Differences in effect from baseline to posttreatment by type of massage therapy were also analyzed: Swedish massage, improvement=57 percent; light touch=62 percent; foot=50 percent. No significant difference was found when comparing the Swedish and light touch massage (95 percent confidence interval (CI) −0.11, 0.13; p=0.12). Overall, the data is promising regarding improvement in the symptoms of cancer patients receiving massage therapy. If a pharmacist chooses to recommend massage therapy to a patient, then it is best to recommend that the patient visit a massage therapist who has been trained to work with cancer patients. There are various training and certification programs available for massage therapists seeking to offer specialized care to cancer patients.10 Table 2. Improvements in Symptom Scores after Massage Therapy.9 Symptom

Improvement

Overall

52.0%

Pain

47.8%

Fatigue

42.9%

Anxiety

59.9%

Nausea

51.4%

Depression

48.9%

Other

48.3%

A systematic review of massage for symptom relief in cancer patients based on 10 trials came to the conclusion that the results from the wide variety of studies included in the review on massage therapy were inconclusive as a whole.10 There were improvements in nausea and pain after massage therapy. However, the improvements in psychological symptoms had mixed results with most of the trials concluding that anxiety was improved but without a firm conclusion regarding other psychological benefits of massage therapy.

Overall, the trials completed on massage therapy have methodological limitations. Larger sample sizes, better randomization and longer follow-up times in order to determine long-term effects of massage are needed in the future for stronger results.

Mindfulness-based stress reduction (MBSR) is another nonpharmacologic treatment that has shown an association with improving symptom presentation in cancer patients.11 Psychological and self-management skills for coping are important components for cancer survivors. Mindfulness specifically involves being aware of and attentive to one’s surroundings. These skills can be taught through an eightweek program during which patients learn to cope with stress by being more aware of the present moment through meditation and relaxation. A randomized, controlled trial of

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MBSR was carried out in 229 women with stage 0 to stage III breast cancer by Hoffman et al. The investigators found that intervention with MBSR was associated with decreases in fear of recurrence, depression, anxiety and pain. Symptoms were measured at baseline (T1; weeks -2 to 0), weeks 8 to 12 (T2), and weeks 12 to 14 (T3). The average age of participants in the study was 49 years, and 214 women completed the trial. The primary outcome measured was mood, assessed using the Profile of Mood State (POMS). An improvement in mood is represented by lower scores. The mean score from the POMS at T3 for total mood disturbance was 29.83 for the experimental group versus the mean score of 45.47 for the control group. The mean adjusted differences at T1 and 95 percent CI at T2 and T3 showed that the mood state scores in the experimental group were significantly lower. Thus, this study concluded that MBSR could be included in supportive care for breast cancer patients to help alleviate symptoms related to mood.

A study by Rahmani et al. also showed that MBSR can lead to reduction in fatigue severity in cancer patients.12 The Fatigue Severity Scale was used to assess the fatigue severity of chronic diseases including various forms of cancer. The patients in the study ranged in age from 30 to 55 years. In the control group, the fatigue score was 76.85±5.721 pretest and 71.29±12.938 posttest with a higher score indicating a higher level of fatigue. The score significantly improved for those with an MBSR intervention from 77.77±4.737 pretest to 37.96±8.810 posttest. Based on these results, MBSR shows potential as a useful method to decrease fatigue severity in cancer patients. A pharmacist can recommend a patient to enroll in an MBSR program which typically lasts for eight weeks and is taught by psychologists or other instructors who have been specially trained in MBSR through professional coursework. In a typical MBSR program, skills for managing stress and how to become aware of the present time are taught through various methods including meditation, relaxation and yoga. Specifically, these exercises help cancer patients learn to pay attention to and accept what is happening to them in the present time without judgment.

There are a variety of other nonpharmacologic options currently being studied that may prove to be beneficial for cancer patients.13 Options that involve mental components are behavioral interventions such as MBSR, hypnosis and music therapy. The goal of hypnosis is achieving an extremely focused state of mind that can be then used to modify how a patient perceives sensations. Music therapy and engaging in prayer have shown to be useful in calming patients with pain and in training them to better manage their pain. Educational interventions through videos and specially trained chronic pain coaches who teach patients about their pain may also prove beneficial in aiding patients to better understand their pain. More research on use of these methods in cancer patients has yet to be completed.

Some aspects of Traditional Chinese Medicine (TCM) have also seen a resurgence of use in cancer patients.13 While not all TCM is nonpharmacologic, this text focuses on the non-

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pharmacologic components. It is thought that good health is achieved through a balance between an individual and their environment. Illness is thought to occur when the flow of qi, which is an energy force, is inappropriate or blocked. The balance must be restored with regard to all of the flow patterns. Acupuncture is one form of TCM that is being studied in cancer patients. There is the belief that imbalances of qi have physical manifestations, such as joint pain, and that imbalance can be corrected by inserting small-gauge needles to help release pressure and restore proper flow. There is some limited evidence thus far for the use of acupuncture in cancer patients with postprocedural pain. Additionally, acupuncture is currently being studied to treat patients who have xerostomia caused by radiation and in patients with edema in the lower extremities following lymph node dissection. Qigong is another form of TCM and involves altering energy through slow movements, breathing techniques and meditation. Similar to acupuncture, the goal is to restore the flow of qi. The use of Qigong is rare in studies with cancer patients, but it is thought that it could reduce pain and relieve anxiety.

A review was completed on the current evidence provided by 2,385 randomized, controlled trials and 579 nonrandomized, controlled studies for TCM in cancer care with 72 percent of the studies using TCM along with standard cancer treatment (chemotherapy, Western medicine, surgery and radiotherapy).14 The types of TCM used in the studies included acupuncture, music therapy and Qigong. Also, it is worth noting that herbal products, which fall under complementary and alternative medicine rather than nonpharmacologic treatment, were also included in many of the studies analyzed. Once again, the results were inconclusive on whether TCM is beneficial. The sample sizes of many of the studies available were inadequate, and several of the studies did not provide adequate reporting of criteria for cancer diagnosis and patient selection. More standardization is necessary in future trials as well as a longer follow-up period to assess long-term benefits. Common benefits such as improved pain management and decreased depression symptoms were reported across the majority of the studies. This suggests that TCM does have the potential to be used as nonpharmacologic treatment, but, as stated previously, more research is necessary. The review suggests that future studies need to include data on survival times, extent of relapse and metastasis, and details on effects related to quality of life.

Nonpharmacologic care also includes options that are more physically oriented.13 Rehabilitative treatments have the potential to improve strength, pain and neuromuscular control in cancer patients. Transcutaneous electrical stimulation (TENS) provides low electrical shocks or signals to painful areas on the body. Studies on nonmalignant pain have shown that rehabilitative treatment and TENS may show beneficial results after one to three months. However, studies specifically with cancer patients must be done before pharmacists can provide appropriate recommendations. Table 3 shows a comprehensive list of the nonpharmacologic interventions mentioned in this article.

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Table 3. Summary of Nonpharmacologic Interventions.9-14 Procedure

Massage Therapy

Manipulation of soft tissue areas of the body

Benefit More effective in managing anxiety, fatigue and well-being ~40% decrease in pain and anxiety Decreases in fear of recurrence, depression, anxiety, physical functioning, energy and pain

Quality of Evidence NCCN recommends inclusion of massage therapy in treatment guidelines for refractory cancer pain

Mindfulness-Based Stress Reduction (MBSR)

Eight-week long program taught by psychologists or other trained instructors during which patients learn to cope with stress via meditation and relaxation

Hypnosis

Behavioral intervention aimed at achieving an extremely focused state of mind

Modifies how patients react to pain

Further studies needed

Music Therapy

Behavioral intervention

Calming effect by training patients to improve management of pain

Further studies needed

Prayer

Behavioral intervention

Calming effect by training patients to improve management of pain

Further studies needed

Pain Education

Educational intervention through use of videos and trained chronic pain coaches

Help patients better understand their pain

Further studies needed

Traditional Chinese Medicine (TCM) -Acupuncture

Insertion of small-gauge needles to help release pressure and restore qi (life energy force)

Increased analgesia after 3 weekly acupuncture appointments in ~50% of patients

Limited evidence available

Traditional Chinese Medicine (TCM) -Qigong

Altering energy through slow movements, breathing techniques and meditation to restore qi (life energy force)

May reduce pain and relieve anxiety

Limited evidence available

Physically oriented treatment aimed at improving strength, pain and neuromuscular control

May have beneficial results after 1-3 months of use

Further studies needed

Low electrical shocks or signals applied to painful body areas

May have beneficial results after 1-3 months of use

Further studies needed

Rehabilitative Treatment

Transcutaneous Electrical Stimulation (TENS)

Reduction in fatigue severity

Associated with improved symptom presentation and exhibits great potential for use in supportive care

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Role of the Pharmacist Pharmacists play an integral role in the management of palliative care. The distinguishing factor of palliative care is the pharmacist’s focus on symptomatic relief, whether it is relief from nausea, pain, fatigue, vomiting, constipation, insomnia or dyspnea.15,16 In addition to pharmacologic monitoring, pharmacists have a role in recommending and implementing various nonpharmacologic options. The current health care culture offers patients and providers multiple options for providing palliative care in cancer and cancer therapy. There is also an increasing number of validated nonpharmacologic options. Thus, health care providers have a responsibility to remain up-to-date on the established guidelines for palliative care, but should not ignore other modes of care patients may use. While communicating with patients regarding possible options it is important to assess patient willingness and compliance with recommended nonpharmacologic options as there are options available that are less conventional. 17 Treatment regimens vary from patient to patient; however, optimal treatment involves concurrent pharmacologic and nonpharmacologic treatments. The most efficient strategy to ensure the best health outcomes in cancer patients, is the utilization of a multidisciplinary team. Pharmacists are accountable not only for providing needed knowledge and skills regarding medication use but also can be helpful in ensuring collaboration with certified professionals trained specifically for the symptomatic treatment of cancer patients.

The list of responsibilities is not exhaustive as pharmacists are evolving into more of a provider role across multiple practice settings. Provider status would allow pharmacists to directly monitor and adjust drug therapy based on lab tests ordered by the pharmacist and be reimbursed for such services. A need exists to expand the accessibility of palliative care to community settings in order to better control symptomatic care. The community setting requires enhanced communication between community pharmacists and palliative care pharmacists in order to provide optimal collaborative care for the patient. Pharmacists in the community can help educate patients on options available to them and where to go to receive appropriate, safe and effective care. As easily accessible and highly trusted health care professionals, pharmacists have a duty to know about both appropriate pharmacologic palliative care and nonpharmacologic alternatives to recommend to patients and providers .

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

based recommendations for cancer fatigue, anorexia, depression, and dyspnea. J Clin Oncol. 2008 Aug 10;26(23):3886–95.

Simon ST, Higginson IJ, Booth S, Harding R, Bausewein C. Benzodiazepines for the relief of breathlessness in advanced malignant and nonmalignant diseases in adults. Cochrane Database Syst Rev. 2010 Jan 20; (1):CD007354.

Navari RM, Brenner MC. Treatment of cancer-related anorexia with olanzapine and megestrol acetate: a randomized trial. Support Care Cancer. 2010 Aug;18(8):951-6.

Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer: a meta-analysis of randomized controlled clinical trials. Ann Surg. 1999 Apr;229(4):467-77.

Cassileth BR, Vickers AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage. 2004 Sep;28(3):244-9.

Wilkinson S, Barnes K, Storey L. Massage for symptom relief in patients with cancer: systematic review. J Adv Nurs. 2008 Aug 11;63(5):430-9.

Hoffman CJ, Ersser SJ, Hopkinson JB, Nicholls PG, Harrington JE, Thomas PW. Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well-being in stage 0 to III breast cancer: a randomized, controlled trial. J Clin Oncol. 2012 Apr 20;30(12):1335-42.

Rahmani S and Talepasand S. The effect of group mindfulness-based stress reduction program and conscious yoga on the fatigue severity and global and specific life quality in women with breast cancer. Med J Islam Repub Iran. 2015 Feb 8;29:175.

Menefee LA, Monti DA. Nonpharmacologic and complementary approaches to cancer pain management. J Am Osteopath Assoc. 2005 Nov;105(11 Suppl 5):S15-S20.

Li X, Yang G, Li X, Zhang Y, Yang J, Bensoussan A, et al. Traditional Chinese medicine in cancer care: a review of controlled clinical studies published in Chinese. PLoS One. 2013 April;8(4):e60338.

ASHP statement on the pharmacist’s role in hospice and palliative care.

Am J Health-Syst Pharm. 2002;59:1770-3.

Walker KA, Scarpaci L, McPherson ML. Fifty reasons to love your palliative care pharmacist. Am J Hosp Palliat Care. 2010 Dec;27(8):511-3.

17. Cortis LJ, McKinnon RA, Anderson C. Palliative care is everyone’s business, including the pharmacist. Am J Pharm Educ. 2013;77(2):1-2.

The authors have no conflict of interest or funding support to disclose.

References 1. Levy M, Smith T, Alvarez-Perez A, Back A, Baker JN, Beck AC, et al. Palliative care. J Natl Compr Canc Netw. 2016;14:82-113.

2. Swarm RA, Anghelescu DL, Benedetti C, Buga S, Chwistek M, Cleeland C, et al. NCCN clinical practice guidelines in oncology: adult cancer pain. J Natl Compr Canc Netw [Internet]. 2016 [updated 2016 Mar 17; cited 2016 Apr 22]. Available from:www.nccn.org/professionals/physician_ gls/pdf/pain.pdf.

3. Ferrell B, Levy MH, Paice J. Managing pain from advanced cancer in the palliative care setting. Clin J Oncol Nurs. 2008 Aug;12(4):575-81.

4. McNicol E, Horowicz-Mehler N, Fisk R, Bennett K, Gialeli-Goudas M, Chew PW, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003 Jun;4 (5):231-56.

5. Dy SM, Lorenz KA, Naeim A, Sanati H, Walling A, Asch SM. Evidence-

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Pharmacologic and Nonpharmacologic Approaches to Palliative Care in Oncology

Drug Abuse Oncology

Assessment Questions 1.

The National Comprehensive Cancer Network (NCCN) goals for palliative care aim to “_____, _____ and _____ suffering.�

A. detect, prevent and reduce B. anticipate, eliminate and reduce C. anticipate, prevent and modify D. anticipate, prevent and reduce

7.

Inclusion of which type of nonpharmacologic intervention does the NCCN recommend for refractory cancer pain?

A. Transcutaneous Electrical Stimulation (TENS) B. Massage therapy C. Pain education D. Traditional Chinese Medicine (TCM)

2.

What patient characteristic should be determined in order to provide the best overall approach for management of palliative care in anticancer therapy?

A. Stage of cancer progression B. Estimated life expectancy C. Level of pain experienced by the patient D. Number of medications the patient is taking

8.

Mindfulness-based stress reduction involves enrolling the patient in a program taught by a _________ that lasts ______.

A. psychologist, 4 weeks B. pharmacist, 8 weeks C. pharmacist, 4 weeks D. psychologist, 8 weeks

3.

What is the primary difference in pain management for patients with shorter life expectancies?

A. Patients with shorter life expectancies require a more aggressive approach in titrating medications.

B. Decreasing doses for management of blood pressure, respiratory rate or consciousness is necessary for patients with a shorter life expectancy.

C. Dose reduction of opioid medication should occur in patients with a shorter life expectancy.

D. Patients with a shorter life expectancy require rehydration therapy.

9.

Studies on nonmalignant pain have shown that rehabilitative treatment and transcutaneous electrical stimulation (TENS) may have beneficial results after _____.

A. 8 weeks B. 6 months C. 1-3 months D. 6-8 weeks

4.

What is a unique aspect to palliative care providers?

A. Helping the patient find an appropriate treatment regimen that is cost-effective.

B. Compounding specialty medications for patients experiencing severe symptoms.

C. Reassuring the patient that following recommendations will halt disease progression.

D. Preparing the patient psychologically for disease progression and treatment.

5.

Which of the following should be recommended if firstline treatment for constipation fails?

A. Sennosides B. Polyethylene glycol C. Bisacodyl D. Docusate

6.

Recognizing which of the following inducible factors is imperative to improving patient outcomes related to cachexia?

A. Dysgeusia B. Hypogonadism C. Thyroid dysfunction D. Oral or pharyngeal candidiasis infection

10. What is the main focus of the role of pharmacists in palliative care?

A. Symptom relief B. Compounding nonstandard dosage forms C. Ensuring adherence to legal regulations related to drug containment and disposal D. Monitoring therapy and adjusting doses based on renal and hepatic status

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 1/2/2020.

To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/ to enter the required information. Please allow two to three weeks for electronic distribution of your continuing education certificate, which will be sent to your valid email address in PDF format.

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Hormonal Therapy and Preventive Care of Transgender Patients Angela Chu, Jana Randolph, Austin Hopkins, Victoria Cho, Sophocles Chrissobolis, Ph.D. Abstract Transgenderism occurs when an individual’s gender identity conflicts with the individual’s biological sex. A variety of methods may be used in order to reconcile this disparity in transgender individuals including psychological counseling, cross-sex hormone therapy and sex reassignment surgery.

The most important role for pharmacists in the treatment of transgender patients is in dispensing hormonal medications for cross-sex treatment. Hormone therapy may be used to suppress characteristics of the patient’s biological sex as well as to induce development of characteristics that correlate with the patient’s gender identity. In male-to-female (MtF) transgender patients, the most commonly used medications include agents which suppress testosterone such as mineralocorticoid receptor antagonists and gonadotropin-releasing hormone (GnRH) agonists. This is in addition to estrogen therapy, which causes feminization. By far the most commonly used medication for female-to-male (FtM) transgender patients is testosterone to induce masculinization.

Medroxyprogesterone or GnRH agonists may also be used in FtM patients to suppress female characteristics. Pharmacists should be aware of the risks associated with cross-sex hormone therapy in transgender patients as well as the side effects and monitoring required for these therapies. Pharmacists may also play a role in being able to recognize signs of appropriate feminization or masculinization in MtF and FtM patients.

Key Terms Transgender Persons, Transsexualism, Testosterone, Estrogens, Gonadotropin-releasing Hormone, Pharmacists Introduction In today’s changing world, the patient population continues to increase in its diversity. A recently emerging population is the transgender population. A transgender individual can be defined as a person whose gender identity and birth sex are in conflict with one another. This means a biological female identifies one’s gender as being male, or a biological male identifies one’s gender as being female. When it comes to transgendered individuals, a majority may experience gender dysphoria, defined as discomfort or distress caused by a discrepancy between the individual’s sex and perceived gender role.1 This differs from gender nonconformity in which the individual expresses one’s gender that differs from the culture and social norm.

Gender dysphoria can be associated with transgender individuals. A set Diagnostic and Statistical Manual of Mental Disorder (DSM) criteria does exist for gender dysphoria. It should be noted that there is controversy with the DSM-5

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criteria for gender dysphoria. Health care providers should use the criteria to identify if an individual who claims to be transgender meets the criteria of gender dysphoria, not necessarily transgenderism itself. If the individual meets the DSM-5 criteria, only then should therapy be initiated. Currently, the DSM-4 and V should not be considered mutually exclusive. The two criteria build on one another, providing a better case for an individual who identifies as transgender.

The DSM-4 criteria are established on diagnosing gender dysphoria rather than transgenderism. The DSM-5 criteria are an established set of behaviors observed in individuals with gender dysphoria in which the more criteria that are met, the stronger the indication for gender dysphoria.2 The DSM-4 criteria for gender dysphoria in adolescents and adults follows (adapted from Belluardo-Crosby and Lillis2):  A resilient and adamant identification with the opposite gender (not merely a desire for any perceived cultural advantages of being the other sex). In children, the disturbance is manifested by four (or more) of the following:  Repeatedly stated to be, or insistence that he or she be addressed as the other gender (pronouns of the other gender);  In boys, preference for cross-dressing or appearing in female attire; in girls, insistence on wearing only stereotypical masculine clothing (presentation of the other gender);  Strong and persistent preferences for roles in make-believe play or persistent fantasies of being the other sex (assuming the role of the other gender);  Intense desire to participate in the stereotypical games and pastimes of the other sex (further assumption of the role of the other gender);  Strong preference for playmates of the other sex (experiencing interaction with the other gender).  Persistent discomfort with his or her sex or sense of inappropriateness in the gender role of that sex.  The disturbance is not concurrent with a physical intersex condition (not a biological issue).  The disturbance causes clinically significant distress or impairment in social, occupational or other important areas of functioning.

What DSM-5 aimed to accomplish compared to DSM-4 included the use of “incongruence” in place of “disorder” and other patient-friendly language to diminish the stigma that is often associated with transgenderism and gender dysphoria being considered mental illness that should be remedied.

Likewise, it humanizes the patients being subjected to the criteria. Lastly, the language is shifted to note the incongru-

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ence between biology and identity. This allows the focus to be on matching gender identity to gender presentation.2 The DSM-5 criteria for gender dysphoria in adolescents and adults follows (adapted from Belluardo-Crosby and Lillis2):  A separation between one’s expressed gender and assigned sex of at least six months’ duration, as marked by at least two of the following:  Incongruence between one’s experienced/ expressed gender and primary/secondary sex characteristics (or, in prepubescent adolescents, the foreseen secondary sex characteristics);  Strong desire to be rid of one’s current sex characteristics because of a marked dissociation with one’s expressed gender (or, in prepubescent adolescents, a desire to prevent the development of the expected secondary sex characteristics following puberty);  Strong desire for the primary and/or secondary sex characteristics of the other biological sex;  Strong desire to be or present as the other gender (or some alternative gender different from one’s assigned gender);  Strong desire to adapt or change the other gender and its societal role (or some alternative gender different from one’s assigned gender);  Strong principle that one has the typical feelings and reactions of the other gender (or some alternative gender different from one’s assigned gender);  The condition is associated with clinically significant

Drug Abuse Endocrine

misery or dysfunction in activities of daily living or with a significantly increased risk of suffering such as distress or disability.

The following discusses treatment options, monitoring parameters and risk prevention strategies related to transitioning the patient between male-to-female (MtF) and female-tomale (FtM), and the role a pharmacist has in this transition.

Male-to-Female (MtF) Testosterone Suppression Male-to-female hormone therapy begins with an antiandrogen agent to reduce the amount of natural testosterone produced. This is achieved with spironolactone (oral, 100-200 mg/d), a mineralocorticoid receptor antagonist that produces decreased testosterone production.3 Spironolactone is contraindicated in patients with renal failure; therefore, monitoring for hypotension, hyponatremia, hyperkalemia and renal function should be done throughout the first week, every month for three months, and then every three months. 4 Gonadotropin-releasing hormone (GnRH) agonists can also be used to suppress testosterone production, in that they result in receptor down-regulation, ultimately resulting in reduced testosterone levels. These GnRH agonists also reduce testosterone levels through a complex negative feedback mechanism whereby excess testosterone production results in suppression of the hypothalamic-pituitary-gonadal axis, thus ultimately resulting in reduced testosterone levels (Figure 1).5 The only agent studied and reportedly displaying clinical efficacy is goserelin, given 3.6 mg subcutaneously every 28

Figure 1. Negative Feedback Mechanism with GnRH Stimulation.5

Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus to the anterior pituitary gland to stimulate the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Luteinizing hormone acts on Leydig cells in the testes to produce testosterone which contributes to spermatogenesis. Follicle stimulating hormone acts on Sertoli cells in the testes to contribute to spermatogenesis. Gonadotropin-releasing hormone agonists, such as goserelin, result in receptor down-regulation, ultimately resulting in reduced testosterone levels. Gonadotropin-releasing hormone agonists also lead to increased levels of FSH, LH and testosterone resulting in negative feedback to ultimately decrease endogenous GnRH, FSH and LH release and their downstream effects.

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Hormonal Therapy and Preventive Care of Transgender Patients

days.3 Adverse effects in men are minimal compared to women, but hypercalcemia and hyperglycemia should be monitored.6 In either therapy, testosterone levels should be assessed every three months until in the normal female range (15-70 ng/dL).7 Estrogen Estrogen therapy can be initiated simultaneously with testosterone suppression, but is most effective when ideal testosterone levels have been achieved.3 Estrogen forms vary but are equally effective and can be chosen based on patient preference. Common dosage forms and doses are as follows: oral estradiol (2-6 mg/d), transdermal estradiol (0.1-0.4 mg twice weekly), intramuscular estradiol valerate (5-20 mg every two weeks) or intramuscular estradiol cypionate (2-10 mg weekly). Estrogen levels should be monitored every three months with testosterone and kept within normal female range, ideally <200 pg/ml.8 Antiandrogen and estrogen therapies will have noticeable feminizing effects on patients within three to six months of initiation.9 These include a decrease in hair growth, libido, spermatogenesis, erection, testicle size and muscle mass, and an increase in breast growth, nipple size and fat distribution.

Clinical and Lab Monitoring Regular monitoring of serum electrolytes (specifically sodium, calcium and potassium), liver function, renal function, lipids, complete blood cell count, blood pressure, weight and a physical exam should occur pretherapy and every three months in the first year of therapy and then at least once annually.3 Surgical Options If the patient is considering sexual reassignment surgery, the patient should be adherent to hormone therapy for at least one year prior to surgery to ensure drug therapy adherence thereafter for life.3 The patient should also have a committed surgeon and physician who will prescribe and monitor established hormone therapy. Surgical options for MtF patients include breast augmentation, facial reconstruction, orchiectomy (removal of the testes) or penile disassembly (repositioning the skin, nerves and blood supply of the penis to form female parts) followed by vaginoplasty, clitoroplasty and urethral repositioning.10 Noninvasive interventions can be coupled with surgery to further feminize the MtF patient, including voice therapy to adjust voice pitch and laser hair removal.3 Following surgery, estrogen therapy needs to be continued.

Risks and Prevention In women, unopposed estrogen has been known to increase the risk of breast cancer, hypertension, cerebrovascular disease and cardiovascular disease, including cardiovascular events such as venous thromboembolism and myocardial infarction.11 In transgender patients, an increased risk of the same cardiovascular events has been documented in multiple studies due to estrogen therapy.12-15 Lifestyle factors such as smoking and sedentary lifestyle further exacerbate these risks.9 However, in patients also taking spironolactone for its

20

antiandrogen properties, hypertension may not be an issue because spironolactone is a mineralocorticoid receptor antagonist that results in increased sodium, chloride and water excretion and thus decreased blood pressure. Routine monitoring of vital signs (specifically blood pressure) and a physical assessment should be done at each office visit to reduce the risk of cardiovascular events.

No long-term study on transgender patients has been conducted to adequately describe if MtF patients are at an increased risk of breast cancer.3 The Endocrine Society guidelines recommend that all MtF patients still follow routine breast, prostate and colon cancer screenings to minimize their risk. An increase in prolactin levels has been documented with estrogen stimulating the pituitary gland to produce more lactotrophs (cells in the pituitary gland that secrete prolactin) leading to an enlarged gland. Excess prolactin levels have the additional effect of decreasing GnRH release to suppress testosterone production which is desired in these patients. Despite these desired effects, prolactin levels should still be monitored at baseline prior to estrogen therapy, in one year and biannually thereafter for development of prolactinoma. Transient liver enzyme elevations of three times the upper limit of normal and cholecystitis (inflammation of the gallbladder from bile buildup) can be increased; hence, liver function tests should be performed at least annually.

The MtF patients do not present an increased or decreased risk for hypercholesterolemia, diabetes, osteoporosis or other chronic disease states uncommon to their existing risk factors or sex.3 Therefore, health care professionals should monitor, treat and educate on these conditions based on the individual patientâ&#x20AC;&#x2122;s health profile following standard guidelines.

Female-to-Male (FtM) Testosterone The main cross-sex hormone therapy used for FtM transgender individuals is testosterone.3 Transdermal or parenteral dosage forms may be used, and the regimens follow the principles used to treat hypogonadism in men. Testosterone is an endogenous androgen which acts to promote growth of male sex organs and maintain secondary sex characteristics.16 Some effects of testosterone therapy in FtM transgender patients are the same as the effects that occur in hypogonadal men including increased muscle tissue, decreased fat tissue, increased body and facial hair, increased acne, male pattern baldness and increased libido.3 Effects of testosterone therapy that occur specifically in FtM patients include clitoromegaly, decreased fertility, deepening of voice, and cessation of menses. In the Endocrine Society guidelines, specific testosterone formulations listed include intramuscular testosterone enanthate and testosterone cypionate, transdermal testosterone 1 percent gel, and testosterone patch. In addition, although listed in the guidelines as unavailable in the United States, an intramuscular testosterone formulation of testosterone undecanoate (AveedÂŽ), was approved by the U.S. Food and Drug Administration (FDA) in March 2014.17

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This formulation is indicated to treat hypogonadism in males. Perhaps it may soon be used for the treatment of FtM transgender patients as well since testosterone treatment in FtM patients follows the guidelines used for male hypogonadism. Although new to the United States, testosterone undecanoate has been used safely for FtM treatment in Europe for several years.18-20 Suggested doses of different testosterone formulations for FtM transgender patients are listed in Table 1.21 Monitoring of Testosterone Therapy Maintaining testosterone levels within the normal male range (320-1000 ng/dL) is important as levels in the supraphysiological range increase the risk of serious adverse events which include erythrocytosis, excessive acne and fluctuation in mood. Rarely, coughing episodes may occur following intramuscular injection.21 The Endocrine Society suggests that physicians measure serum testosterone levels every two to three months until levels are within the normal male range.3 For testosterone enanthate and testosterone cypionate, injections levels should be measured midway between injections, and the dose should be adjusted accordingly if the serum testosterone level is more than 700 ng/dL or less than 300 ng/dL. For testosterone undecanoate injection, testosterone levels should be measured just before administration of the next injection. For transdermal testosterone preparations, testosterone levels may be measured any time after one week of therapy.

Other Drug Agents In cases in which testosterone therapy fails to cause cessation of menses, a progestin-like agent such as medroxyprogesterone acetate may be added to the patient’s therapy or endometrial ablation may be performed.3 Medroxyprogesterone induces amenorrhea by transforming a proliferative endometrium into a secretory endometrium.22 Additionally, depot medroxyprogesterone or GnRH agonists may be administered to FtM patients before beginning testosterone therapy to decrease the levels of estrogen to the level found

Drug Abuse Endocrine

in biological males.3 The Endocrine Society does not delineate dosing or monitoring parameters for medroxyprogesterone or GnRH therapy in FtM transgender patients.

Gonadotropin-releasing hormone agonists are generally used in adolescents to suppress development of unwanted sex characteristics.3 Drug therapy to suppress puberty may begin after the patient begins exhibiting the physical changes of puberty, which in girls is when breast development begins.

The GnRH agonists are advantageous for pubertal suppression because their effects are reversible with cessation of therapy. In girls, GnRH agonists will cause cessation of menses as well as atrophy of breasts. However, physical sex characteristics that are not completely reversible with GnRH agonists include large breasts as well as short stature.

Normal pubertal development resumes immediately upon termination of GnRH agonist therapy. Treatment with crosssex hormone therapy may be initiated at 16 years of age.

Surgical Options Sex reassignment surgery may be recommended for patients following at least one year of compliant cross-sex hormone therapy.3 Surgical sex reassignment options for FtM transgender patients include subcutaneous mastectomy, hysterectomy/salpingo-oophorectomy, reconstruction of the urethra which may be combined with phalloplasty, vaginectomy, scrotoplasty and implantation of erection and/or testicular prosthesis.1 Additional aesthetic procedures may also be performed such as liposuction, lipofilling, pectoral implants and voice surgery. Patients who undergo gonadectomy will need hormone replacement therapy in addition to postsurgery monitoring in order to prevent adverse events due to chronic hormone deficiency. Patients who do not continue hormone therapy after gonadectomy will be at an increased risk for bone loss due to a decline in estrogen and testosterone levels.

Preventive Care-Disease Risk Factors The use of cross-sex hormone therapy has raised concerns

Table 1. Testosterone Doses in Female-to-Male Transgender Patients.21

Formulation

Dosage

Testosterone enanthate (generic only) or testosterone cypionate (Depo®-Testosterone) IM (intramuscular) injection

150-200 mg IM every 2 weeks or 75-100 mg/week

Testosterone undecanoate IM injection (Aveed®)

750 mg (3 mL) IM initially, 750 mg IM after 4 weeks, then 750 mg IM every 10 weeks thereafter

Testosterone 1% gel (AndroGel®, Testim®, Vogelxo™)

5-10 g/day

Testosterone patch (Androderm®)

Apply 1 or 2 patches daily to deliver 5-10 mg over 24 hours

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about whether administration of hormonal agents may alter an individual’s risk factors for certain diseases. Conditions of particular concern in FtM patients include cardiovascular health, bone density and cancer risk.

Cardiovascular Health: Testosterone therapy in FtM transgender patients has been found to cause a decrease in high-density lipoprotein levels and an increase in triglyceride levels resulting in a lipid profile that is more atherogenic, but data is conflicting regarding whether the change in lipid profile has a negative influence on cardiovascular health. 23 For example, Van Kesteren et al. found no difference in cardiovascular outcomes in FtM patients compared to the general population,24 whereas a systematic review and meta-analysis of 10 studies that included FtM groups found that data were insufficient to evaluate cardiovascular outcomes.23 More research is needed to evaluate the effect that cross-sex hormone treatment has on cardiovascular disease risk.3 Therefore, since optimum management of cardiovascular risk factors in FtM transgender patients is currently unknown, clinicians should follow currently established guidelines for cardiovascular management, such as the National Cholesterol Education Program’s Adult Treatment Panel III or the practice guidelines from the American College of Cardiology/American Heart Association. 3,25-26 These publications offer guidance on how to assess an individual’s risk of atherosclerotic cardiovascular disease and how to treat dyslipidemias. However, the clinical guidelines for transgender treatment do not suggest whether physicians should use the patient’s biological sex or gender identity when assessing cardiovascular risk.

Bone Density: Bone mineral density (BMD) should be measured at baseline before cross-sex hormone administration for FtM transgender patients who also have risk factors for fractures due to osteoporosis.3 Risk factors include previous fracture, family history of osteoporosis, use of glucocorticoids and prolonged hypogonadism. Appropriate dosing of testosterone is important for maintaining BMD in FtM patients.27 In a study examining BMD and bone metabolism in transgender patients, BMD measurements were reportedly the same after one year of testosterone administration compared to baseline, but BMD declined after long-term examination at 28 to 63 months. Due to the decline in estrogen levels, FtM transgender patients may experience decreased BMD over time, so testosterone dosing needs to be sufficient to maintain bone mass. Serum luteinizing hormone (LH) levels may be a useful biological marker for assessing whether testosterone dose is adequate to maintain BMD, as LH levels were found to be inversely related to BMD. Cancer Risk: Cross-sex testosterone therapy may increase the risk of endometrial and ovarian cancer. A proposed mechanism for the elevation of endometrial cancer risk is the conversion of testosterone to estrogen which in turn causes endometrial hyperplasia and may progress to endometrial carcinoma.3,28 However, no cases of endometrial cancer have been reported in FtM patients.3 The increased risk of ovarian cancer may be due to the increased expression of androgen

22

receptors in the ovaries after long-term testosterone administration, but this cause and effect relationship is not yet fully established.29 Estrogen receptors may also play a role in increasing ovarian cancer risk because of the excess estrogen that exists after the conversion of testosterone to estrogen.

Three cases of ovarian cancer development in FtM transgender patients have been reported: two cases occurred in the Netherlands and the third occurred in Rhode Island, USA.30-31 In all three cases, the medical practitioners were unable to determine whether the ovarian cancer was caused by testosterone therapy. These risks of endometrial and ovarian cancer may be eliminated if the patient chooses to undergo total hysterectomy and oophorectomy.3 Clinical and Laboratory Monitoring The Endocrine Society’s clinical practice guidelines recommend that FtM transgender patients on cross-sex hormone therapy should be monitored by a physician every two to three months for the first year of therapy and then once or twice per year during subsequent years.3 Physical exams during these visits should include measurement of weight, blood pressure and complete blood count as well as monitoring of renal function, hepatic function, lipid levels and glucose levels. In addition, FtM transgender patients should be monitored for signs of appropriate virilization as well as adverse reactions from testosterone therapy. Estradiol levels should be measured until there has been no menstruation for six months. For FtM patients, estradiol levels should be below 50 pg/mL. Bone mineral density should be measured starting at 60 years of age as well as in patients who are not adherent to hormone therapy. Additionally, patients should receive an annual pap smear if cervical tissue is still present.

Guidelines also recommend that if a FtM patient has not had a mastectomy, the patient should receive mammograms according to the current recommendations from the American Cancer Society. It is important to realize that these screenings may be emotionally as well as physically painful to FtM patients since they directly conflict with the patient’s gender identity.1 Health care providers should be aware of the distress FtM transgender patients may feel about receiving a pap smear or mammogram, but providers still need to reaffirm the necessity of such screenings for protecting the patient’s health.

Role of the Pharmacist With the expanding role of the pharmacist, pharmacists may have the opportunity to assist with transition of their transgender patients. Transition can be defined in two ways: first, it can refer to the time period during which the individual undergoes change in his or her physical, legal and social characteristics of the gender opposite to one’s biological sex in order to align with one’s gender identity; and second, it can refer to the consistent process of physical and psychological adaptation.3 Pharmacists who are involved should know a general timeline of characteristics that may manifest themselves in transgender individuals transitioning from MtF or FtM. Figure 2 contains estimates for when certain feminizing (Figure 2A) or masculinizing (Figure 2B) effects appear in transgender individuals.24,32-33

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Figure 2. Timeline of Feminizing Effects Observed in MtF Patients on Hormonal Therapy (2A) and Timeline of Masculinizing Effects Observed in FtM Patients on Hormonal Therapy (2B). 24, 32-33

Figure 2A.

Figure 2B.

Please note: These timelines are only a reference, and individuals undergoing transitional therapy may experience these characteristics earlier or later than what has been described. Individuals should consult their prescriber if they believe their therapy is ineffective.

*Further actions such as laser treatment may be needed to remove all male sexual hair.

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Hormonal Therapy and Preventive Care of Transgender Patients

Being able to recognize these characteristics is important as they give pharmacists and clinicians markers in the timeline of a patient’s transition. Additionally, lab values including hormone levels pertaining to cross-hormonal therapy or transitional therapy also play an important role in a patient's transition especially in the first year.3 All MtF patients should be evaluated in general every two to three months within the first year to ensure a stable and safe transition.34 Similarly, FtM patients should be evaluated along the same general timeline as MtF patients with one every two to three months for the first year and annual or biannual follow ups after the first year. As with MtF patients, serum testosterone should be measured about every two to three months until at a normal physiological range equal to a biological male.35 The transgender population remains an underserved population in the medical field. By educating health care professionals on the therapies and issues surrounding an individual undergoing transition, the stigma surrounding transgender individuals can be eliminated. 36 Questions should be asked in regard to issues surrounding transgenderism but to a point that they are addressed in a sensitive and professional manner. Keep in mind, not all individuals who are transgender struggle with issues pertaining to gender.37 Pharmacists are usually the first health care professional an individual may approach for help, thus being able to triage a situation with a transgender patient may be very important for that individual. In cases where pharmacists are beyond their resources to help a transgender patient, the patient should be referred to their physician or a mental health professional experienced in gender identity issues.

References 1. Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G, Feldman J, et al. Standards of care for the health of transsexual, transgender, and gender nonconforming people. 7th ed. Inter J Transgend. 2012;13(4):165–232.

2. Belluardo-Crosby M and Lillis PJ. Issues of diagnosis and care for the transgender patient: is the DSM-5 on point? Issues in Mental Health Nursing. 2012;33:583–90.

3. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, Spack NP, et al. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

4. Lexicomp [Internet]. Hudson (OH): Lexicomp Inc. c.1978-2016. Spironolactone, Warnings and precautions, Monitoring parameters; [Updated 2016 Feb 26; cited 2016 Feb 26]; [2 screens]. Available from: online.lexi.com/.

5. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s Review of Medical Physiology, 25 ed. New York, NY: McGraw-Hill; 2016. Chapter 23, Function of the male reproductive system; p. 417-428.

6. Lexicomp [Internet]. Hudson (OH): Lexicomp Inc. c.1978-2016.

Goserelin, Warnings and precautions, Monitoring parameters; [Updated 2016 Feb 15; cited 2016 Feb 26]; [3 screens]. Available from: online.lexi.com/.

7. University of Rochester Medical Center [Internet]. Rochester (NY): University of Rochester Medical Center; 2016. Total testosterone [Updated 2016 Feb 26; Cited 2016 Feb 26]; [4 screens]. Available from: www.urmc.rochester.edu/encyclopedia/.

8. University of Rochester Medical Center [Internet]. Rochester (NY): University of Rochester Medical Center; 2016. Estradiol (blood)

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[Updated 2016 Feb 26; Cited 2016 Feb 26]; [2 screens]. Available from: www.urmc.rochester.edu/encyclopedia/.

Feldman JL and Safer J. Hormone therapy in adults: suggested revisions to the sixth version of the standards of care. Inter J Transgend.

2009;11: 146-82.

Raigosa M, Avvedimento S, Yoon TS, Cruz-Gimeno J, Rodriguez G, Fontdevila J. Male-to-female genital reassignment surgery: a retrospective review of surgical technique and complications in 60 patients. J Sex Med [Internet]. 2015 Aug [Cited 2016 Mar 27]; 12(8): 1837-45. Available from:www.jsm.jsexmed.org.

American College of Obstetricians and Gynecologists (ACOG). Management of menopausal symptoms. ACOG Practice Bulletin [Internet].

2014 Jan 15 [Cited 2016 Feb 26];141 [about 15 pages]. Available from: www.guideline.gov.

Basson R and Pryor J. Towards optimal hormonal treatment of male to female gender identity disorder. Journal of Sexual and Reproductive Medicine. 2001;1(1):45-51.

Asscheman H and Gooren LJ. Hormone treatment in transsexuals. Journal of Psychology & Human Sexuality. 1992;5(4):39-54.

Tangpricha V, Ducharme SH, Barber TW and Chipkin SR. Endocrinologic treatment of gender identity disorders. Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2003;9: 12-21.

Toorians AW, Gooren LJ and Asscheman H. Venous thromboembolism and (oral) estrogen use [Abstract]. International Journal of Transgenderism [Internet]. 2003 [cited 2016 Apr 22];5(4). Available from:www. symposion.com/ijt/hbigda/2001/43toorians.htm.

Micromedex [Internet]. Truven Health Analytics. Testosterone; [updated 2016 Mar 22; cited 2016 Apr 1]; [about 1 screen]. Available from:www.micromedexsolutions.com/home/dispatch.

Aveed® (testosterone undecanoate) injection for intramuscular use [package insert on the Internet]. Malvern (PA): Endo Pharmaceuticals Inc; [updated 2015 May; cited 2016 Feb 23]. Available from:www.endo. com/File%20Library/Products/Prescribing%20Information/AVEED _prescribing_information.html#section-1.

Jacobeit JW, Gooren LJ, Schulte HM. Long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals. J Sex Med. 2007;4:1479-84.

Meriggiola MC, Armillotta F, Costantino A, Altieri P, Saad F, Kalhorn T, et al. Effects of testosterone undecanoate administered alone or in combination with letrazole or dutasteride in female to male transsexuals. J Sex Med. 2008;5:2442-53.

Wierkcx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher A, Toye K, et al. Cross-sex hormone therapy is safe and effective at short-term follow-up: results from the European Network for the Investigation of Gender Incongruence. J Sex Med. 2014;11:1999-2011.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.

J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59.

Micromedex [Internet]. Truven Health Analytics. Medroxyprogesterone acetate; [updated 2016 Mar 22; cited 2016 Apr 1]; [about 1 screen].

Available from:www.micromedexsolutions.com/home/dispatch.

Elamin MB, Garcia MZ, Murad MH, Erwin PJ, Montori VM. Effect of sex steroid use on cardiovascular risk in transsexual individuals: a systematic review and meta-analysis. Clin Endocrinol. 2010;72:1-10.

Van Kesteren PJM, Asscheman H, Megens JAJ, and Gooren LJG. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol. 1997;47:337-42.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-97.

Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel

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27.

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RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-S45.

Van Kesteren P, Llps P, Gooren LJG, Asscheman H, Megens J. Long-term follow up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones. Clin Endocrinol. 1998;48:347-54.

Futterweit W. Endocrine therapy of transsexualism and potential complications of long-term treatment. Arch Sex Behav. 1998;27(2):209-26.

Chadha S, Pache TD, Huikeshoven FJM, Brinkmann AO, Vad der Kwast TH. Androgen receptor expression in human ovarian and uterine tissue of long-term androgen-treated transsexual women. Hum Pathol. 1994 Nov;25(11):1198-204.

Dizon DS, Tejada-Berges T, Koelliker S, Steinhoff M, Granai CO. Ovarian cancer associated with testosterone supplementation in a female-tomale transsexual patient. Gynecol Obstet Invest. 2006;62:226-8.

Hage JJ, Dekker JJML, Karim RB, Verheijhen HM, Bloemena E. Ovarian cancer in female-to-male transsexuals: report of two cases. Gynecol Oncol. 2000;76:413-5.

Gooren LJ and Giltay EJ. 2008 Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females. J Sex Med. 2008. 5:765–76.

Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J. 2003. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab. 2003;88:5723–9.

Moore E, Wisniewski A, Dobs A. 2003 Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects. J Clin Endocrinol Metab. 2003;88:3467–73.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. 2006 Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006;91:1995– 2010.

Feldman JL, Goldberg JM. Transgender Primary Medical Care. International Journal of Transgenderism. 2006;9(3/4):3-34.

Bockting WO, Knudson G, Goldberg JM. Counseling and mental health care for transgender adults and loved ones. International Journal of Transgenderism. 2006;9(3/4): 35-82.

The authors have no conflict of interest or funding support to disclose.

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Use of Botulinum Toxin in Central Nervous System Disorders Julie Puvogel, Paige Torbet, Jourdan Ujlaki, Rebecca Worden, Lindsey Peters, PharmD, RPh, BCPS

Abstract Botulinum toxin is a neurotoxin that is produced by Clostridium botulinum. At one time, this toxin was only seen as a lethal substance, but now scientists have found many medical uses for it. There are eight distinctive toxins (A-H), but only A and B currently have clinical uses. Botulinum toxin A has three different versions that are U.S. Food and Drug Administration (FDA) approved: onabotulinumtoxinA (Botox®), abobotulinumtoxinA (Dysport®), incobotulinumtoxinA (Xeomin®). Botulinum toxin B is also FDA approved as rimabotulinumtoxinB (Myobloc®). The toxins work by inducing reversible, local, dose-dependent chemodenervation by inhibiting acetylcholine release from presynaptic terminals.

These drugs are approved to treat many different types of disorders but have found significant use for the treatment of migraines, dystonias and cerebral palsy. Botulinum toxin has proven to be efficacious in prophylactically treating those patients with migraines who have failed other pharmacologic and nonpharmacologic treatments. Botulinum toxin is also FDA approved for the treatment of dystonias; more specifically, all three types of botulinum toxin A and the rimabotulinumtoxin B have FDA approval for the treatment of cervical dystonia. Perhaps the most important use for botulinum toxin is in patients with cerebral palsy. Botulinum toxin is efficacious in patients with upper limb spasticity who are not good surgical candidates. It also proves useful as an adjunct to physiotherapy in these patients. This can help reduce or slow progression in patients with cerebral palsy. Exercise has been shown to be an efficacious treatment in patients with migraines, dystonias and cerebral palsy. Further research is necessary to determine the potential benefits the combination of exercise and botulinum toxin can have in these patients. While the high cost of botulinum toxin might deter some patients, it is a good option for those that have exhausted other options or are not good candidates for surgery.

therapeutic uses for the toxin. Due to the human body’s response to botulinum toxin, Kerner proposed that small amounts should “reduce or block the hyperactivity and hyperexcitability of the motor and autonomic nervous system.”1 Since this publication, several researchers have expanded upon this concept. The explorations of these researchers have resulted in the first successful application of the gastric tube, the discovery of botulinum toxin-producing bacteria (Bacillus botulinus, later named Clostridium botulinum) and many additional therapeutic uses of botulinum toxin, some of which are examined below. In this article, botulinum toxin will be described including which preparations are currently available. The specific uses of botulinum toxin will be identified, and clinical trials will be evaluated for botulinum toxin use in the diagnoses and treatment of migraines, dystonias and cerebral palsy. The progression in the understanding of this toxin is evident as scientists have utilized a toxin that was once lethal to now treat numerous disorders and improve the quality of many lives. Further research will only continue to unveil new opportunities for the medical use of botulinum toxin.

Key Terms Acetylcholine; Acetycholine Release Inhibitors; Botulinum Toxins Type A; Cerebral Palsy; Chronic Disease; Clostridium botulinum; Migraine Disorders; Muscle Spasticity; Nerve Block; Neurotoxins; Pharmaceutical Preparations; Physical Therapy Modalities; Presynaptic Terminals; Torticollis

Botulinum Toxin Botulinum toxin is produced by Clostridium botulinum and includes eight antigenically distinct toxins, labeled A through H.2 Botulinum toxin is composed of a core neurotoxin and many nontoxic accessory proteins which protect and stabilize it from temperature changes, variable pH and enzymatic degradation. The toxin is activated after secretion by scission, either with endogenous or exogenous proteases, and is then able to induce reversible, local, dose-dependent chemodenervation by inhibiting acetylcholine release from presynaptic nerve terminals. The binding domain of the toxin binds to presynaptic nerve endings and is internalized via endocytosis. The catalytic domain, a zinc endopeptidase, is released in the cytoplasm and irreversibly cleaves proteins that are essential for regulating exocytosis. This prevents the acetylcholine vesicles from fusing with the plasma membrane, thus preventing the release of acetylcholine into the synaptic cleft. It takes approximately three months for new exocytosis regulating proteins to be resynthesized, which leads to a full recovery of the neuromuscular junction.

Introduction The application and knowledge of botulinum neurotoxin has increased exponentially since its first documentation in 1815

by Professor Johann Heinrich Ferdinand Autenrieth.1 Justinus Kerner made the first major breakthrough in the understanding of botulinum toxin several years later in 1822.

Kerner found and recorded the symptoms of the toxin, hypotheses of pathophysiology and the idea that there were

After years of clinical use and repeated injections of botulinum toxin, sensitization has been known to occur.2 This sensitization is due to the formation of anti-botulinum toxin antibodies. These antibodies can be targeted against the core of botulinum toxin resulting in complete inhibition of the toxin.

However, there can also be antibodies that are targeted against proteins in the toxin and therefore not interfere with the toxin’s biological activity. The formation of these antibodies is the

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main reason to be cautious when using botulinum toxin, as these antibodies can cause adverse effects for the patient.

There are four main botulinum toxins used as pharmaceuticals: onabotulinumtoxinA (Botox®), abobotulinumtoxinA (Dysport®), incobotulinumtoxinA (Xeomin®) and rimabotulinumtoxinB (Myobloc®).2 They differ in purity, potency, immunogenicity, complexity and manufacturing.

There are many U.S. Food and Drug Administration (FDA) indications for the use of botulinum toxin (summarized in Table 1).3 Botulinum toxin is considered a first-line treatment in patients with cervical dystonia (CD) which presents as a combination of dystonic movements and postures and, frequently, pain.2 The first choice of therapy for patients with blepharospasm, an involuntary closure of the eyelids, is also botulinum toxin; safety and efficacy have been proven in clinical trials. There is also strong evidence in support of using botulinum toxin for upper limb spasticity. A common FDA approved indication is the treatment of glabellar lines, more commonly referred to as “frown lines.”3 Other indications vary according to which toxin is being used. OnabotulinumtoxinA has the most indications, other than those al-

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ready mentioned, including axillary hyperhidrosis, chronic migraine, lateral canthal lines, lower limb spasticity, overactive bladder, strabismus and blepharospasm associated with dystonia and urinary incontinence due to detrusor overactivity.3 Adverse reactions to botulinum toxins can occur.3 The incidence of the adverse reaction depends on what the toxin is being used to treat as well as the brand of the toxin. Some more prominent adverse reactions that have been reported to be caused from botulinum toxin include urinary tract infection, urinary retention, headache, neck pain, injection site irritation, upper respiratory tract infection, dizziness and strabismus. Botulinum toxin is associated with an administration warning: botulinum toxin can spread beyond the site of injection and can cause life threatening injury such as dysphagia.

Botulinum toxin is dosed in units, and it is recommended that the lowest dose should be used when initiating treatment and increasing the dose as necessary to alleviate symptoms of disease.3 No dose adjustments are required for patients with renal or hepatic impairment. The onset of ac-

Table 1. A Summary of Available Botulinum Toxins.3 Generic Name (Brand Name)

AbobotulinumtoxinA (Dysport®)

IncobotulinumtoxinA (Xeomin®)

OnabotulinumtoxinA (Botox®)

RimabotulinumtoxinB (Myobloc®)

Botulinum Toxin Type

Type A

Type A

Type A

Type B

Axillary hyperhidrosis (severe); blepharospasm associated with dystonia; cervical dystonia; migraine (chronic) prophylaxis; overactive bladder; strabismus; upper limb spasticity (severe); urinary incontinence (due to detrusor overactivity associated with a neurologic condition) Cosmetic: Glabellar and lateral canthal lines (moderate to severe)

Cervical dystonia

Injection, powder for solution

Injection, solution

Blepharospasm, cervical dystonia, glabellar lines (moderate to severe), upper limb spasticity

Labeled Indication(s)

Cervical dystonia; glabellar lines (moderate to severe)

Dosage Forms Available

Injection, powder for solution

Injection, powder for solution

Dosage Strengths Available

300 and 500 units

50, 100 and 200 units

100 and 200 units

2,500 units per 0.5 mL; 5,000 units per 1 mL; 10,000 units per 2 mL

Route of Administration

IM

IM

IM, intradermal, intradetrusor

IM

Adapted from: Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. 2016.

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tion, represented by improvement of symptoms, can occur anywhere from days after injection to weeks after injection and is dependent on the toxin used. The toxin typically has a duration of months but is also dependent on toxin used and indication.

It should be noted that botulinum toxin is costly. Depending on the brand, botulinum toxin can cost around $700 for 100 units.3 Insurance coverage varies, though most insurances require a patient to be nonresponsive to at least one treatment prior to trying botulinum toxin.4 In light of this, cost can be a major barrier to treatment for patients and should be weighed against other, less-costly treatment options.

A review follows of the current nonpharmacologic and pharmacologic treatment options for the three common indications: migraine, dystonia and cerebral palsy. An evaluation of the literature for both safety and efficacy is also included. A summary of the trials discussed is shown in Table 2.

Migraines The prevalence of migraines varies by age and gender, but in the United States it is reported that more women than men experience migraine headaches.5 It has been reported that prevalence is highest in patients between 30 and 49 years of age.

The etiology and pathophysiology of migraines are not completely understood, however, most clinicians believe the pathogenesis may be related to complex dysfunctions in neuronal and broad sensory processing.5 The pain due to migraines is thought to come from activity within the trigeminovascular system, which is a network of visceral afferent fibers arising from the trigeminal ganglia and projects peripherally to innervate pain sensitive cranial blood vessels, dura mater and large venous sinuses. These fibers also project centrally where they terminate in the trigeminal nucleus caudalis in the brainstem and upper cervical spinal cord providing a pathway for nociceptive transmission to the higher centers of the central nervous system (CNS). Activation of trigeminal sensory nerves releases vasoactive neuropeptides, which interact with dural blood vessels to promote vasodilation and dural plasma extravasation, causing neurogenic inflammation. Conduction along the trigeminovascular fibers transmits pain inputs to the trigeminal nucleus caudalis where the pain information is relayed to higher pain centers. Continued afferent input can cause sensitization of the central sensory neurons which produces a state that maintains the headache. It is thought that those who experience migraines have a lower threshold of response to specific environmental factors that govern the balance of CNS excitation and inhibition. The responsiveness of the migrainous brain may be due to genetic factors that cause abnormalities in ion channels and pumps that control the release of neurotransmitters in the brain.

Treatment strategies for migraines are generally individualized, based on the patient’s long-term and short-term goals, and usually aim to minimize headache-related disability and

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distress to improve the patient’s quality of life.5 In general, treatment includes both pharmacologic and nonpharmacologic options that are both prophylactic and symptomatic and depend on the severity of the migraine. It is noted when migraine medications are used frequently and/or excessively, a phenomenon occurs in which the headache symptoms recur with increased frequency or intensity. This is known as “rebound headaches” or “medication overuse” headaches.

No specific treatments have been shown to be effective for this other than tapered withdrawal of the medications being overused.

Nonpharmacologic treatment for migraines can include keeping a headache journal to identify triggers to avoid, performing behavioral interventions such as relaxation therapy, and adhering to a general wellness program including sleep, exercise, healthy eating, smoking cessation and limiting caffeine intake.5 The effects of aerobic exercise and yoga on migraine severity and recurrence are based on limited research.

According to a review of literature on these and other alternative treatment methods, studies have found opposing results, but recent research has shown positive effects on reduction of migraine symptomology.6 In a study of 72 patients with migraines, headache intensity, medication use and pain ratings were found to be significantly lower (P <0.001) in the group who completed 12 weeks of 60 minutes of yoga five times a week versus the control group.7 Additionally, the intervention group displayed a significant decrease in anxiety and depression (P <0.001). A Turkish study examined the relationship between migraines and aerobic exercise delivered in three (one hour) sessions per week and reported that the severity, frequency and duration of migraines were decreased with regular activity compared to the control group.8 Additional information regarding these and alternative treatment methods can be obtained from Karakurum Goksel’s review of therapeutic options for migraine patients.6 Due to the lack of research on these topics, the combination of botulinum toxin and exercise has not been examined. Further research should be conducted to determine whether the benefits of each treatment can be additive or synergistic for greater gains in symptom relief.

Common pharmacologic treatments include analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs).5 Serotonin receptor agonists, such as sumatriptan, are also used as migraine relief medications. Migraine relief is a result of normalizing dilated intracranial arteries, inhibiting vasoactive neuropeptide release and inhibiting transmission to the thalamus. Beta adrenergic antagonists are most widely used for migraine prophylaxis. While the precise mechanism of how this class of drug prevents migraines is unknown, it is thought that they may raise the migraine threshold by modulating adrenergic or serotonergic neurotransmission in cortical or subcortical pathways. Antidepressants are also potentially beneficial in migraines most likely due to the downregulation of central serotonin receptors, increased levels of synaptic norepinephrine and enhanced endogenous opioid receptor actions. Anticonvulsants are emerging as an option in treating migraines, especially in patients who also

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Table 2. Summary of Studies Discussed.

Authors

Study Design

Disease State Studied

Main Endpoints

Author’s Conclusions

Randomized, double-blind, placebo controlled

Migraines

Change in number of headache days

Botox® is an effective prophylactic treatment in migraine patients who are not using any other prophylactic migraine medications.

Jankovic J, Adler CH, Charles D, et al.14

Prospective, observational, multicenter registry

Cervical Dystonia

Clinical safety and efficacy of onabotulinumtoxinA in cervical dystonia

OnabotulinumtoxinA is safe and efficacious in the treatment of cervical dystonia.

Evidente VGH, Fernandez HH, LeDoux MS, et al.15

Randomized, double-blind, repeated-dose

Cervical Dystonia

Efficacy and safety of incobotulinumtoxinA for cervical dystonia in repeated doses

IncobotulinumtoxinA is safe and efficacious in the treatment of cervical dystonia.

Truong D, Brodsky M, Lew M, et al.16

Randomized, double-blind, placebo controlled

Cervical Dystonia

Long-term efficacy and safety of Dysport®

Dysport® is safe and efficacious in long-term treatment of cervical dystonia.

Dressler D, Tacik P, Saberi FA17

Prospective, open-label crossover study

Cervical Dystonia

Comparing potency of the drugs Botox® and Xeomin®

Similar therapeutic effect durations; doses were exchanged at a 1:1 ratio, concluded similar efficacy and potency.

Yun JY, Kim JW, Kim HT, et al.18

Randomized, double-blind, multicenter, non-inferiority, two-period crossover study

Cervical Dystonia

Compared Dysport® and Botox® by looking at changes in TWSTRS and Tsui scale scores

No significant difference between groups in the TWSTRS ratings or the Tsui scale; concluded that Dysport® and Botox® are comparable at dosage conversion of 2.5:1.

Koman LA, Smith BP, Williams R, et al.24

Randomized, double-blind, placebocontrolled

Cerebral palsy (upper limb)

Assess efficacy of botulinum toxin A on Upper Extremity Rating scale, HC, Modified House Functional Classification and Melbourne Assessment of Unilateral Upper Limb Function of patients

Those that received therapy had statistically significant improvement in the Melbourne Assessment compared to placebo, authors concluded that it was safe and a good option for patients who are not good candidates for surgery.

Ferrari A, Maoret AR, Muzzini S, et al.25

Randomized placebocontrolled

Spastic hemiplegic upper limb cerebral palsy

Study the effects of botulinum toxin combined with physiotherapy measured by the Assisting Hand Assessment (AHA)

Botulinum therapy was significantly better than placebo when combined with physiotherapy.

Dodick DW, Mauskop A, Elkind AH, et al.4

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experience seizures, anxiety and bipolar illness. These agents are thought to be beneficial due to the modulation of the excitatory neurotransmitter glutamate and inhibition of sodium and calcium ion channel activity.

Botulinum toxin has been shown to inhibit the release of nociceptive mediators, causing anti-nociceptive action separate from its neuromuscular activity.5 Also, botulinum toxin has been shown to inhibit sensitization of central trigeminovascular neurons, which is felt to be important in the development, progression and maintenance of migraines. Thus, botulinum toxin has been an area of research for prophylaxis of migraine headaches.

A randomized, double-blind, placebo-controlled study of 355 patients experiencing 16 or more headache days during a 30-day baseline period was conducted.4 The study included a 30-day baseline period, followed by a 30-day, single-blind, placebo-run-in period in which placebo response was determined, followed by a nine month, double-blind treatment period in which patients received three treatment cycles of either Botox® or placebo, separated by 90 days. During the study, characteristics of the patient’s headaches were recorded using an electronic telephone diary. The participants in the study were grouped into those taking prophylactic medications and those that were not. Of those that were not taking any prophylactic medication, 117 received the botulinum toxin and 111 received placebo. Analysis of these 228 patients was conducted. At baseline, the number of headachefree days between these placebo and treatment groups were similar. The increase in headache-free days for the botulinum toxin group was 10 days, compared to the placebo group of 6.7 days, and was statistically significant with a p-value of 0.038. Mean usual headache severity decreased over the course of the study for both the placebo and the treatment group. However, the decrease was greater in the botulinum toxin group and was statistically significant from day 180 to day 270. This study also evaluated the use of acute headache pain medication in addition to either the toxin or the placebo.

It was found that there was a statistically significant difference between the placebo and toxin group in the use of pain medication. The placebo group decreased by only 4.1 days, compared to the toxin group, which decreased its use of pain medication an average of 7.8 days. This study showed that headache symptoms improved in patients receiving botulinum toxin in all efficacy parameters studied.

In another study, Mitchel and colleagues looked into the costeffectiveness and quality of life (QOL) improvements in using botulinum toxin to treat refractory migraine headaches.9 Surveys were sent to 54 patients, and 32 were returned. The survey included six QOL measures: headache severity, headache frequency, use of rescue medications, productivity/ absenteeism, recreational activities and life enjoyment. Participants used a five-point scale to assess those categories, which were no improvement, little improvement, moderately improved, quite a bit improved, or extremely improved. A composite QOL score was calculated by summing up the measures for each category, and 73 percent of participants

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reported moderate or better improvement in overall migraine QOL measures. However, analysis of total migrainerelated pharmacy costs (cost of the toxin and overall migraine-related medications) shows that costs went up by 80.9 percent after initiating toxin treatment. There was no change in the number of migraine-related emergency room visits. Limitations with this study include a short follow-up period, the use of concomitant pain medications and no comparison group.

For the treatment of chronic migraines, botulinum toxin appears to be as effective as current therapy, with a decreased need for additional pain medications. More large scale research needs to be performed with standardization of injection site location and dosage to solidify efficacy and safety of the toxin and determine if there is a place for using the toxin to treat refractory migraines.

Dystonias Dystonia is a type of prolonged muscle tone that presents in patients in many different ways and can be mistakenly diagnosed as Parkinson’s disease due to the repetitive and shaky movements with which some people present.10,11 Due to the underdiagnosis of dystonia, often due to misdiagnosing, the true prevalence is hard to calculate.10 The hallmark symptoms of dystonias are dystonic postures and movements (flexing or twisting movements, rigidity), sensory tricks (a trick is touching the affected body part to relieve dystonia), mirror dystonias (repetitive movements occur in a nonaffected limb) and overflow dystonias (dystonia occurring in an atypical body region for the patient).11 The etiology is broken down into multiple parts, so it is important to classify the cause and type of dystonia in order to improve quality of life for the patient. The 2011 guidelines for dystonia provide a classification system to differentiate the types instructing clinicians to look at the etiology of the dystonia, the age of onset (early or late) and the distribution (focal, segmental, multifocal, generalized or hemidystonia).10 Genetic testing can be done on symptomatic individuals to diagnose certain types of dystonia as well. For the most part, each type of dystonia has its own validated rating scale to evaluate the disease, monitor progression and predict impact on quality of life.

In general, nonpharmacologic treatment options that are utilized include occupational therapy, physical therapy, deep brain stimulation and selective peripheral denervation and myectomy.12 Common medication classes that doctors prescribe for dystonias are skeletal muscle relaxants (especially intrathecal baclofen), anticholinergic drugs, anticonvulsant drugs, anti-dopaminergic drugs and dopaminergic drugs. The guidelines do suggest the use of botulinum toxin for different types of dystonias. As mentioned above, all three formulations of botulinum toxin A and botulinum toxin B are FDA approved for the treatment of cervical dystonia (CD).10, 13 OnabotulinumtoxinA (Botox®) had previously been the gold standard in cervical dystonia treatment. It was the first botulinum toxin that the FDA approved and has demonstrated

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safety and efficacy in a prospective, observational registry that tracked 502 patients receiving Botox® for cervical dystonia.14 IncobotulinumtoxinA (Xeomin®) is a newer preparation of botulinum toxin that does not have accessory proteins, which helps prevent possible immunogenicity problems. It, too, has shown to be efficacious and safe in a double-blind, repeated-dose 88 week study.15 Similarly, the third type of botulinum toxin, abobotulinumtoxinA (Dysport®) demonstrated efficacy in a randomized, double-blind, placebocontrolled study, followed by an open-label extension.16 Botulinum toxin B was noninferior to Botox® for the treatment of cervical dystonia in a randomized, double-blind, noninferiority trial.13 Therefore, in today’s practice, botulinum toxin B can be used as an alternative to botulinum toxin A.10

Because all three types of botulinum toxin A are safe and efficacious, studies are now comparing the different types. In a prospective, open-label crossover study comparing Botox® and Xeomin®, researchers compared the time between the injection and when the patient reported a decrease in the therapeutic effect.17 They also compared the potency of the two drugs by giving participants at least four injection series of each drug at a 1:1 dose ratio. The mean time to decrease in therapeutic effect was 11.2 ± 1.1 weeks for Botox®, compared to Xeomin®, which had a time to decrease in effect of 11.4 ± 1.3 weeks. Researchers concluded that because there were similar therapeutic effect durations and that the doses were exchanged at a 1:1 ratio, Botox® and Xeomin® have similar efficacy and potency.

Similarly, researchers compared Dysport® and Botox® in a randomized, double-blind, multicenter, noninferiority, twoperiod crossover study.18 The purpose of this study was to determine if a 2.5:1 ratio was an adequate conversion by looking at changes in the Tsui scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to follow-up (weeks 4, 8, 12, and 16). The Tsui scale is a short rating system that looks at sustained movement amplitudes, duration, shoulder elevation and dystonic tremor but does not assess how cervical dystonia affects a patient’s daily life.19 The TWSTRS is a validated scale that does look at the impact on a patient’s life by summing up three different categories related to the participants’ experience with cervical dystonia: severity, disability and pain.16 They also evaluated the participants’ preferences and the reasons for their preferences.18 There was no significant difference between groups in the TWSTRS ratings, and while participants’ ratings in the Tsui scale favored Botox®, the difference was not significant. When asked, more participants chose Dysport® (n=36) to Botox® (n=34), and 21 participants said they did not have a preference. In both cases of preference, the main reason that was given by patients was a perceived increase in efficacy. Adverse events were not statistically different between the two groups. Because neither version had a statistically significant preference, both drugs are comparable at a dosage conversion of 2.5:1 Dysport® to Botox®.

Since the three forms are all efficacious, safe and comparable, it is important to consider the cost-effectiveness to deter-

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mine the best option for a patient. In a cost-utility analysis, authors compared Botox®, Dysport® and Xeomin® use in cervical dystonia from a federal government payer perspective.

Outcomes were evaluated by measuring quality-adjusted life years (QALYs).20 Assuming a willingness-to-pay value of $100,000 per QALY, all three formulations are considered cost-effective; however, the most effective was Xeomin® with a cost-effectiveness ratio of $27,548 per QALY, followed

by Dysport® ($36,678), and Botox® ($49,337). The QALY gained in a one-year period was comparable with 0.06 QALY gained for Dysport® and 0.07 QALY gained for both Xeomin® and Botox®. The authors of the analysis also looked at wastage during injections because each manufacturer recommends using one vial per patient. Dysport® had the lowest wastage (2.2 percent) followed by Xeomin® (10 percent) and Botox® (22.9 percent). Xeomin® has an advantage over Botox®; it is available in 50 unit vials, whereas the smallest vial available for Botox® contains 100 units. The 50 unit vial allows for dose individualization with less waste. This analysis provides a useful comparison between the drugs from a cost perspective.

A current area of dystonia research surrounds the combination of exercise and botulinum toxin injections. Induced muscle weakness can result from botulinum toxin due to neuroparalysis and denervation.21 Inclusion of treadmill training programs has been assessed in rats to examine the results of this combination. Researchers found that exercise diminished muscle atrophy following injections and positively affected muscle contractile strength recovery. There is a possibility that treadmill training could cancel out the response of spasticity reduction from the botulinum toxin injection. The current knowledge base does not include research that has confirmed or denied these theories in human participants. Due to the nature of both methods, this relationship should be explored to determine the effect on patients with muscle spasticity, including patients with dystonias.

Cerebral Palsy Cerebral palsy is a debilitating disease that starts in infancy or young children.22 Currently, it is the number one cause of childhood disabilities. The disease begins when damage occurs to the cerebral cortex either during fetal development, during birth, or after birth and is permanent. Types of damage could be periventricular leukomalacia, cerebral dysgenesis, intracranial hemorrhage or a lack of oxygen. It manifests in a variety of symptoms such as limb weakness, spasticity, crouched gait, ataxia and delays in reaching motor skill milestones. Every patient with cerebral palsy will have individualized presentation and severity of the disease. Doctors can diagnose the disease by testing motor skills, monitoring motor development and performing neuroimaging techniques like cranial ultrasounds, computed tomography (CT) and magnetic resonance imaging (MRI). While this disease is not curable, botulinum toxin has become a standard of treatment for cerebral palsy patients of all ages to help improve gait function by controlling spasms.

Nonpharmacologic options might include surgeries like rhizotomy to kill certain nerve roots responsible for cerebral

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palsy or peripheral neurectomy to remove the nerves. 23 Orthopedic surgical options might include tendon lengthening or transfer, osteotomy or joint fusion to help with movement.

Oral treatment options for cerebral palsy include dantrolene sodium, baclofen, tizanidine and benzodiazepines. Patients can also receive parenteral therapy to aid in chemical denervation, such as ethanol 45 to 100 percent, phenol 5 to 7 percent, botulinum toxin or intrathecal baclofen. Because not all patients are good surgical candidates, and botulinum toxin is not something a patient has to receive every day, it becomes a good option for many patients.

Children with cerebral palsy that affects their upper extremities often have spasticity patterns like internal shoulder rotation, elbow flexion, forearm pronation, wrist and finger flexion and thumb-in palm.24 Many of these patients are not good candidates for surgery due to their age, so botulinum toxin therapy would be a good option to help control spasms until they are a better candidate for surgery. In a randomized, double-blind, placebo-controlled study of botulinum toxin A, researchers used the House Classification (HC) system to rate participantsâ&#x20AC;&#x2122; functional ability. The participants received either botulinum toxin A or placebo at baseline, week 8, and week 20 if indicated. Visits were conducted at baseline and weeks 4, 8, 14, 20 and 26. At the visits where the patient received an injection, the patient met independently with both a physician and an occupational therapist, and if the visit did not include an injection, the patient was evaluated by just the occupational therapist. Doses were individualized to the patient, and if the physician felt that the patient did not need another injection the injection was not given at that appointment. The physician evaluated based on the Upper Extremity Rating scale (used to evaluate the range of motion of the limbs), the HC, and the Modified House Functional Classification. The occupational therapist used these same scales along with the Melbourne Assessment of Unilateral Upper Limb Function. The study also looked at Health-Related Quality of Life outcomes for the caregivers and also safety of botulinum toxin A by assessing any adverse events.

The study showed that the patients in the botulinum toxin A group had a statistically significant improvement in the Melbourne Assessment compared to placebo.24 The study also showed a better improvement in the mean range of motion at weeks 20 and 26 for the botulinum toxin A group. There was not, however, any difference in the Health-Related Quality of Life data for the caregivers. Botulinum toxin A did prove to be relatively safe for the patients in the study with only mild to moderate adverse events reported such as muscle soreness at the injection site, muscle cramps, excessive weakness, headache, rash and fatigue. Overall, the study proved that botulinum toxin A is a good option for those patients with upper limb spasticity related to cerebral palsy that are not currently candidates for surgery.

In a similar randomized, placebo-controlled trial, botulinum toxin was compared with placebo in children with spastic hemiplegic upper limb cerebral palsy.25 One of the major differences in the study was that the injections were combined

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with physiotherapy. The participants received injections at baseline and had follow-up visits at one, three and six months. The participants also had a physiotherapy program that included three (45 minute) weekly sessions for 24 weeks. The program included activities started out as unimanual and then moved bimanual and more complex as the study progressed. After the injection, participants received a customized positional splint. The study used the Assisting Hand Assessment (AHA) scale as a primary outcome to measure the use of the affected upper limb. Both the placebo group and the botulinum toxin A group showed improvement in the AHA score after receiving an injection and physiotherapy, but the botulinum toxin A group showed a faster and more substantial change. At the six month visit, the botulinum toxin group stopped showing improvement, while the placebo group continued to change. This correlates with other studies that concluded that the average length of effectiveness for botulinum toxin injections is around 12 weeks.17 Because this study was small (only 27 participants), further studies need to be done on larger groups over a longer period of time; however, this study did confirm that botulinum toxin is effective in these patients, and that physiotherapy works as an adjunct when individualized to each patient.25 The treatment of cerebral palsy can vary due to the patientâ&#x20AC;&#x2122;s needs. One common component of cerebral palsy treatment is exercise. It has been found that the inclusion of treadmill exercises benefits the symmetry, speed and endurance of cerebral palsy patients.26 Spasticity of muscles results in weak lower extremity muscles and bone development due to the delay in independent ambulation. In a study of 37 children with diagnosed cerebral palsy, an experimental group completed treadmill sessions twice a week for three months in addition to rehabilitation programs twice a week. At the conclusion of the study, the results between the treadmill program participants and the control group, who did not exercise, were compared. Participants who completed treadmill exercise were able to walk significantly faster, longer and farther during the postparticipation testing (p<0.001).

The results of this study supported the conclusion that had been found and documented previously; ambulation and exercise tolerance are improved with the inclusion of treadmill exercise. Various exercise methods were examined for effects on postural control of cerebral palsy patients in a metaanalysis performed by Dewar, Love and Johnston.27 Treadmill training was supported as well as gross motor task training, hippotherapy, trunk-targeted training and reactive balance training.

In theory, the combination of exercise and botulinum toxin should compound the benefits of these treatments and reduce the potential adverse effect of nontargeted muscle weakness. In a study of 15 children, 10 weeks of a home strength program were performed three times a week in patients who also received Botulinum Type-A (BoNT-A) injections.28 Significant results were documented in both groups that participated in the exercise program; one before the injections and the other after. The levels of muscle spasticity were reduced, in addition to increased strength in the exer-

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cise and BoNT-A combined treatment group. As recorded in this study, the inclusion of exercise in conjunction with botulinum toxin injections can have a profound impact in cerebral palsy patients. Further research should continue to examine the timing, exercise method and other types of botulinum toxin for optimal treatment development.

Conclusion Botulinum toxin has been established as an integral part in the treatment of disorders caused by muscle overactivity.

Many clinical trials, shown in Table 2, have confirmed the safety and efficacy of its use. The benefits of the botulinum neurotoxin in the treatment of migraines, dystonias and cerebral palsy are only some of the uses for the toxin in the health care field. Botulinum toxin has also been included in the treatment of many ophthalmological disorders and movement disorders and continues to undergo testing for applications in smooth muscle overactivity disorders and hypersecretion of glands.29 Although some adverse effects can occur, the discovery and use of this toxin has led to a higher quality of life for many patients with various disorders. The use of this drug in combination with other forms of treatment has the potential for even greater outcomes for patients. Further research will increase the impact botulinum toxin will have on the progression of treatments for disorders of spasticity.

References 1. Erbguth F. Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord.

2004 Mar; 19(Suppl 8):S2-6.

2. Bentivoglio AR, Del Grande A, Petracca M, Ialongo T, Ricciardi L. Clinical differences between botulinum neurotoxin type A and B. Toxicon.

2015 Dec; 107:77-84.

3. Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. 2016. Neuromuscular blocker agent, toxin; [2016; 20 Feb 2016]. Available from:0online.lexi.com.polar.onu.edu/lco/action/search/pharmacat/patch_f? q=Neuromuscular+Blocker+Agent%2C+Toxin.

4. Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD. Botulinum toxin type A for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized, double-blind, placebo-controlled study. Headache.

2005 April; 45:315-24.

5. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors.

Pharmacotherapy: a pathophysiologic approach [Internet]. 9th ed. New York: McGraw-Hill; 2014. Chapter 45, Headache Disorders; [cited 2016 Feb 20]; [about 20 screens]. Available from:0-accesspharmacy.mhmed ical.com.polar.onu.edu/content.aspx?bookid=689&sectionid=45310495.

6. Goksel, BK. The use of complementary and alternative medicine in patients with migraine. Noro Psikiyatr Ars (Archives of Neuropsychiatry). 2013 Sept; 41-6.

7. John PJ, Sharma N, Sharma CM, Kankane A. Effectiveness of yoga therapy in the treatment of migraine without aura: a randomized controlled trial. Headache. 2007 May; 47(5):654–61.

8. Narin S, Pinar L, Erbas D, Ozturk V, Idiman F. The effects of exercise and exercise-related changes in blood nitric oxide level on migraine headache. Clin Rehabil. 2003 Sept; 17(6):624-30.

9. Mitchell MP, Schaecher K, Cannon HE, Speckman M. Humanistic, utilization, and cost outcomes associated with the use of botulinum toxin for treatment of refractory migraine headaches in a managed care organization. J Manag Care Pharm. 2008 June; 14(5):442-50.

10. Albanese A, Asmus F, Bhatia KP, Elia AE, Elibol B, Filippini G, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol. 2011; 18:5-18.

11. Albanese A, Lalli S. Is this dystonia? Mov Disord. 2009; 24(12):1725-31.

12. Albanese A, Barnes MP, Fernandez-Alvarez E, Fllippini G, Gasser T, Krauss JK, et al. A systematic review on the diagnosis and treatment of

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primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES task force. Eur J Neurol. 2006; 13:433-44.

Pappert EJ, Germanson T. Botulinum toxin type B vs. type A in toxinnaive patients with cervical dystonia: randomized, double-blind, noninferiority trial. Mov Disord. 2008; 23(4):510-17.

Jankovic J, Adler CH, Charles D, Comella C, Stacy M, Schwartz M, et al.

Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxinA efficacy (CD PROBE). J Neurol Sci. 2015; 349:84-93.

Evidente VGH, Fernandez HH, LeDoux MS, Branshear A, Grafe S, Hanschmann A, Comella CL. A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin) in cervical dystonia. J Neural Transm. 2013; 120:1699-707.

Truong D, Brodsky M, Lew M, Brashear A, Jankovic J, Molho E, et al.

Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia. Parkinsonism Relat Disord. 2010; 16:316-23.

Dressler D, Tacik P, Saberi FA. Botulinum toxin therapy of cervical dystonia: comparing onabotulinumtoxinA (Botox) and incobotulinumtoxinA (Xeomin). J Neural Transm. 2014; 121:29-31.

Yun JY, Kim JW, Kim HT, Chung SJ, Kim JM, Cho JW, et al. Botox at a ratio of 2.5:1 units in cervical dystonia: a double-blind, randomized study.

Mov Disord. 2015; 30(2): 206-13.

Jost WH, Hefter H, Stenner A, Reichel G. Rating scales for cervical dystonia: a critical evaluation of tools for outcome assessment of botulinum toxin therapy. J Neural Transm. 2013; 120(3):487-96.

Kazerooni R, Broadhead C. Cost-utility analysis of botulinum toxin type A products for the treatment of cervical dystonia. Am J Health-Syst Pharm. 2015; 72:301-7.

Tsai SW, Chen HL, Chang YC, Chen CM. Molecular mechanisms of treadmill therapy on neuromuscular atrophy induced via botulinum toxin A. Neural plasticity. 2013 Nov 12;2013.

National Institute of Neurological Disorders and Stroke [Internet].

Bethesda, MD: National Institute of Health; Cerebral palsy: hope through research; [updated 2016 Mar 16; cited 2016]; [about 12 screens]. Available from:www.ninds.nih.gov/disorders/cerebral_palsy /detail_cerebral_palsy.htm.

Koman LA, Paterson Smith B, Balkrishnan R. Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin.

Paediatr Drugs. 2003; 5(1):11-23.

Koman LA, Smith BP, Williams R, Richardson R, Naughton M, Griffin L, Evans P. Upper extremity spasticity in children with cerebral palsy: a randomized, double-blind, placebo-controlled study of the short-term outcomes of treatment with botulinum a toxin. J Hand Surg. 2013; 38A:435-46.

Ferrari A, Maoret AR, Muzzini S, Alboresi S, Lombardi F, Sgandurra G, et al. A randomized trial of upper limb botulinum toxin versus placebo injection, combined with physiotherapy, in children with hemiplegia.

Res Dev Disabil. 2014; 35:2505-13.

Saritaş N, Abakay H, Karakuş M, Coşkun B. Somatotype profiles and changes depending on treadmill exercise in children with cerebral palsy. Journal of Physical Education & Sports Science. 2014 Aug; 8 (2):207-14.

Dewar R, Love S, Johnston L. Exercise interventions improve postural control in children with cerebral palsy: a systematic review. Dev Med Child Neurol. 2015 June; 57(6):504-20.

Williams SA, Elliott C, Valentine J, Gubbay A, Shipman P, Reid S. Combining strength training and botulinum neurotoxin intervention in children with cerebral palsy: the impact on muscle morphology and strength. Disabil Rehabil. 2013 April; 35(7): 596-605.

Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ (Int Ed). 2000 Jan 15; 320(7228):161–5.

The authors have no conflict of interest or funding support to disclose.

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Comparison of Long-Term Oral Anticoagulation Therapies Including Newly Approved Reversal Agent for Dabigatran Mackenzie DeVine, Natalie Lennartz, Michaela Wolford, Rebecca Worden, Joelle Farano, Erin Petersen, PharmD, BCPS

Abstract Anticoagulants are a well-known class of agents essential for the prevention of blood clots, which may further develop into deep vein thrombosis, pulmonary embolism or stroke. Individuals at a high risk of clotting, such as those with atrial fibrillation, multiple risk factors or recent hip/knee surgery, are in need of long-term anticoagulation therapy. The purpose of this review is to highlight the pros and cons for each available anticoagulant as well as discuss pivotal clinical trials that evaluated the safety and efficacy of these agents.

Warfarin, the oldest anticoagulant, requires the patient to attend frequent appointments with a health care professional in order to test their international normalized ratio (INR).

Newer anticoagulants, including dabigatran, rivaroxaban and apixaban, do not require frequent INR testing and have a quicker onset of action than warfarin, providing convenience for the patient. However, many health care professionals prefer warfarin because the INR may indicate its efficacy, its dosages can be easily changed and it is typically more affordable. Additionally, dabigatran may be chosen because it is the only one of these drugs that has a reversal agent, which can be utilized in the case of major bleeding or emergent surgery.

There are many opportunities for pharmacists to impact patient outcomes in the anticoagulation therapy setting. From clinics to the community pharmacy setting, the pharmacist’s role in patient counseling and education is crucial in reducing mortality. Additionally, drug development is a growing market as reversal agents are needed for many of these newer anticoagulation therapies.

Key Terms Warfarin; Apixaban; Dabigatran; Rivaroxaban; Idarucizumab; Pharmacist, Anticoagulation; Vitamin K, Pulmonary Embolism; Deep Vein Thrombosis; Factor Xa; INR; Myocardial Infarction; Stroke Introduction Thromboemboli often follow the abnormality of at least two of the three factors included in Virchow’s triad.1 The triad includes hypercoagulability, stasis and vascular endothelial injury damage as the three most important anomalies in determining a patient’s risk of developing a blood clot. A CHADS2 score is used in atrial fibrillation patients to assess their risk for stroke and eligibility for anticoagulation therapy.2 Factors in this assessment include congestive heart failure (1 point), hypertension (1 point), age 75 years and older (1 point), diabetes mellitus (1 point), and prior stroke or transient ischemic attack (2 points). Anticoagulation therapy should be considered in patients scoring one point and should be recommended in patients scoring two or more

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points. Some thromboembolic disorders are congenital, innate or recurring.1 Risks factors of clot formation also include pregnancy, obesity, immobility for long periods of inactivity, smoking, oral contraceptives, trauma, surgeries, autoimmune disorders, hormone therapy, inflammatory disorders, age, heart valve replacements, postsurgery, congenital heart defects and other coagulation and heart-related disorders.1,3,4 With many risk factors, and the commonality of their prevalence, the need for an easily managed anticoagulant therapy is important for many patients.4 As described by the Virchow’s triad, clot formation predominantly occurs when the triad is compromised which is especially common after stasis and/or venous injury, two usual events that occur post-op.5 Following vascular injury, factors of the coagulation process become exposed and initiate the clotting cascade allowing platelets to adhere to vascular endothelium and become activated. Upon activation, successive platelets aggregate via platelet adhesion receptors resulting in thrombus formation.

The aggregation of clotting factors and platelets causes a blood clot which, if large enough, can cause blockage of blood flow through the vessel.5 These clots can form in the peripheral extremities causing deep vein thrombosis (DVT) or can become dislodged and enter the lungs causing pulmonary embolism (PE). In the United States, venous thromboembolism (VTE) causes more than 300,000 admissions to hospitals every year, and PEs are responsible for death in approximately 12 percent of hospitalized patients claiming the lives of 50,000 to 250,000 patients every year. 4 In a study conducted by O’Reilly, Burgess and Zicat including 5,999 patients undergoing total knee replacement (TKR), total hip replacement (THR) or bilateral TKR while on DVT prophylaxis, the prevalence of DVT was 25.6 percent, 8.9 percent and 36.9 percent, respectively.6 In the same study, symptomatic PE was present in 1.9 percent of all patients, and the prevalence of fatal in-hospital PE was 0.05 percent.

Anticoagulant therapy is common in patients with atrial fibrillation (AF), a common type of heart arrhythmia.7 Arrhythmias include the heart beating too fast, too slow or irregularly; more specifically, AF is caused by an irregular conduction of the atrial chambers allowing them to fibrillate.

Atrial fibrillation increases the risk of stroke, which may be reduced with anticoagulation therapy. To prevent these serious outcomes, anticoagulant therapy can be very beneficial.

The goal of this article is to summarize the various anticoagulant therapies and emphasize the value of reversal agents, especially the new reversal agent, idarucizumab (Praxbind), for the anticoagulant dabigatran (Pradaxa®).

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Comparison of Long-Term Oral Anticoagulation Therapies Including Newly Approved Reversal Agent for Dabigatran

Warfarin Warfarin was approved in the United States in 1954, making it one of the oldest drugs still used therapeutically today. 8 Warfarin was discovered in the 1920s after a bout of cattle disease named “sweet clover disease.”9 During the Great Depression, moldy hay, which unknowingly contained molds such as Penicillium nigricans and Penicillium jensi, was fed to cattle causing severe hemorrhagic bleeding resulting in death of the cattle. Two veterinary surgeons, Schofield and Roderick, found that avoiding the moldy sweet clover hay prevented the bleeding effects in cattle. Roderick later discovered that the acquired coagulation disorder was caused by a “plasma prothrombin defect” and, for the next 10 years, farmers avoided feeding their cattle sweet clover hay in fear of the bleeding disorder. Eventually Karl Link and his student, Wilhelm Schoeffel, isolated the causative agent that is now known as dicoumarol. Dicoumarol was found to be formed by oxidation of natural coumarin in the moldy hay. In 1945, Link used the derivative as a rodenticide that killed rodents by causing internal hemorrhage. After success as a rodenticide, the transition to a compound with clinical application under the name “Coumadin” began.

Warfarin, the generic of Coumadin, is an anticoagulant that functions by competitively inhibiting the vitamin K epoxide reductase (VKOR) complex which works by reactivating inactive vitamin K to active vitamin K, thus depleting active vitamin K.10 With decreased active vitamin K, synthesis of active clotting factors is reduced causing diminished coagulation effects of the blood.

Warfarin is approved for prophylaxis and treatment of thromboembolic complications, which include valvular and nonvalvular atrial fibrillation; mechanical prosthetic cardiac valves; prophylaxis and treatment of venous thrombosis and its extension, including PE; and as adjunct therapy in reducing the risk of systemic embolism following a myocardial infarction (MI).8,10 Warfarin is dosed anywhere between 1 mg and 10 mg daily. 8 Dosing varies on hepatic impairment, vitamin K intake, chronic heart failure (CHF), age, and functional variants of CYP2C9 (*2 or *3 alleles) or VKORC1 (-1639 polymorphism).10 Full therapeutic effects of warfarin are typically seen five to seven days after beginning therapy which generally requires bridging therapy overlap with low molecular weight heparin (LMWH) or unfractionated heparin for at least five days and with an international normalized ratio (INR) of 2 or higher for at least 24 hours.

The major adverse reactions of warfarin are fatal and nonfatal hemorrhage from any tissue or organ, and the most severe are spontaneous intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding.10 Warfarin use should be avoided as the monotherapy in treating heparin induced thrombocytopenia (HIT) as warfarin initially inhibits the synthesis of Protein C, the body’s own anticoagulant factor, and possibly accelerates the thrombotic process. Warfarin is considered pregnancy category D or X as warfarin crosses

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the placenta, and incidents of teratogenic effects have been reported in exposure after the first trimester, and central nervous system (CNS) events to the fetus have been observed while taking warfarin in any trimester. In most cases, warfarin is contraindicated in pregnancy, except in women with mechanical heart valves where the possible benefits of warfarin should be weighed against the risks and risks/ benefits of switching to another anticoagulation therapy.

Warfarin has a narrow therapeutic index, and several factors, including other medications and alterations in diet, can play a role in the extent of clotting factor inhibition; therefore, anticoagulation must be carefully monitored.8 An INR increased by 2 to 3.5 times normal should be achieved to balance between preventing thrombosis and avoiding major bleeding complications.11 International normalized ratio should be monitored at least every one to four weeks depending on INR consistency or variations including recent warfarin dose, medication, disease and diet changes.8 When other products that affect warfarin are initiated, discontinued or taken irregularly, additional INR testing should be performed. It is also important to note that whole blood clotting and bleeding times are not effective in measuring and monitoring warfarin therapy, and an INR greater than 4 generally does not provide an additional benefit and is often associated with increased bleeding risk.10 Before starting a new prescription or over-the-counter medication, a patient should discuss the risks with a trusted health care professional as some medications can affect INR and require more frequent blood testing.12 Patients should avoid aspirin, unless instructed otherwise by a physician, as this may increase a patient’s bleeding risk. Other medications that can interact with warfarin include antibiotics, pain medicines such as nonsteroidal anti-inflammatory drugs (NSAIDs), and acid reflux medications such as cimetidine.

Some foods may also alter the effects of warfarin.10 Excessive acute consumption of alcohol (binge drinking) should be avoided in patients taking warfarin as it decreases the metabolism of oral anticoagulants and increases prothrombin time (PT) and INR, whereas, chronic alcohol use may increase the metabolism of anticoagulants and decrease PT and INR. Patients taking warfarin should maintain a consistent diet because the effects of warfarin are decreased with an increase of vitamin K intake. Foods, especially green leafy vegetables, are high in vitamin K, and changes in ingestion of these foods may alter warfarin effects. Patients should do their best to take their warfarin medication at the same time every day to maintain consistency in their therapy.

In cases of warfarin overdose, patients may have extensive bleeding requiring reversal. In excessive bleeding, warfarin should be discontinued and vitamin K1 may need to be administered parenterally.8 Urgent warfarin reversal may also require fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC). The 2015 American Heart Association/ American Stroke Association (AHA/ASA) Guidelines on intracerebral hemorrhage (ICH) compares FFP, PCC and re-

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combinant activated factor VIIa (rFVIIa) as potential therapies with the use of vitamin K in reversal of warfarin induced over-anticoagulation.13 Congruent recommendations are found in the 2012 CHEST Guidelines on Evidenced-Based Management of Anticoagulant Therapy. The CHEST Guidelines advise the administration of vitamin K in overanticoagulated patients as follows: patients with an INR between 4.5 and 10 and no evidence of bleeding should not be given vitamin K, patients with an INR of 10 or higher with no evidence of bleeding should be given oral vitamin K, and patients with major bleeding associated with warfarin should undergo rapid reversal of anticoagulation with PCC rather than plasma and with vitamin K 5 mg to 10 mg administered by slow intravenous injection.2

Dabigatran Dabigatran etexilate (Pradaxa), is a direct thrombin inhibitor.14 It was approved by the U.S. Food and Drug Administration (FDA) in 2010 for use in DVT, PE, nonvalvular atrial fibrillation and postoperative thromboprophylaxis. Dabigatran etexilate is a prodrug which is converted into its active form, dabigatran. Dabigatran reversibly inhibits thrombin which is both free and fibrin-bound, preventing thrombinâ&#x20AC;&#x2122;s endogenous activity of cleaving fibrinogen to fibrin, activating clotting factors V, VII, XI, XIII and promoting platelet aggregation.

The inhibition of these functions leads to the inhibition of clot formation.

Four studies were credited with the approval of dabigatran by the FDA. The first study, Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism (RECOVER) was a randomized, double-blind, double-dummy, noninferiority trial comparing oral dabigatran to warfarin. 15 Patients enrolled in the study had acute venous thromboembolism and were initially treated with parenteral anticoagulation medication for a median of nine days prior to the initiation of oral therapy with either dabigatran or warfarin.

Dabigatran was dosed at 150 mg twice daily while warfarin was dosed per patient to achieve an INR between 2.0 and 3.0.

The study included 2,550 patients with 1,275 patients in each treatment arm.15 Patients were started on oral therapy, assessed seven days later, and then continually checked once monthly for a total of six months. The primary outcome was the incidence of venous thromboembolism and related death.

Within the six month treatment period, 30 patients in the dabigatran arm and 27 in the warfarin arm experienced the primary outcome. This was not a statistically significant difference, determining dabigatranâ&#x20AC;&#x2122;s noninferiority to warfarin.

Treatment of Acute Venous Thromboembolism with Dabigatran or Warfarin and Pooled Analysis (RE-COVER II) was a randomized, double-blind, double-dummy trial that was designed after the conclusion of the RE-COVER study to confirm the findings.16 The patients in the trial had been diagnosed with an acute venous thromboembolism and had been treated with heparin for five to 11 days prior to initiation of the study. Dabigatran was dosed at 150 mg twice daily, and warfarin was dosed per patient to achieve an INR

36

between 2.0 and 3.0. The primary outcome of the study was the recurrent incidence of venous thromboembolism and related death. Results of the study showed noninferiority of dabigatran to warfarin due to the 30 positive outcomes (recurrent venous thromboembolism and/or related death) of the dabigatran group and the 28 of the warfarin group.

These treatment arms were not statistically significant proving noninferiority of dabigatran to warfarin.

The Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism (VTE) is an article compiling the results of the RE-MEDY and RE-SONATE trials.17 RE-MEDY, a randomized and double-blind trial, treated patients with dabigatran 150 mg twice daily or with warfarin dosed per patient to achieve an INR between 2.0 and 3.0. The primary efficacy outcome was venous thromboembolism or related death. The study included 2,866 patients who had been diagnosed with VTE and treated with anticoagulation therapy for three months prior to initiation of the study. Within the study, 26 patients experienced a VTE or VTE-related death in the dabigatran arm and 18 patients in the warfarin arm. Although the dabigatran treatment group produced more VTE or related deaths, the two treatment arms were not statistically significant, concluding that dabigatran was noninferior to warfarin.

RE-SONATE, another randomized and double-blind trial, compared the treatment of 150 mg of dabigatran twice daily to placebo.17 The study included 1,343 patients previously diagnosed with a VTE and treated with anticoagulation therapy for three months prior to trial initiation. The patients were selected through expert opinion to be included in the RE-SONATE trial over the RE-MEDY trial if they were considered low-risk patients who were thought to be able to withstand placebo treatment. The primary outcome of the study was recurrent VTE or related death. Recurrent venous thromboembolism occurred in three patients in the dabigatran group and 37 of the patients in the placebo group. These results were statistically significant, concluding that dabigatran is more effective than placebo at preventing a recurrent VTE. Additionally, major bleeding occurred in 36 patients in the dabigatran group and only 12 patients within the placebo group (95 percent confidence interval (CI), 1.52 to 5.60 and P=0.001).

Dabigatran dosing for DVT and PE is identical and instructs to administer one 150 mg capsule twice daily, directly following five to 10 days of parenteral anticoagulation therapy.14 Dabigatran is also dosed at 150 mg twice daily for the treatment of nonvalvular atrial fibrillation. For the postoperative thromboprophylaxis following hip and knee replacements, 110 mg of dabigatran is administered one to four hours after completion of surgery. If the patient is not started on dabigatran the day of surgery, it should be initiated when homeostasis is achieved and should be given 220 mg once daily. The maintenance dose is also 220 mg once daily and can be given for up to 28 to 35 days.

Most common side effects associated with the use of dabigatran include hemorrhage and gastrointestinal symp-

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toms such as dyspepsia or gastritis-like symptoms.14 Less common adverse drug reactions include wound discharge, hematuria, anemia, hematoma, increased serum alanine aminotransferase (ALT), anaphylaxis and angioedema.

Therefore, an allergy to dabigatran presents a large risk to patients. Additionally, it is important to determine the patientâ&#x20AC;&#x2122;s renal function prior to the initiation of therapy and periodically throughout treatment or when clinically indicated. No exact recommendation for the frequency of renal function is provided. Routine coagulation tests, on the other hand, are not required but can be used if the medical team wishes to determine the levels of dabigatran in the blood and the level of therapy the patient is receiving. Such tests include activated partial thromboplastin time (aPTT), ecarin clotting test (ECT) or thrombin time (TT).

Praxbind, generic name idarucizumab, is a monoclonal antibody which was developed as a reversal agent of dabigatran.14 Idarucizumab for Dabigatran Reversal (REVERSE AD) was the study that lead to the approval of idarucizumab by the FDA.18 The RE-VERSE AD was a prospective cohort study that included 90 patients, split into two groups, who all received idarucizumab for the reversal of dabigatran.

The first group consisted of patients who were taking dabigatran and experiencing uncontrollable or lifethreatening bleeding, while the second group was composed of patients who were in need of emergent surgery. The primary end point of the study was the maximum percentage of reversal for dabigatran by 5 g dose of idarucizumab given IV. The normalized results of the study concluded that 88 to 98 percent of the patients experienced a reversal of dabigatran within minutes. In 79 percent of patients, unbound dabigatran concentrations continued to remain below 20 ng/ml for 24 hours following idarucizumab administration. Within the study, only one patient experienced a thrombotic event after receiving the reversal agent. Due to the emergent need and high efficacy displayed, idarucizumab was approved by the FDA in 2015.19 Idarucizumab is indicated as a reversal agent for dabigatran in the incidence of emergent surgery or if the patient has uncontrolled or life-threatening bleeding.14 The humanized monoclonal antibody fragment binds to both dabigatran and its acylglucuronide metabolites. Its affinity to dabigatran is approximately 350 times greater than that of thrombin, therefore inhibiting dabigatran within minutes.

Idarucizumab adult dosing is 5 g IV as two separate 2.5 g doses, administered no more than 15 minutes apart.14 If the patient still has elevated coagulation parameters after the initial 5 g dose, an additional 5 g dose may be given. The most common side effects include delirium, headache, hypokalemia, constipation, pruritus, pneumonia and fever.

Hypersensitivity symptoms may also occur such as rash, hyperventilation and pruritus.

Rivaroxaban Rivaroxaban (XareltoÂŽ) was approved as an anticoagulation therapy by the FDA in 2011. It was the first novel oral antico-

Drug Abuse Cardiovascular

agulant (NOAC) approved, nearly 50 years after the approval of warfarin.20 Rivaroxaban is an oral direct factor Xa inhibitor that works by prolonging activated thromboplastin time and increasing levels of anti-factor Xa. This medication is indicated for the treatment and prophylaxis of PE and DVT in patients who have undergone surgeries such as knee or hip replacement and patients diagnosed with nonvalvular atrial fibrillation. Currently, this therapy is being studied in the treatment of acute coronary syndromes.

Rivaroxaban was compared to warfarin in a multi-center, randomized, double-blind, double-dummy, event-driven trial including 14,264 patients with nonvalvular atrial fibrillation with an increased risk of stroke in the ROCKET AF trial.21 The study recognized that vitamin K antagonists, like warfarin, are beneficial in patient populations with nonvalvular atrial fibrillation and increased risk of stroke. However, the increased monitoring, dosing adjustments, and food and drug interactions, among other requirements, certainly demonstrated a need for a more convenient and manageable patient therapy.

Rivaroxaban was targeted in this study as a once daily anticoagulant with the potential to provide a more consistent, predictable and convenient therapy as opposed to warfarin. The study compared rivaroxaban with dose-adjusted warfarin in patients with the previously mentioned indications for the prevention of stroke and systemic embolism.

Patients were identified as having a moderate-to-high risk of stroke if they had a history of previous stroke, transient ischemic attack or systemic embolism (SE) with either heart failure, left ventricular ejection fraction < 35 percent, hypertension, diabetes or were at least 75 years of age.21 Patients were then randomly assigned to either receive a fixed once daily dose of rivaroxaban in the evening (20 mg or 15 mg based on CrCl of 30 to 49 mL/min) or adjusted warfarin (target INR 2.0-3.0). The primary endpoints included hemorrhagic or ischemic stroke and systemic embolism. Secondary endpoints consisted of stroke, SE or death from cardiovascular causes; a composite including the previous or MI; and individual components of the endpoints. Safety endpoints measured were composites of major and minor bleeding.

Primary analysis was used to conclude rivaroxabanâ&#x20AC;&#x2122;s noninferiority to warfarin, and secondary analysis was used to conclude superiority.

Over a span of three years, 14,264 patients were randomized.21 The median age of patients was 73 years, and patients also had substantial comorbid conditions including hypertension, heart failure and diabetes. The per-protocol population demonstrated significant differences in the primary outcome of stroke or systemic embolism (P<0.001). In the rivaroxaban group, only 188 events occurred in the 6,958 patients representing 1.7 percent/year, as opposed to 241 events of the 7,004 patients in the warfarin group (2.2 percent/year). Relevant nonmajor bleeding occurred in 1,475 patients in the rivaroxaban group and 1,449 patients in the warfarin group, but the difference was not clinically significant (P=0.44). Major bleeding rates also occurred at similar rates between the two treatment groups (P=0.58). Fatal

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bleeding rates of intracranial hemorrhage were significantly lower in patients of the rivaroxaban group (0.5 percent versus 0.7 percent; P=0.02)). Decreases in hemoglobin and major gastrointestinal bleeding were more common in the rivaroxaban group than in the warfarin group. In evaluation of the secondary outcomes in the as-treated population, MI and death occurred less frequently in the rivaroxaban group than the warfarin group, but the difference was not clinically significant. Results were similar in the intention-to-treat analysis of secondary outcomes. Findings concluded that rivaroxaban was noninferior to warfarin in primary analysis. In the analysis of patients receiving at least one dose of study drug, rivaroxaban was found to be superior to warfarin.

Rivaroxaban dosing is specific for each individual indication.

For the treatment of DVT and PE, it is recommended that the patient initially be started on 15 mg twice daily with food for 21 days, and then the patient should have their dose modified to 20 mg daily with food.22 For the prevention of recurrent DVT and PE after six months of treatment, the suggested regimen is 20 mg once daily with food. For postoperative DVT thromboprophylaxis, it is recommended that therapy be initiated after hemostasis has been established six to 10 hours postoperatively. In knee replacement, the recommended dosage is 10 mg once daily for 12 to 14 days (maximum 35 days). For hip replacement, 10 mg once daily is appropriate for 10 to 14 days (maximum 35 days). In the treatment of nonvalvular atrial fibrillations, 20 mg once daily with the evening meal is recommended. In cases of DVT and PE prophylaxis and treatment, dose reduction is recommended in older adults with CrCl between 30 and 50 mL/min. If the CrCl is <30 mL/min, avoid use of rivaroxaban. In patients with nonvalvular atrial fibrillation, no dosage adjustment is necessary if the CrCl is >50 mL/min. If the CrCl is 15 to 50 mL/min, a dose reduction to 15 mg is recommended. Use is discouraged if the CrCl is <15 mL/min or if the patient has end stage renal disease (ESRD) requiring dialysis. Beer’s criteria recommend a dose reduction in patients over the age of 65 years with CrCl between 30 and 50 mL/min and discourage use in patients with CrCl <30 mL/min.

There is strong evidence to support the use of rivaroxaban in patients with atrial fibrillation and at least one additional stroke risk factor.20 Newer agents like rivaroxaban are indicated for this condition due to the fact that routine lab monitoring is not required, which has become a key advantage for this therapy. It has been proven to be as effective as warfarin in this indication. Common side effects of rivaroxaban include bleeding, nausea and fatigue.22 Renal function should be monitored at baseline and regularly during therapy.20 Rivaroxaban has a black box warning stating that patients with nonvalvular atrial fibrillation may have an increased risk of thrombotic events if therapy is discontinued without adequate tapering of therapy through use of additional anticoagulation. Additionally, this warning states that patients who are receiving neuraxial anesthesia or are undergoing spinal puncture have an increased risk of epidural or spinal hematoma while taking rivaroxaban. This medication is contraindicated in patients with hypersensitivity to rivaroxaban

38

or pathological bleeding. Rivaroxaban therapy is not recommended in those patients who are pregnant or breastfeeding.

One of the disadvantages of rivaroxaban over warfarin, aside from increased cost, is that there is currently no specific reversal agent for rivaroxaban in the event of severe hemorrhage.23 Upon suspected bleed associated with rivaroxaban, further evaluate the patient for signs and symptoms of blood loss, and consider the need for blood or blood products if necessary. Partial reversal has been seen in healthy volunteers after administration of prothrombin complex concentrates. One study demonstrated that prothrombin complex concentrates (Cofact) nearly neutralized the anticoagulant effects of rivaroxaban in healthy patients. However, further research needs to be targeted in this area.24 Apixaban Apixaban (Eliquis®) is also a factor Xa inhibitor approved by the FDA in 2012.20 Apixaban is indicated for the prevention of SE and stroke in patient populations with nonvalvular atrial fibrillation. It can also be used for the treatment of DVT and PE, as well as thromboprophylaxis of postoperative DVT. Apixaban provides an advantage over warfarin due to warfarin’s narrow therapeutic range, drug-drug and drug-food interactions, and required monitoring.

Apixaban inhibits formation of fibrin clots and platelet activation through direct reversible inhibition of both the free and bound form of factor Xa.25 It is predominantly metabolized in the liver by CYP3A4/5 enzymes and interacts with p-glycoprotein. Due to its metabolism by this enzyme, there are specific drug interactions with other inducers of CYP3A4 and p-glycoprotein.20 Avoid apixaban in combination with CYP3A4 inducers like carbamazepine, phenytoin and rifampin. It is not recommended in patients with severe liver impairment, active pathological bleeding, prosthetic heart valves and those pregnant or breastfeeding. Additionally, use of nonsteroidal anti-inflammatory drugs and clopidogrel should be avoided with apixaban due to increased risk of bleeding.

In the ARISTOTLE trial, a randomized, double-blind, doubledummy trial, patients were randomly assigned either apixaban or dose-adjusted warfarin.26 The objective of this study was to prove the noninferiority of apixaban as compared to warfarin in reducing the incidence of stroke in patients with nonvalvular atrial fibrillation and at least another risk factor.

Secondary outcomes were death from any cause and rate of MI. Patients enrolled in this study had at least two documented episodes of atrial fibrillation or atrial flutter by electrocardiogram. Other risk factors included age of at least 75 years, previous incidence of stroke, transient ischemic attack, heart failure, diabetes or hypertension. This trial also measured the safety outcome of major bleeding as well as whether apixaban was superior to warfarin with respect to reduction of stroke and reduction in major bleeding.

Apixaban was given twice daily in either 2.5 mg or 5 mg doses.26 There was a significant difference in death between the apixaban and warfarin treatment groups. The rate of death in

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the apixaban group was 3.52 percent as compared to 3.94 percent in the warfarin group (p=0.047). Stroke or SE occurred in 212 patients in the apixaban group and 265 patients of the warfarin group, showing that apixaban demonstrated a significant lower incidence of the primary outcomes (p<0.001). Hemorrhagic stroke was 49 percent lower in the apixaban group than the warfarin group. Ischemic stroke was 8 percent lower in the apixaban group than the warfarin group. Approximately 84 patients in the apixaban group experienced fatal or disabling stroke as compared to 117 patients in the warfarin group (p=0.01). Secondary outcomes also showed similar differences among treatment groups.

Death from any cause (3.52 percent versus 3.94 percent), rate of death from cardiovascular events (1.80 percent versus 2.02 percent) and rate of death from noncardiovascular events (1.14 percent vs. 1.22 percent) was significantly lower in the apixaban group than warfarin group.

The rate of MI was lower in the apixaban group, but the difference was not statistically significant (P=0.37).26 Major bleeding occurred at a statistically significantly higher rate in the warfarin group than the apixaban group (p<0.001). According to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria for bleeding, there was a greater reduction in risk of bleeding in the apixaban group.

Fewer patients experienced intracranial hemorrhage and overall major bleeding in the apixaban group than the warfarin group. Rates of adverse events were similar among groups. Overall, this study concluded that there was a significant reduction in risk of stroke or SE in treatment with apixaban over treatment with warfarin. No unexpected side effects were noted in the apixaban group. While the authors noted that warfarin is still extremely efficacious in the prevention of stroke in patients with atrial fibrillation, they identified that apixaban did not have many of the issues seen in warfarin therapy. The dose that was most efficacious for the prevention of stroke in these study patients was 5 mg twice daily. This study concluded that apixaban was noninferior to warfarin in preventing the primary outcomes.

Apixaban is normally dosed at 5 mg twice daily for atrial fibrillation.20 It is recommended that the dose be reduced to 2.5 mg twice daily if the patient is 80 years of age or older, has a bodyweight of 132 pounds or less or has a serum creatinine level of 1.5 mg/dL or above. Currently there is no data for dosing in patients on dialysis with a CrCl < 15 mL/min or patients with liver impairment. For the treatment of DVT and PE 10 mg twice daily for seven days followed by 5 mg twice daily maintenance is recommended.25 To reduce the risk of recurrence of DVT and PE, 2.5 mg twice daily is recommended for at least six months following treatment for DVT. In postoperative prophylaxis, initiate 2.5 mg twice daily 12 to 24 hours postoperatively in both knee and hip replacement.

The most common adverse effect of apixaban is bleeding.

However, clinically relevant bleeding comprises only a small portion of this adverse event.20,25 Similar to rivaroxaban, there is no specific reversal agent for apixaban at this time. 20 The clinician and patient should monitor for signs of bleed-

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ing during treatment. Currently, studies are being conducted to investigate potential reversal agents in patients receiving this therapy.24 We should expect to see more research on this topic in the future.

Apixaban is best suited for patients who are unable or unwilling to adhere to the monitoring parameters associated with vitamin K antagonists like warfarin.27 While warfarin requires strict monitoring of specific blood parameters, apixaban does not require such monitoring. This criteria should be considered when selecting the appropriate therapy for patients eligible for anticoagulation therapy.

Role of the Pharmacist With the recent approval of advanced anticoagulation therapy, the pharmacist must make it a priority to keep up to date on changes.28 Additionally, the pharmacist must be able to identify the advantages and disadvantages of newer therapies as compared to traditional therapies like warfarin in making patient specific recommendations. Refer to Table 1 as a guide in recommending appropriate anticoagulation therapy. Pharmacists certainly continue to play a large role in management of patients requiring anticoagulation therapy. For pharmacists specifically working in the area of anticoagulation, such as clinics, a national certification exam is available through the National Certification Board for Anticoagulation Providers. Pharmacists will continue to play a crucial role in assessing patients for appropriate therapy and adjusting accordingly to provide exceptional patient care.

Impact of Patient Care and Counseling Points Anticoagulation therapy provides a large area for pharmacist intervention. Anticoagulation therapy is common, especially in patients suffering from congenital heart defects, heart valve replacements, surgery and other heart and coagulation related disorders.29 Patients receiving anticoagulation therapy who become pregnant need to take special precautions and be monitored. The cardiologist and the obstetrician of the patient should address her specific and individualized management.

While frequent monitoring is a drawback of warfarin use, some competent, well-controlled patients may be eligible to self-monitor their INR at home.20 Point-of-care monitors, which are normally used in clinics and physiciansâ&#x20AC;&#x2122; offices, may be provided to patients for home use. Patient selftesting has demonstrated an increase in INR control, decreased thromboembolic events, improved quality of life and patient satisfaction with treatment. Self-testing may not be appropriate in all patients taking warfarin. Patients should not be considered for self-testing if they do not demonstrate competency, are treated with warfarin for less than six months, have atypical INR target ranges, have intellectual impairment, have a known drug or alcohol problem or have language barriers that would impede with communication. It is important to consider these criteria when deciding if a patient is eligible for self-monitoring of INR. Table 2 identifies important counseling points for pharmacists for each individual therapy. It is crucial to educate these

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Table 1. Comparison of Anticoagulation Therapy for Pharmacist Recommendation. 6,10,13-14 Anticoagulant

Dosing

FDA Approved Indications

Monitoring

Once daily; with or without food10

Prophylaxis and treatment of thromboembolic disorders and embolic complications arising from Afib or cardiac valve replacement; adjunct to reduce risk of systemic embolism after myocardial infarction.10

No dosage adjustment necessary.10 However, patients with renal failure have an increased risk of bleeding complications; monitor closely.

INR should be monitored at least every one to four weeks.10 When products that affect warfarin are initiated, discontinued, or taken irregularly, additional INR testing should be performed.

Once daily; with food

DVT prophylaxis and treatment; PE prophylaxis and treatment; nonvalvular Afib

DVT & PE: CrCl > 30 mL/min - no dose adjustment Avoid use in CrCl < 30 mL/min Nonvalvular Afib: CrCl > 50 mL/min - no dose adjustment CrCl 15 to 50 mL/min, reduce dose to 15 mg once daily with evening meal.

Avoid use if CrCl < 15 mL/min Postoperative thromboprophylaxis: CrCl > 50 mL/min - no adjustment Use with caution in CrCl 30 to 50 mL/min Avoid use in CrCl < 30 mL/min

Routine lab monitoring not required

Twice daily; with or without food

DVT prophylaxis and treatment; PE prophylaxis and treatment; nonvalvular Afib

DVT & PE: No dose adjustment

Routine lab monitoring not required

Nonvalvular Afib: sCR < 1.5 mg/dL no adjustment necessary unless > 80 years of age and body weight < 60 kg - reduce dose to 2.6 mg twice daily. sCr > 1.5 mg/dL and either > 80 years of age or body weight < 60 kg 2.5 mg twice daily

Not recommended in severe liver impairment

Twice daily; with or without food

DVT treatment and prophylaxis; nonvalvular AFib; postoperative thromboprophylaxis

CrCl > 30 mL/min - no adjustment unless CrCl , 50 mL/min and patient is receiving concomitant P-gp inhibitors - avoid coadministration

Routine monitoring not required. Can use aPTT, ECT or TT if desired

Warfarin

Rivaroxaban

Apixaban

Dabigatran

Renal dosing

Avoid use if CrCl <30 ml/min

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Table 1 (continued). Comparison of Anticoagulation Therapy for Pharmacist Recommendation. 6,10,13-14 Reversal Agent

Adverse Effects

Interactions

Procedure Considerations

Vitamin K, and in severe bleeding complications PCC or FFP is also used6,10,13

Increased risk for bleeding10

Many drug and food interactions, but dose can be adjusted for interactions.10

Hold 5 days prior to surgery.10 If urgent procedure, may administer low-dose IV or oral vitamin K. Continue warfarin during minor dental and dermatological procedures or cataract surgery.

No specific reversal agent May consider PCC, activated PCC or recombinant factor VIIa

Fatigue, nausea, increased bleeding risk

CYP3A4 and P-gp drug interactions

Longer cessation may be required based on clinical judgment

Do NOT use dialysis

No specific reversal agent

Hold 24 hours prior to surgery

Bleeding, nausea, bruising

CYP3A4 and P-gp drug interactions

Hold 24 to 48 hours prior to surgery

Hemorrhage, dyspepsia

P-gp drug interactions

CrCl â&#x2030;Ľ50 mL/minute: Hold 1 to 2 days prior to surgery CrCl <50 mL/minute: Hold 3 to 5 days prior to surgery Consider holding more than 5 days before major surgery spinal puncture, or insertion of a spinal or epidural catheter or port

May consider PCC, activated PCC or recombinant factor VIIa for major bleeding Do NOT use dialysis Activated charcoal may be used if ingestions within 2-4 hours of presentation

Idarucizumab

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Table 2. Counseling Guide for Pharmacists in Anticoagulation Therapy. 10,14,22,25 Anticoagulant Therapy

Indication The medication is used to treat blood clots and is used to thin the blood so more clots will not form.

Warfarin

Monitoring/ Expectations The patient may notice more bleeding or bruising.

Common side effects include fatigue, nausea or abdominal pain.

This medication can cause severe bleedingâ&#x20AC;&#x201D;itâ&#x20AC;&#x2122;s important to monitor for signs of extreme bruising and bleeding like bloody stools, blood in the urine, excessive dizziness and severe weakness.

If the patient falls and/or hits their head, advise patient to seek medical attention immediately.

This medication requires frequent blood work monitoring (INR) by the physician. It is important to keep these appointments.

The medication is used to treat blood clots and is used to thin the blood so more clots will not form.

The patient may notice more bleeding or bruising.

Spinal or epidural procedures are more likely to have bleeding issues in that area. While this effect is rare, if it does happen it can cause paralysis in some cases. Consult physician.

Risk of bleeding is increased with aspirin or NSAIDs.

Rivaroxaban

While there is no routine monitoring for this drug, it is important to have regular blood work done.

If the patient falls and/or hits their head, advise patient to seek medical attention immediately.

The medication is used to treat blood clots and is used to thin the blood so more clots will not form.

Apixaban

The patient may notice more bleeding or bruising.

Other common side effects of this medication include nausea and anemia.

Spinal or epidural procedures are more likely to have bleeding issues in that area. While this effect is rare, if it does happen it can cause paralysis in some cases. Consult physician.

Risk of bleeding is increased with aspirin or NSAIDs. While there is no routine monitoring for this drug, it is important to have regular blood work done.

If the patient falls and/or hits their head, advise patient to seek medical attention immediately.

The medication is used to treat blood clots and is used to thin the blood so more clots will not form.

Dabigatran

The patient may notice more bleeding or bruising.

Other common side effects of this medication include upset stomach or heartburn.

Spinal or epidural procedures are more likely to have bleeding issues in that area. While this effect is rare, if it does happen it can cause paralysis in some cases. Consult physician.

Risk of bleeding is increased with aspirin or NSAIDs. While there is no routine monitoring for this drug, it is important to have regular blood work done.

If the patient falls and/or hits their head, advise patient to seek medical attention immediately.

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Missed Dose If a dose is missed, take the dose as soon as patient thinks of it if on the same day as the missed dose.

If it is close to the time of the next dose, skip to missed dose and go back to normal schedule.

Do not take extra doses or more than one dose in the same day.

Don’t stop taking this medication unless directed by a doctor.

Stopping the drug increases risk of blood clots.

For dosing 15 mg twice daily and miss a dose, take the missed dose as soon as patient thinks of it to get 30 mg in for the day. In this case, the patient can take two doses at the same time. Return to normal time the following day.

For all other doses: If a dose is missed, take the dose as soon as patient thinks of it if on the same day as the missed dose. If it is close to the time of the next dose, skip to missed dose and go back to normal schedule. Do not take extra doses or more than one dose in the same day.

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Other Precautions The patient may notice bleeding of the gums or bleeding while shaving. Recommend a soft bristle toothbrush or electric razor.

Inquire about new medications or dietary supplements.

Many foods may interact with this medication. Keep the diet consistent to minimize fluctuations in lab values.

Avoid excessive consumption of leafy greens, green tea and alcohol.

The patient may notice bleeding of the gums or bleeding while shaving. Recommend a soft bristle toothbrush or electric razor.

Take this medication with food and a full glass of water in the evening.

There are no food interactions with this medication.

Don’t stop taking this medication unless directed by a physician.

Stopping the drug can increase risk of blood clots.

If a dose is missed, take the dose as soon as patient thinks of it if on the same day as the missed dose.

If it is close to the time of the next dose, skip the missed dose and go back to normal schedule.

Do not take extra doses or more than one dose in the same day.

The patient may notice bleeding of the gums or bleeding while shaving. Recommend a soft bristle toothbrush or electric razor.

Take this medication with or without food.

There are no food interactions with this medication.

Don’t stop taking this medication unless directed by a physician.

Stopping the drug can increase risk of blood clots.

If a dose is missed, take the dose as soon as patient thinks of it if on the same day as the missed dose.

If it is less than 6 hours until the next dose, skip the dose and return to normal schedule.

Do not take extra doses or more than one dose in the same day.

Don’t stop taking this medication unless directed by a physician.

Stopping the drug can increase risk of blood clots.

The patient may notice bleeding of the gums or bleeding while shaving. Recommend a soft bristle toothbrush or electric razor.

Take this medication with or without food and with a full glass of water.

Do not store this medication in a pill box or organizer.

It is important to leave this medication in its original container.

Throw away any unused capsules after four months.

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patients to manage their conditions and reduce their risk of stroke and other cardiovascular events.

Economic Concerns The cost of these new anticoagulant medications is offset by both adverse effect mitigation and the economic impact of cardiovascular events such as stroke. In 2008, an alarming 780,000 patients experienced a stroke, costing an estimated $65.5 billion. While it is important to note that not all strokes are caused by atrial fibrillation, prevention of stroke secondary to atrial fibrillation through anticoagulation therapy is crucial. The economic burden of bleeding in patients receiving anticoagulation therapy is limited in comparison to the costs associated with stroke. In 2011, studies estimated the cost of these bleeding events to be around $35,000; however, the severity of the bleed will ultimately determine the true impact.

For over a decade, warfarin therapy has consistently been more cost-effective compared to aspirin therapy.30 Warfarin is cost-effective in patients at least 65 years of age with atrial fibrillation and at least one additional risk factor for stroke.

These risk factors include history of transient ischemic attack (TIA), hypertension, diabetes and heart disease. Even in patients without additional risk factors for stroke, the costeffectiveness of warfarin over aspirin remains high.

Dabigatran is certainly more expensive than warfarin due to a higher acquisition cost, raising the question of whether or not it is a cost-effective option as compared to warfarin.30 One model studied the cost-effectiveness of dabigatran using CHADS2 score based on the presence or absence of risk factors. Dabigatran 150 mg dosed twice daily was determined to be cost-effective in patients older than 65 years who had at least one point based on their CHADS2 score with no contraindications against dabigatran therapy. However, 110 mg daily was not determined to be cost-effective.

Another model by Shah and Gage estimated the cost of dabigatran at approximately $9 per day.30 Cost-effectiveness was measured over 20 years of treatment. In patients with a CHADS2 score of 0, aspirin was preferred over dabigatran therapy in terms of cost-effectiveness. In patients with a CHADS2 score of 1 or 2, warfarin was preferred over dabigatran unless the patient was at high risk of bleeding or was rarely within therapeutic range while on warfarin. If the patient had a CHADS2 score of 3 or higher, 150 mg of dabigatran was preferred in terms of cost-effectiveness. This recommendation stands regardless of bleeding risk or time within target INR. Dabigatran dosed at 110 mg twice daily was determined not to be cost-effective in this model. The third model studying the cost-effectiveness of dabigatran compared dosing of 150 mg in patients who had previously experienced a stroke or TIA. This study determined that 150 mg twice daily was not cost-effective as compared to warfarin.

Rivaroxabanâ&#x20AC;&#x2122;s cost-effectiveness was studied in patients at a high risk of stroke.30 Over a time period of 35 years or until death, it was found that rivaroxaban 20 mg daily is more

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cost-effective than warfarin therapy if the patient was at least 65 years of age and at a high risk of stroke. The authors noted that this effectiveness was also sensitive to change in risk of stroke.

Apixabanâ&#x20AC;&#x2122;s cost-effectiveness was studied in three separate models.30 In the first Markov model, the cost-effectiveness of apixaban was studied compared to aspirin in patients 70 years of age with atrial fibrillation, high risk of stroke, low risk of bleeding or not suitable for warfarin therapy. Apixaban was more costly than aspirin in the first year. However, after 10 years the data showed a reversal in this conclusion.

Apixaban became more cost-effective over longer periods of time. The second Markov model studied the costeffectiveness of apixaban compared to warfarin in patients 65 years of age with atrial fibrillation and a CHADS2 score of 2. Apixaban was determined to be more cost-effective over a timeline of 35 years. In a third model, the subject of study was the cost reduction of clinical events such as major bleeding associated with anticoagulation oral therapy. It was determined that the medical cost reduction was significantly more with newer anticoagulation therapy compared to warfarin. The yearly medical cost of these events with dabigatran, rivaroxaban and apixaban were $1,905; $1,995; and $1,598, respectively, versus $2,084 with warfarin.

Future of Anticoagulation Therapy In the future, pharmacists should expect to see further advancements in anticoagulation. Specifically, studies are currently being conducted to potentially identify a reversal agent for rivaroxaban and apixaban.24 While there have been numerous advancements in medications in the last two decades, it is expected that there will be an increased focus on disease prevention and patient safety with this therapy. This focus is primarily due to quality care assessments and their direct impact on hospital accreditation and reimbursement.

Overall, anticoagulation therapy provides a number of opportunities for drug development, further improvements in disease state management and promotion of health care professional collaboration.

References 1. Indiana Hemophilia & Thrombosis Center, Inc. [Internet]. Indianapolis (IN): Indiana Hemophilia & Thrombosis Center, Inc.; c2011-2012.

Blood Clot Formation (Thrombosis); [cited 2016 Feb 27]; [about 5 screens]. Available from:www.ihtc.org/patient/blood-disorders/clot ting-disorders/thrombosis/.

2. Holbrook A, Schulman S, Witt DM, et al. Evidence-Based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012 Feb; 141(2):e152Se184S. 3. American Society of Hematology [Internet]. Washington (DC): American Society of Hematology. Blood Clots; [cited 2016 Feb 27]; [about 8 screens]. Available from: www.hematology.org/Patients/Clots/.

4. Hirsh J, Anand SS, Halperin JL, et al. Guide to anticoagulant therapy: heparin A statement for health care professionals from the American Heart Association. J Am Heart Assoc. 2001 June 19; 103:2994-3018.

5. DiPiro, JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors.

Pharmacotherapy: a pathophysiologic approach [Internet]. New York: McGraw-Hill; 2014 [cited 2016 Apr 23]. Available from:0-access pharmacy.mhmedical.com.polar.onu.edu/Content.aspx?bookId=689& sectionId=48811458.

6. Oâ&#x20AC;&#x2122;Reilly RF, Burgess IA, Zicat B. The prevalence of venous thromboem-

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bolism after hip and knee replacement surgery. Med J Aust. 2005 Feb 21;182(4):154-159.

National Heart, Lung, and Blood Institute [Internet]. Bethesda (MD): National Heart, Lung, and Blood Institute; [updated 2014 Sep 18; cited 2016 Feb 27]; [about 3 screens]. Available from:www.nhlbi.nih.gov/ health/health-topics/topics/af/types.

Coumadin (warfarin sodium) [package insert on the Internet]. BristolMyers Squibb; [updated 2011 Oct; cited 2016 Feb 27]. Available from: packageinserts.bms.com/pi/pi_coumadin.pdf.

Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol. 2008 Mar 18; 141:757-63.

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer. c19782016. Warfarin; [cited 2016 Feb 27]; [about 32 screens]. Available from: 0-online.lexi.com.polar.onu.edu/lco/action/doc/retrieve/docid/ patch_f/7879.

Barnes GD, Kline-Rogers E. Engaging with quality improvement in anticoagulation management. J Thromb Thrombolysis. 2015 Feb 11;39:403-409.

American Heart Association [Internet]. Dallas (TX): American Heart Association; c2016. Anticoagulation; [updated 2015 Aug 21; cited 2016 Feb 27]; [about 2 screens]. Available from: www.heart.org/ HEARTORG/Conditions/CongenitalHeartDefects/TheImpactofCongeni talHeartDefects/Anticoagulation_UCM_307110_Article.jsp#.VtO3q8e5P wy.

Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for health care professionals from the American Heart Association/ American Stroke Association. J Am Heart Assoc [Internet]. 2015 July [cited 2016 Mar 31];[30 p.]. Available from:stroke.ahajournals.org/ content/early/2015/05/28/STR.0000000000000069.full.pdf.

Lexicomp [Internet]. Hudson (OH). Wolters Kluwer. 2016 [cited 2016 Feb 22]. Available from:0-online.lexi.com.polar.onu.edu/lco/action/ home.

Schulman S, Kearon C, Kakkar A, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10; 361:24.

Schulman S, Kakkar A, Goldhaber S, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. J Am Heart Assoc. 2014 Feb 18; 129:764-772.

Schulman S, Kearon C, Kakkar A, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21; 368:8.

Pollack C, Reilly P, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015 Aug 6; 373:6.

U.S. Food and Drug Administration: FDA approved drug products [Internet]. Rockville (MD): U.S. Food and Drug Administration. Drug approval reports; [updated 2013 Mar 7; cited 2013 Mar 22]. Available from:www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm 467396.htm.

Wigle P, Hein B, Bloomfield HE, Tubb M, Doherty M. Updated guidelines on outpatient anticoagulation. Am Fam Physician. 2013 Apr 15; 87 (8):556-66.

Patel M, Mahaffey K, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Eng J Med. 2011 Sep 8; 365(10):883-91.

Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. c1978-2016. Rivaroxaban; [Updated 2016 Mar 28]; [about 5 screens]. Available from: 0online.lexi.com.polar.onu.edu/lco/action/doc/retrieve/docid/patch_ f/1275239#f_dosages.

XareltoÂŽ (rivaroxaban) tablets [package insert on the internet]. Titusville (NJ): Janssen Pharmaceuticals; [updated 2014 Dec; cited 2016 Feb 26]. Available from:www.xareltohcp.com/shared/product/xarelto /medication-guide.pdf.

Erenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. Circulation. 2011 Oct 4; 124(14):1573-9.

Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. c1978-2016. Apixaban; [Updated 2016 Mar 28]; [about 5 screens]. Available from:0online.lexi.com.polar.onu.edu/lco/action/doc/retrieve/docid/patch_f/ 3804162.

Granger CB, Alexander JH, McMurray JV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Eng J Med. 2011 Sep 15; 365(11):981-92.

Connolly S, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al.

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Apixaban in patients with atrial fibrillation. N Eng J Med. 2011 Mar 3; 362(9):981-92.

28. Smythe MA. Advances in anticoagulation management: the role of pharmacy. Ann Pharmacother. 2007; 41(3):493-5.

29. American Heart Association [Internet]. Dallas (TX): American Heart Association; c2016. Anticoagulation; 2015 Aug 21 [cited 2016 Feb 24]; [about 2 screens]. Available from:www.heart.org/HEARTORG/Condi tions/CongenitalHeartDefects/TheImpactofCongenitalHeartDefects/ Anticoaglation_UCM_307110_Article.jsp#.VtMuPlKNTzI. 30. Von Scheele B, Fernandez M, Hogue SL, Kwong WJ. Review of economics and cost-effectiveness analyses of anticoagulant therapy for stroke prevention in atrial fibrillation in the US. Ann Pharmacother. 2013 May; 47:671-85.

The authors have no conflict of interest or funding support to disclose.

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Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach Morgan Homan, Haval Norman, Victoria Cho, Yousif Rojeab, Ph.D.

Abstract Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCB1 has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is still inconclusive as to which variations are correlated with drug response. Current genotypic guidelines are largely proactive and clinical trials utilizing genotypic dosing have shown significant reductions in side effects and health care costs. Further studies of genotypic targets are needed and, if the possible clinical benefits are confirmed, the use of genotyping will be an important tool in optimizing antidepressant therapy.

Key Terms ABCB1 Protein, Human; Antidepressants; Tricyclic; Cytochrome P450 CYP2C19; Cytochrome P450 CYP2D6; Depression; Depressive Disorder, Major; Genotype; Health care Costs; Mental Health; p-glycoprotein; Pharmacogenetics; Psychotherapy; Serotonin Uptake Inhibitors Depression Background The National Institute of Mental Health (NIMH) defines major depressive disorder (MDD) as “severe symptoms that interfere with your ability to work, sleep, study, eat and enjoy life. An episode may occur only once in a person’s lifetime, but more often a person has several episodes.”1 Depression can be caused by a multitude of factors, a few of which include environmental, genetic, psychological and biological influences.

Patients with MDD typically experience a low quality of life.2 Often, depressed patients experience a decrease in physical, social and role functioning more than individuals with other chronic conditions such as diabetes or osteoarthritis. Patients with MDD often report poor intimate relationships, poor social interactions and social irritability. These individuals typically have a greater household or financial strain as well. It is also common for depression patients to experience limitations in the workplace, exhibit poor overall health and have a higher level of missed days of work.

Major depressive disorder is the most prevalent mental health disorder in the United States.3 It is estimated that 6.7

46

percent of adults in the United States experienced a major depressive episode in 2014. The female population was more likely to experience these episodes (8.2 percent) versus the male population (4.8 percent). Major depressive episodes were also more prevalent in adults aged 18 to 25 years (9.3 percent) compared to adults aged 26 to 49 years (7.2 percent) and those aged 50 years and older (5.2 percent). The prevalence of MDD was even greater in adolescents aged 12 to 17 years (11.4 percent) than in adults in 2014. In this adolescent age group, the female population was also more likely to experience a major depressive episode (17.3 percent) than males (5.7 percent). Prevalence in adolescents increased with age. Twelve-year-olds had a prevalence of 5.7 percent while 17-year-olds had a prevalence of 15.1 percent.

While MDD varies between patients, the NIMH identifies several signs and symptoms that may indicate the onset of depression.1 A few of these include feelings of hopelessness, pessimism, guilt, worthlessness, fatigue, decreased energy, insomnia and persistent sad, anxious or empty feelings. A depressed patient may also experience thoughts of suicide, have difficulty concentrating, making decisions and remembering details.

The diagnosis criteria for MDD has been described by the American Psychiatric Association (APA) in the fifth edition of the Diagnostic and Statistic Manual of Mental Disorders (DSM-5).4 The diagnosis criteria are summarized in Table 1.

It is important to note that an individual responding to a significant loss, such as financial or loss of a loved one, may exhibit some of the criteria specified in section A of Table 1; therefore, the medical professional’s clinical judgment must be exercised to determine if this constitutes a major depressive episode.

Upon diagnosis of MDD, the APA recommends psychiatric management which includes establishing and maintaining a therapeutic alliance.5 The patient should undergo a psychiatric assessment and be evaluated for safety, functional impairment and quality of life. The patient’s care should be coordinated with other clinicians, and his or her psychiatric status should be monitored. The health care team should integrate measurements into psychiatric management, assist with treatment adherence and provide education to the patient and the family.

The acute phase of MDD treatment begins with the initiation of treatment.5 This often constitutes the introduction of pharmacotherapy but may also include depression-focused psychotherapy, a combination of the two, electroconvulsive

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Table 1. Diagnostic Criteria of Major Depressive Disorder (MDD).4 A. The patient must demonstrate at least five of the following symptoms, which must have been present almost every day during a consecutive 14-day period. It is important to point out that these symptoms must demonstrate a change from the patient’s normal functioning. These symptoms may be given as a subjective report or as observed by others. Several of the diagnosis criteria may present differently in children as noted below.

The patient must demonstrate at least one of the following.

 Depressed mood for the majority of the day. (Note: In children and adolescents, may

present as irritable mood.)

 Noticeably decreased interest or pleasure in all, or nearly all, activities for the majority

of the day.

The patient must demonstrate at least four of the following.

 Notable weight loss when not attempting to diet or weight gain or change in appetite.

(Note: In children, may present as failure to make expected weight gain.)

 Insomnia or hypersomnia.

 Psychomotor agitation or retardation (this criterion must be noted by others and not

solely based on subjective feelings of the patient of uneasiness or being slowed down).

 Fatigue or lack of energy.

 Feelings of inadequacy or excessive or inappropriate guilt (which may be deranged),

not solely self-blame or guilty feelings about being sick.

 Decreased ability to think, concentrate or make decisions.

 Frequent thoughts of death that expand beyond fear of dying, periodic suicidal

thoughts without a definitive plan, a suicide attempt or a definitive plan for committing suicide.

B. The symptoms must cause a significant distress or impairment in normal daily functions such as social, occupational or other important areas of operation.

C. The symptoms exhibited must not be attributed to any other factor such as the psychological effects of a substance or a symptom of another medical condition.

D. The major depressive episode as expressed above must not be better attributed to a psychotic disorder, including schizophrenic disorders.

E. The patient must not have experienced a manic or hypomanic episode. The exception to this criterion is if the episode can be attributed to another medical condition.

Adapted from: American Psychiatric Association: Desk Reference to the Diagnostic Criteria from DSM-5. Arlington (VA): American Psychiatric Association; 2013. Major Depressive Disorder; p. 94-95.

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Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach

therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. For patients with mild to moderate MDD, the APA recommends an antidepressant as initial treatment. In individuals with severe MDD, the APA deems an antidepressant necessary for treatment unless the patient plans to undergo ECT. The medications initially recommended for depression patients include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine, or bupropion. The individual agent, however, may be chosen based on anticipated side effects, patientâ&#x20AC;&#x2122;s ability to tolerate the drug, safety considerations targeted to the individual patient and pharmacologic properties of the drug itself. These properties include the half-life, drug-drug interactions and the drugâ&#x20AC;&#x2122;s action on cytochrome P (CYP) 450 enzymes. Monoamine oxidase inhibitors (MAOIs) are typically reserved for patients who do not respond to first-line treatments.

Careful monitoring should occur during the acute phase, and dosage or drug modifications should be made based on side effects or adverse events.5 When assessing the efficacy of an agent in a particular patient, the medication should be discontinued after one month if the patient shows no signs of symptomatic improvement. If a patient is unresponsive or only partially responsive after four to eight weeks, the drug and dose should be adjusted and reevaluated in another four to eight weeks. When adjustments are necessary, the dose is titrated first as long as the patient has not experienced any adverse events and the side effects are well-tolerated. If a dose adjustment does not demonstrate any improvement, the patient may be prescribed a different medication either from the same class or another class of antidepressants. A patient is considered to be in the acute phase of treatment until he or she has demonstrated a response to medication. A response may not appear with the first treatment choice, so the acute phase is not limited to a specific time frame and may continue for an extended period of time.

Once a patient has demonstrated some success with an agent in the acute phase, he or she moves on to the continuation phase.5 Here, the patient is monitored for potential relapse while on the medication initiated with success in the acute phase. This drug is typically continued for four to nine months, and the APA recommends depression-focused psychotherapy for prevention of relapse. A patient may move onto the maintenance phase of therapy using the same agent he or she used in the acute and continuation phases with success, but the medication may be adjusted to a full therapeutic dose. The maintenance phase is strongly recommended for patients who have high risk factors for recurrence of a major depressive episode. These risk factors may include family history of depression or mood disorders, presence of psychosocial triggers or appearance of lingering symptoms. Maintenance treatment continues indefinitely unless a patient and physician come to the decision to discontinue treatment. If pharmacologic treatment is discontinued, the dose should be tapered to prevent relapse and discontinuation symptoms.

The patient should also be counseled on the signs of a relapse and have a plan in place if such an incident occurs.

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Monitoring of the patient should continue for several months after discontinuation.

While there are many options for initiating antidepressant therapy, adverse effects and poor efficacy often lead to a game of trial and error. This can waste money and time on an ineffective agent. It often takes at least one month to determine if the chosen treatment will be successful in a particular patient, so it may take months to years for a patient to find the right medication in the acute treatment phase to control his or her MDD. Genomic testing can help determine how a patient will react pharmacokinetically and pharmacodynamically to a particular drug and increase the likelihood of choosing an effective drug therapy at the initiation of treatment.

CYP2D6 and CYP2C19 PK/PG The CYP2D6 and CYP2C19 genes code for members of the CYP450 liver enzymes, which are heavily involved in the metabolism of many antidepressant medications.6,7 CYP2D6 metabolism influences clearance of the SSRIs fluvoxamine and paroxetine and, also, tricyclic antidepressants (TCAs) such as amitriptyline, clomipramine, desipramine, imipramine, nortriptyline and trimipramine. CYP2C19 metabolism is observed with SSRIs including citalopram, escitalopram and sertraline, as well as TCAs like amitriptyline, clomipramine, imipramine and trimipramine.

Both CYP2D6 and CYP2C19 have numerous polymorphisms in the population, with some alleles coding for decreased or increased activity compared to the standard function seen in the most common genotypes.6,7 Combinations of these alleles result in several phenotypic classes: poor, intermediate, extensive and ultrarapid metabolizers. Two of the primary concerns are that poor metabolizers build up higher plasma concentrations of antidepressants and may be at greater risk of toxicities and side effects, while ultrarapid metabolizers may be more likely to experience treatment failure if plasma concentrations are too low. Pharmacogenomic guidelines have been developed and published for many SSRIs and TCAs to adjust dosage or recommend alternative therapies. However, the clinical significance for these guidelines is still being debated and is additionally complicated by an uncertain dose -response relationship of antidepressant medications.

A pair of studies by Hodgson and colleagues with information from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP) questioned the association of pharmacogenomic dosing and SSRI/TCA side effects and treatment response.8,9 The first study examined 223 patients on escitalopram and 161 patients on nortriptyline using a pragmatic design and flexible dosing protocol, where serum antidepressant concentration was assessed 8 weeks after treatment.8 Patients were additionally genotyped. Variation in CYP2C19 significantly correlated with escitalopram concentration (p=9.35*10-9), while CYP2D6 genotype was significantly associated with nortriptyline levels (p=1.90*10-6).

Neither genotyping nor serum concentration was significantly related to treatment response for either medication. The

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second study examined the connection between CYP450 genotype and side effects with escitalopram and nortriptyline.9 No significant association was found between genotype and side effects; serum concentration significantly predicted only a few minor effects, including the risk of dry mouth (p= 0.0107), diarrhea (p=4.96*10-4) and dizziness (p=3.28*10-5) with escitalopram, and dry mouth (p=0.0331) with nortriptyline. The authors acknowledged possible bias from the pragmatic design and flexible dosing, recognizing limited application of the results and the need for further study. This study demonstrates, again, that CYP genotyping is ineffective for predicting patient response.

ABCB1 PK/PG The ABCB1 gene codes for the amino acid transporter P-glycoprotein (P-gp) in many organs, including brain capillary endothelial cells where it drives out substrates and helps maintain the blood-brain barrier (BBB).10 Many drug classes, including the TCAs, SSRIs and SNRI venlafaxine are substrates for P-gp and have limited uptake into the brain because of this efflux activity. Because of this limitation, genetic variation in ABCB1 could result in altered P-gp function and clinically significant changes in antidepressant distribution to the brain.

A 2015 meta-analysis by Breitenstein and colleagues examined 16 pharmacogenetic studies associating ABCB1 variants and antidepressant outcomes for MDD patients (n = 2,695). 10 A total of six single nucleotide polymorphisms (SNPs) were separately analyzed based on all studies, inpatient samples, outpatient samples, Caucasian only samples and without comedication sub-groups. The SNP rs2032583 was associated with treatment outcomes across all studies (p = 0.035) and among all inpatient subjects (p = 1.5*10 -5), while SNP rs2235015 was associated with treatment outcomes only among all inpatient subjects (p = 3.0*10 -4). Both of those SNPs were intronic, meaning they did not alter the protein structure of P-gp but may modify brain delivery of antidepressants through unknown mechanisms. It was noted that the majority of the studies included did not have fixed dosages but were adjusted based on patient condition. If drug doses were decreased because of side effects, P-gp activity and BBB penetration may have been reduced and remain undetected.

Schatzberg and colleagues genotyped 10 ABCB1 SNPs in 683 MDD patients, including all six SNPs analyzed in the Breitenstein meta-analysis.11 Patients were randomized to treatment with escitalopram, sertraline or venlafaxine ER for at least two weeks (576 subjects completed eight weeks of therapy), with treatment efficacy assessed by the 16-item Quick Inventory of Depressive Symptomatology- Self Rated (QIDS-SR). Only SNP rs10245483 was significantly associated with prediction of remission (Wald statistic W=12.64, p<0.001, odds ratio OR=3.48). Common allele (G) homozygotes had significantly better response to escitalopram (p=0.032) and sertraline (p=0.020) than minor (T) allele homozygotes, which had significantly better response to venlafaxine (p=0.018); heterozygote genotypes had no significant differences across treatment. Similarly, major allele

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carriers had less adverse effects with escitalopram (p=0.037) while venlafaxine was associated with fewer side effects in minor allele homozygotes (p=0.017). The T minor allele has been reported to cause higher P-gp expression and may cause increased SSRI clearance, causing the observed, decreased efficacy. Venlafaxine activity as an SNRI may explain why it was more effective with minor alleles. The researchers acknowledged limitations in that serum drug concentrations were not collected and how as a pragmatic study the dosages were slightly lower than traditionally used in clinical drug trials, which could have altered response.

Clinical Applications While pharmacogenomic data continue to be collected, many challenges remain in identifying factors significant to treatment outcomes. In addition to the studies specifically examining the genes coding for CYP enzymes or P-gp transporters, several genome-wide association studies have attempted to detect genetic variations connected with antidepressant outcome in MDD. The three largest were the GENDEP project, the Munich Antidepressant Response Signature (MARS) project and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.12 A meta-analysis of data by the investigators of the three studies, including 2,256 subjects of Northern European descent with MDD, tested 1.2 million SNPs for association with symptom reduction and remission for up to 12 weeks of antidepressant therapy. No individual variant met significance criteria in the main analysis, suggesting antidepressant success to be likely due to numerous minor genetic effects instead of one primary pathway. However, the analysis was limited by the absence of placebo groups in any of the three studies as well as by the heterogeneity of the trials, and the authors concluded that larger cohorts of systemically treated and observed subjects were needed to conclusively test the approach.

Despite the inability to precisely identify the genetic regions associated with antidepressant response, there is some evidence suggesting genotypic-dosing may be a cost-effective tool in antidepressant treatment dosing. A one-year retrospective study of antidepressant therapy was conducted by Winner and colleagues in 2013, where 96 depressive or anxiety disorder subjects were tested for CYP2D6, CYP2C19, CYP2C9, CYP1A2, SLC6A4 and 5HTR2A genotypes.12 Subjects had their medication and genotype combinations categorized as “red-bin,” “yellow-bin” or “green-bin” based on the degree of caution and monitoring required as developed by the AssureRx Health GeneSight, a genotype interpretive report.13 Nine subjects were categorized as red bin, with 48 yellow and 39 green. Compared to the green or yellow bin, subjects with a medication in the red bin had 69 percent more total health care visits during the year (p= 0.014). Also, nonpsychiatric medical visits were 67 percent higher for the red bin (p= 0.039). While red bin assignment was associated with greater numbers of psychiatric medications, there was no correlation between the number of drugs taken and any of the dependent measures, suggesting increase in health care utilization was directly related to red bin status. The authors concluded that pharmacogenomic information can better

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define treatments and increase therapeutic response as well as decrease costs.

A 2015 study by Singh and colleagues provided buccal swabs for DNA analysis to 148 subjects with MDD, but only half were randomized to genotypic testing for CYP2D6, CYP2C19 and ABCB1 polymorphisms with dosing guided by the results.14 Remission rates were assessed by the Hamilton Depression Rating Scale (HDRS) every four weeks for 12 weeks, with rating blinded to treatment groups. Remission from MDD was 2.52 times more likely with the guided treatment (95 percent confidence interval (CI): 1.71-3.73, p<0.0001), while the unguided group was 1.13 times more likely to experience treatment intolerability issues (95 percent CI: 1.01-1.25; p=0.0272). The guided group also had significantly lower risk of requiring sick leave (4 percent versus 15 percent, p=0.0272) and shorter length of leave (4.3 days versus 7.7 days, p=0.014). However, the trial results were not strati-

fied by medication prescribed or genetic profile, so extrapolation of findings to specific drugs or polymorphisms is not possible.

Genotypic Guidelines There are currently no dosing guidelines for ABCB1 genotypes, but the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for SSRIs and TCAs based on CYP2D6 and CYP2C19 genotypes.7,8 Their recommendations are compiled in Table 2 and Table 3.

Conclusion Major depressive disorder is one of the most common mental illnesses in the United States. A large range of therapeutic options, significant adverse effects and a complex dose-response relationship contribute to the uncertainty in optimizing antidepressant therapy. Pharmacogenomics has attempted to explain some of the variability observed, but

Table 2. CYP2D6 Phenotypic Guidelines for Antidepressant Drugs.6,7 Drug

Poor Metabolizers

Intermediate Metabolizers

Extensive Metabolizers

Ultra-rapid Metabolizers

TCAs: Amitriptyline, Nortriptyline, Clomipramine, Desipramine, Imipramine, Trimipramine

*4/*4, *4/*5, *5/*5, *4/*6 Avoid due to potential for side effects, consider alternatives not metabolized by CYP2D6. If used, consider 50% reduction of recommended starting dose (S).

*4/*10, *5/*41 Consider 25% reduction of recommended starting dose (M).

*1/*1, *1/*2, *2/*2, *1/*41, *1/*4, *2/*5, *10/*10 Initiate therapy with recommended starting dose (S).

*1/*1xN, *1/*2xN Avoid due to potential lack of efficacy, consider alternatives not metabolized by CYP2D6. If used, consider increasing starting dose (S).

Fluvoxamine

*3/*4,*4/*4, *5/*5, *5/*6 Consider a 25-50% reduction of recommended starting dose or use an alternative drug not metabolized by CYP2D6 (O).

*4/*10,*4/*41, *5/*9 Initiate therapy with recommended starting dose (M).

*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41 Initiate therapy with recommended starting dose (S).

*1/*1xN, *1/*2xN, *2/ *2xN No recommendation due to lack of evidence (O).

Paroxetine

*3/*4,*4/*4, *5/*5, *5/*6 Select alternative drug not metabolized by CYP2D6, or consider a 50% reduction of recommended starting dose (O).

*4/*10,*4/*41, *5/*9 Initiate therapy with recommended starting dose (M).

*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41 Initiate therapy with recommended starting dose (S).

*1/*1xN, *1/*2xN, *2/ *2xN Select alternative drug not metabolized by CYP2D6 (S).

Recommendation strength: S-strong, M-moderate, W-weak, O-optional Adapted with permission from John Wiley and Sons, Inc., from Hicks et al. Clin Pharmacol Ther. 2013 May;93(5):402-8.Š 2013 American Society for Clinical Pharmacology and Therapeutics.

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The Pharmacy And Wellness Review Summer 2016 Volume 7, Issue 3

Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach

Drug Abuse Pharmacogenomics

Table 3. CYP2C19 Phenotypic Guidelines for Antidepressant Drugs.6,7

Drug

Poor Metabolizers

Intermediate Metabolizers

Extensive Metabolizers

Ultra-rapid Metabolizers

SSRIs: Citalopram, Escitalopram, Sertraline

*2/*2, *2/*3, *3/*3 Consider a 50% reduction of starting dose or select alternative drug not metabolized by CYP2C19 (M).

*1/*2, *1/*3, *2/*17 Initiate therapy with recommended starting dose (S).

*1/*1 Initiate therapy with recommended starting dose (S).

*17/*17, *1/*17 Initiate therapy with recommended starting dose, consider alternative drug not metabolized by CYP2C19 (M).

TCAs: Amitriptyline, Clomipramine, Imipramine, Trimipramine

*2/*2, *2/*3, *3/*3 Consider a 50% reduction of recommended starting dose or select alternative drug not metabolized by CYP2C19 (O).

*1/*2, *1/*3, *2/*17 Initiate therapy with recommended starting dose (S).

*1/*1 Initiate therapy with recommended starting dose (S).

*17/*17, *1/*17 Initiate therapy with recommended starting dose, consider alternative drug not metabolized by CYP2C19 (O).

Recommendation strength: S-strong, M-moderate, W-weak, O-optional Adapted with permission from John Wiley and Sons, Inc., from Hicks et al. Clin Pharmacol Ther. 2015 Aug;98(2):127-34. Š 2015 American Society for Clinical Pharmacology and Therapeutics, and Hicks et al. Clin Pharmacol Ther. 2013 May;93(5):402-8.Š 2013 American Society for Clinical Pharmacology and Therapeutics.

current data are unable to provide specific mechanisms. The metabolic enzyme activity of CYP2D6 and CYP2C19 has been shown to be connected to the plasma concentration of many antidepressants, but the clinical response to antidepressants does not necessarily have a linear relationship to drug concentration; guidelines for CYP2D6 and CYP2C19-based dosing are largely proactive and unconfirmed. While ABCB1 has been examined for its involvement in drug delivery to the brain, there is inconclusive evidence on which variations are significantly associated with antidepressant response.

Further studies are needed to identify significant genetic pathways. While early trials already indicated possible efficacy of genotype-guided drug therapy, further analyses will be required to confirm its benefit. Given the high long-term cost of treating depression, and further health care costs if treatment fails, even modest improvements in patient response could justify the use of genotyping.

References 1. National Institute of Mental Health [Internet]. Bethesda (MD): National Institute of Health. Depression [cited 22 Feb 2016]; [about 4 screens].

Available from:www.nimh.nih.gov/health/topics/depression/index.sht ml.

2. Papakostas GI, Petersen T, Mahal Y, Mischoulon D, Nierenberg AA, Fava M. Quality of life assessments in major depressive disorder: a review of the literature. Gen Hosp Psychiatry. 2004;26:13-17.

3. National Institute of Mental Health [Internet]. Bethesda (MD): National Institute of Health. Prevalence [cited 23 Feb 2016]; [about 4 screens].

Available from:www.nimh.nih.gov/health/statistics/prevalence/index. shtml.

4. American Psychiatric Association: desk reference to the diagnostic criteria from DSM-5. Arlington (VA): American Psychiatric Association;

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2013. Major depressive disorder; p. 94-95.

American Psychiatric Association practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington (VA): American Psychiatric Association; 2010 Oct. p.152.

Hicks JK, Bishop JR, Sangkuhl K, Muller DJ, Ji Y, Leckband SG, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015 Aug;98(2):127-34.

Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013 May;93(5):402-8.

Hodgson K, Tansey K, Dernovsek MZ, Hauser J, Henigsberg N, Maier W, et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. 2014 Feb;28(2):133-41.

Hodgson K, Tansey KE, Uher R, Zvezdana D, Mors O, Hauser J, et al.

Exploring the role of drug-metabolising enzymes in antidepressant side effects. Psychopharmacology (Berl). 2015 Jul;232(14):2609-17.

Breitenstein B, Bruckl TM, Ising M, Muller-Myhsok B, Holsboer F, Czamara D. ABCB1 gene variants and antidepressant treatment outcome: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2015 Jun;168B(4):274-83.

Schatzberg AF, DeBattista C, Lazzeroni LC, Etkin A, Murphy GM Jr, Williams LM. ABCB1 genetic effects on antidepressant outcomes: a report from the iSPOT-D trial. Am J Psychiatry. 2015 Aug 1;172(8):751-9.

Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry. 2013 Mar 19;3:e242.

AssureRx health, Inc. Mason, OH. www.assurerxhealth.com.

Singh AB. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Clin Psychopharmacol Neurosci. 2015 Aug 31;13(2):150-6.

The authors have no conflict of interest or funding support to disclose.

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Drug Abuse

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The Pharmacy And Wellness Review Summer 2016 Volume 7, Issue 3