Issuu

JULY/AUGUST 2019

TIME FOR CARE

SRX PHARMACY: A CHAIN BUILT ON 360° PHARMACEUTICAL CARE

Helping cancer patients quit smoking

PRE-DIABETES: WHAT NOW? “ It’s very rewarding— every day, I feel we make a difference in someone’s life.” Stephanie Gysel, clinical pharmacist and pharmacy manager at SRx Pharmacy in Calgary

CanadianHealthcareNetwork.ca

Addiction care a rewarding niche

1.0 CEU

Managing bipolar disorder

You Will Never Regret Good Advice

has acquired has acquired

Fournier Drugs Ltd. MNP Corporate Finance Inc. acted as exclusive ﬁnancial advisor to Clareview Drug Mart in structuring and negotiating this transaction.

MNP Corporate Finance Inc. acted as exclusive ﬁnancial advisor to Fournier Drugs Ltd. in structuring and negotiating this transaction.

You’ve built a legacy. Make sure you unlock its full value before taking down the shingle. Rofael Corporation

Tap into MNP’s proven expertise helping clients successfully divest their pharmacy business and

has acquired

has acquired Manitoulin’s Family of

Guardian

PHARMACIES

achieve their financial and personal goals. We

Manitowaning - Little Current - Mindemoya

draw on our broad network and relationships

MNP Corporate Finance Inc. acted as exclusive ﬁnancial advisor to Manitoulin’s Family of Guardian Pharmacies in structuring and negotiating this transaction.

with a variety of buyers to maximize your options and opportunities for success.

Contact Brett Franklin President, MNP Corporate Finance 204.336.6190 brett.franklin@mnp.ca

Regent Park Pharmacy

“We Care For You”

MNP Corporate Finance Inc. acted as exclusive ﬁnancial advisor to Regent Park Pharmacy in structuring and negotiating this transaction.

Contents

JULY / AUGUST 2019 [VOL.6 NO.6] PAGES 25-32 CE LESSON

Managing bipolar disorder 1.00 CEU

BY COLETTE RAPHAEL

EDITOR’S MESSAGE

DRUG NEWS

Minding the gap, and your business BY VICKI WOOD

A review of new launches, new indications, new dosage forms, discontinued drugs and Health Canada Advisories BY LU-ANN MURDOCH

PRACTICE EXPERTS

Therapeutic Issues: Update on C. difficile treatment and prevention BY JILLIAN REARDON Practical Diabetes: Pre-diabetes—an indicator for change BY SHELLEY DIAMOND

5 TIPS

CLINICAL FEATURE

ON THE COVER

35 37 38

ERRATUM: Since the CE lesson Optimizing Diabetes Pharmacy Consultations in the Digital Age was published in the June 2019 issue, it has come to our attention that in sections where the author described the blood glucose meters that feature mobile application capabilities currently available, the list was not representative of all of the brands on the market. One such meter is the AccuChek® Guide meter and the mySugr mobile application. Readers should note that this CE is not intended to be a comprehensive list of current meters on the market, so further research is encouraged.

Launching sexual health services in community practice BY ANDREW SCHONBE Helping patients with cancer quit smoking BY SHIRIN ABADI

The Innovators: SRx: New chain’s business model builds in time for specialty care BY SONYA FELIX PHOTOGRAPHY BY COLIN WAY

FINDING YOUR NICHE Addiction care

BY ROSALIND STEFANAC

CLASSIFIEDS

Employment opportunities and services

BACK TALK

BizTalk: How to gauge employee engagement BY DEREK DESROSIERS ILLUSTRATION BY SPENCER FLOCK

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@PharmacyPracticePlusBusiness

[Vol.6 No.6] JULY/AUGUST 2019

BETTER TOGE+HER #

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EDITOR’S MESSAGE

Minding the gap, and your business

ON THE HEELS OF OUR JUNE FEATURE, The Pharmacists’ Dilemma (which outlined the ways in which pharmacists are increasingly feeling stressed, under-paid, over-worked, burnt out and yet at the same time, professionally under-utilized), the Specialty Rx solutions/SRx Pharmacies concept is like a breath of fresh air. As you’ll read in our cover story (starting on page 33), in establishing the model for his growing national pharmacy chain, Adesh A. Vora looked for care and business gaps that weren’t being filled by other pharmacy interests. Rather than enter an already crowded arena and try to compete on speed, price or volume, Vora recognized that there was a space in the market for highlevel, personalized, specialty pharmacy care particularily focused on those with chronic diseases. Granted, those patients with highly individualized pharmaceutical needs, managing life with a health condition, and often on a complex regime of rare and specialty PHARMACY PRACTICE + BUSINESS PRESIDENT, ENSEMBLEIQ CANADA Jennifer Litterick jlitterick@ensembleiq.com GROUP BRAND DIRECTOR, HEALTHCARE Donna Kerry dkerry@ensembleiq.com VICE PRESIDENT/ GENERAL MANAGER EVENTS Michael Cronin mcronin@ensembleiq.com EDITOR Vicki Wood vwood@ensembleiq.com CONSULTING CLINICAL EDITOR Lu-Ann Murdoch, BScPhm VICE PRESIDENT, PRODUCTION Derek Estey ART DIRECTOR Nancy Peterman PRODUCTION MANAGER Lisette Pronovost

drugs, are fewer in number than the typical senior or family who flock to their neighbourhood pharmacy to fill scripts for more commonly dispensed drugs. They also absorb more time and resources, in terms of pharmaceutical care, long-term monitoring and follow up, and the administrative support required to stickhandle reimbursement and reporting. Allowing that time is a justifiable operational cost, says Vora: “We have created a model that allows us the time needed to support those patients in need with better outcomes.” And by no means is specialty pharmacy care an altruistic business concept. Building a national chain of them is actually a brilliant financial strategy. Pharmaceutial companies manufacturing rare, extremely high-cost specialty drugs are keen to work with pharmacies that can smooth the path towards compliance for the patients who need them. Vora seems to have tapped into a winwin-win situation: one in which patients

DIRECTOR OF MARKETING Alex Voulu CONTINUING EDUCATION/ PROJECT MANAGER/PROOFREADER Rosalind Stefanac WEB OPERATIONS MANAGER Valerie White AUDIENCE DEVELOPMENT MANAGER Lina Trunina ltrunina@ensembleiq.com SALES & EVENTS COORDINATOR Claudia Castro BRAND DIRECTOR Martin Rissin mrissin@ensembleiq.com SENIOR ACCOUNT MANAGERS, TORONTO Norman Cook ncook@ensembleiq.com Scott Tweed stweed@ensembleiq.com

ACCOUNT MANAGERS, QUÉBEC Ted Georgaros tgeorgaros@ensembleiq.com Nancy Dumont ndumont@ensembleiq.com COLUMNISTS AND CONTRIBUTING/CONSULTING EDITORS Derek Desrosiers, BSc(Pharm), RPEBC, RPh; Shelley Diamond, BScPhm; Sherilyn Houle, BSP, PhD; Sandra Knowles, BScPhm; Lu-Ann Murdoch, BScPhm; Nardine Nakhla, PharmD; Carlene Oleksyn, BSP Pharm, CTH; Vikas Parihar, BScBiochem, BScPharm, PharmD; Jillian Reardon, BSc(Pharm), ACPR, PharmD, RPh; Rosalind Stefanac; Karen Welds

get the best possible care and access to the medications that improve their quality of life; the business model is stable and lucrative, and the chain’s pharmacists and pharmacy technicians have the opportunity to work at the peak of their professional capabilities, using their skills to make a real difference in patients’ lives. If Stephanie Gysel is representative of the pharmacists working in this model, being encouraged to spend more time with individual patients—in a community pharmacy environment—is a game changer. Says Gysel: “I leave every day feeling good about my job.” Wouldn’t it be nice to hear that sentiment from more pharmacists? NOTE: At the end of The Pharmacists’ Dilemma feature, we promised a sequel article examining the factors that enable some community pharmacists to work happily at the peak of their scope of practice. That feature will run in the September issue.

CORPORATE OFFICERS EXECUTIVE CHAIRMAN Alan Glass CHIEF EXECUTIVE OFFICER David Shanker CHIEF FINANCIAL OFFICER Dan McCarthy CHIEF OPERATING OFFICER Joel Hughes CHIEF INNOVATION OFFICER Tanner Van Dusen CHIEF HUMAN RESOURCES OFFICER Ann Jadown EXECUTIVE VICE PRESIDENT, EVENTS & CONFERENCES Ed Several

Pharmacy Practice + Business, established in 1985, is published 10 times a year by EnsembleIQ, 20 Eglinton Ave. West, Suite 1800, Toronto, ON, M4R 1K8 Phone: 877.687.7321 Fax: 888.889.9522. Website: CanadianHealthcareNetwork.ca. Montreal Office: 1425 René Lévesque ouest, 2e étage, Montréal Quebec, H3G 1T7. Pharmacy Practice + Business is abstracted in International Pharmaceutical Abstracts (IPA). Subscriptions: $98.00 per year, 2 year $156.00, Outside Canada $156.00 per year, Single Copy $12.00, Groups $69.00, Outside Canada Single Copy $16.00. Pharmacy Practice + Business is published 10 times per year except for occasional combined, expanded or premium issues, which count as two subscription issues. Mail Preferences: Occasionally we make our subscriber list available to reputable companies whose products or services may be of interest to you. If you do not want your name to be made available please contact us at contactus@canadianhealthcarenetwork.ca. Contents copyright © 2019 by EnsembleIQ; may not be reprinted without permission. EnsembleIQ does not assume liability for content. Pharmacy Practice + Business receives unsolicited materials (including letters to the editor, press releases, promotional items and images) from time to time. Pharmacy Practice + Business, its affiliates and assignees may use, reproduce, publish, re-publish, distribute, store and archive such unsolicited submissions in whole or in part in any form or medium whatsoever, without compensation of any sort. ISSN 08-29-2809.

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[Vol.6 No.6] JULY/AUGUST 2019

DRUG NEWS

A REVIEW OF NEW LAUNCHES, NEW INDICATIONS, NEW DOSAGE FORMS AND HEALTH CANADA ADVISORIES

CLINICAL EDITOR

LU-ANN MURDOCH, RPh, BScPhm, ACPR is a

consulting clinical editor for Pharmacy Practice +Business and drug information consultant for Pharmacist’s Letter.

NEW PRODUCTS Libtayo: for cutaneous squamous cell carcinoma cemiplimab 50 mg/mL concentrate for solution for infusion; 250 mg/5 mL and 350 mg/7 mL single-use vials, Sanofi-aventis.

INDICATIONS Treatment of metastatic

or locally advanced cutaneous squamous cell carcinoma in adults who are not candidates for curative surgery or curative radiation. Received Notice of Compliance with conditions for this indication, pending the results of additional clinical trials to verify the drug’s clinical benefit. ACTION A recombinant human immunoglobulin G4 monoclonal antibody. Binds to programmed cell death 1 (PD-1) on T cells and blocks its interaction with the ligands PD-L1 and PD-L2. This counters PD-1 mediated inhibition of the immune response, including the antitumour immune response. DOSAGE 350 mg every three weeks administered as an intravenous (IV) infusion over 30 minutes. Continued until there is symptomatic disease progression or unacceptable toxicity. Alternate dose in patients with a low body weight: 3 mg/kg every two weeks. No dose adjustment is recommended for patients with mild or moderate renal impairment. Insufficient data in patients with hepatic impairment. Dosing delay or discontinuation (but not 6

dosage reductions) may be required to manage adverse effects; consult product monograph for details. ADVERSE EFFECTS MOST COMMON: Fatigue, rash, pruritus, diarrhea, hypothyroidism, infusion-related reactions, increase in liver enzymes, pneumonitis. MOST SERIOUS: Immunemediated conditions: pneumonitis, colitis, hepatitis, endocrinopathies (hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, type 1 diabetes), skin adverse reactions, nephritis. Infusion-related reactions (can be severe or life-threatening). DRUG INTERACTIONS No studies have been conducted. STORAGE Store in the refrigerator (2°C–8°C). Keep in original carton until time of use to protect from light.

Lorbrena: for metastatic nonsmall cell lung cancer lorlatinib 25 mg and 100 mg tablets, Pfizer.

INDICATIONS Monotherapy for the

treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic nonsmall cell lung cancer. Intended for patients who have progressed on crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib. Received Notice of Compliance with conditions for this indication, pending the results of additional clinical trials to verify the drug’s clinical benefit.

JULY/AUGUST 2019 [Vol.6 No.6]

ACTION ALK and ROS1 tyrosine kinase

inhibitor; addresses the mechanisms of resistance following previous ALK inhibitor therapy. DOSAGE 100 mg orally once daily, taken with or without food at about the same time each day. Swallow tablets whole (do not chew, crush or split). Dosing interruption and/or dose reduction may be required based on adverse effects and tolerability. ADVERSE EFFECTS MOST COMMON: Edema, peripheral neuropathy, cognitive effects, fatigue, increase in weight, arthralgia, mood effects, diarrhea. MOST SERIOUS: Mental status changes, cognitive effects, mood effects, speech effects, hallucinations, hypercholesterolemia, hypertriglyceridemia, pneumonitis, hepatotoxicity, PR interval prolongation and atrioventricular block, increase in pancreatic enzymes, edema, peripheral neuropathy. DRUG INTERACTIONS Contraindicated with strong CYP3A inducers (e.g., rifampin, carbamazepine, enzalutamide, phenytoin, St. John’s wort) due to increased risk of serious hepatotoxicity; discontinue strong CYP3A inducers for three plasma half-lives before starting lorlatinib. Avoid concomitant use with moderate CYP3A inducers; if concomitant use can’t be avoided, monitor liver enzymes (AST, ALT) and bilirubin 48 hours after starting lorlatinib and at least three times during the first week of therapy. Strong CYP3A inhibitors (e.g., boceprevir, itraconazole, posaconazole, ritonavir, telaprevir, voriconazole) may increase lorlatinib concentrations; avoid combination if possible or lorlatinib dose reduction is recommended. Avoid grapefruit products.

Verzenio: for advanced or metastatic breast cancer abemaciclib 50 mg, 100 mg, 150 mg and 200 mg tablets, Eli Lilly.

INDICATIONS Treatment of hormone

receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Can be used in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy; in combination with fulvestrant in women with disease progression following endocrine therapy (pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone [GnRH] agonist); or as a single agent in women with disease progression following endocrine therapy and at least two prior chemotherapy regimens. ACTION Inhibits cyclin D-dependent kinases 4 and 6. Prevents retinoblastoma protein (Rb) phosphorylation, leading to suppression of tumour growth. In estrogen receptorâ€“positive breast cancer cell lines, prevents rebound of Rb phosphorylation and cell cycle re-entry, resulting in cell death. When dosed daily (as a single agent or in combination with antiestrogens), results in a reduction in tumour size. DOSAGE In combination with aromatase inhibitor or fulvestrant: 150 mg orally twice daily. As a single agent: 200 mg orally twice daily. Dosing interruption, dose reduction and/or permanent discontinuation may be required to manage certain adverse reactions. For all indications, continue treatment until disease progression or unacceptable toxicity occurs. Discontinue if patient is unable to tolerate 50 mg twice daily. ADMINISTRATION Take with or without food at about the same times every day. Swallow tablets whole; do not chew, crush or split. ADVERSE EFFECTS MOST COMMON: Diarrhea, neutropenia, fatigue, infections, nausea, vomiting, abdominal pain, decreased appetite, anemia, alopecia, leukopenia, headache, thrombocytopenia. MOST SERIOUS: Venous thromboembolism, including deaths. Diarrhea, neutropenia, hepatotoxicity, infections (some fatal). Monitor complete blood counts and liver function tests before starting therapy, every two weeks for the first two months, monthly for the next two months, and then as clinically indicated. DRUG INTERACTIONS Abemaciclib is primarily metabolized by CYP3A4 to several active metabolites. Avoid concomitant use of strong CYP3A inhibitors (e.g., voriconazole); use caution with moderate (e.g., ciprofloxacin) or weak (e.g., ranitidine) CYP3A inhibitors.

If co-administration with a CYP3A inhibitor is unavoidable, consult product monograph for guidance on adjusting the abemaciclib dose. Avoid concomitant use of strong CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, St. Johnâ€™s wort). Avoid grapefruit products.

daily for four weeks as tolerated. Should not be applied around the eyes, in the nose or mouth, or to mucous membranes (can cause local inflammation and ulceration).

NEW DOSAGE FORMS Tasigna

OTHER NEW PRODUCTS Stramucin mupirocin 2% cream (as mupirocin calcium); 15 g and 30 g tubes, Glenmark Pharmaceuticals Canada.

(nilotinib capsules), Novartis. New 50 mg capsule joins the original 150 mg and 200 mg capsules. The 50 mg capsule is available only through the Alliance Patient Support Program (1-855-4894362). See also New Indications section.

Tremfya One-Press (guselkumab 100 mg/1 mL solution for injection), Janssen. New patient-controlled, single-dose injector joins the original Tremfya (guselkumab 100 mg/1 mL solution) prefilled syringe.

INDICATION Treatment of adults with

INDICATIONS Topical treatment of

secondarily infected traumatic lesions (e.g., small lacerations, sutured wounds, abrasions) in patients 18 months of age or older. Not suitable for ophthalmic or intranasal use. DOSAGE Using a cotton swab or gauze pad, apply a small amount of cream to the affected area three times daily for up to 10 days. Treated area may be covered with a dressing. Wash hands before and after application.

Tolak fluorouracil 4% topical cream, as fluorouracil sodium; 40 g tube, Hill Dermaceuticals.

moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. DOSAGE 100 mg by subcutaneous injection at Week 0 and Week 4, then every eight weeks thereafter. ADMINISTRATION Take carton out of the refrigerator at least 30 minutes before injection (to allow it to reach room temperature). Remove injector from the carton and twist and pull off bottom cap. Place bottom end of patient-controlled injector flat on the skin (front of thighs [preferred] or lower abdomen), push the handle straight down until a click is heard and the teal-coloured body is no longer visible, then lift device straight up off the skin (yellow band indicates that the needle guard is locked). Discard in a sharps disposal container.

NEW INDICATIONS Adcetris (brentuximab vedotin for injection), Seattle Genetics (US). Canadian distributor: McKesson Specialty Distribution.

INDICATIONS Topical treatment of

actinic keratosis lesions of the face, ears and/or scalp. DOSAGE Apply once daily as a thin film in an amount sufficient to cover the lesions of the face, ears and/or scalp. Gently massage uniformly into the skin. Wash hands well after application. Apply

EXPANDED INDICATION Treatment of

previously untreated patients with stage IV Hodgkin lymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD). (Also indicated for treatment of HL in other situations, as well as for treatment of anaplastic large cell lymphoma; consult product monograph for details.)

[Vol.6 No.6] JULY/AUGUST 2019

(New indications continued)

DOSAGE Stage IV HL in combination with

AVD: brentuximab vedotin 1.2 mg/kg (maximum 120 mg) by IV infusion over 30 minutes, in combination with AVD. Given (with granulocyte colony-stimulating factor prophylaxis) every two weeks for a maximum of 12 doses or until disease progression or unacceptable toxicity.

Hydromorphone HP 10, 20, 50 and Forte (hydromorphone hydrochloride injection), Sandoz.

NEW INDICATION Used as supervised

injectable opioid agonist therapy in adults with severe opioid use disorder who are using injectable opioids and have failed previous attempts at opioid agonist therapy. Should only be administered under the supervision of a physician experienced in treatment of severe opioid use disorder and trained in injectable opioid agonist therapy. Must be administered in facilities that allow for prompt recognition of serious adverse reactions (including potentially fatal respiratory depression) and immediate resuscitation measures. (Originally indicated only for the relief of severe pain.) DOSAGE Supervised injectable opioid agonist therapy: Initiation and titration of hydromorphone should be individualized to minimize harms, particularly those related to opioid overdose. A six-month clinical trial demonstrated the efficacy of supervised injectable hydromorphone for severe, refractory opioid use disorder. In this trial, by the end of the titration period, hydromorphone was dosed up to three times per day and supplemented with oral methadone as needed. Following titration, the average total daily dose of hydromorphone in the trial was 261 mg/day. Serious adverse events occurred during the titration phase and afterwards; therefore, patient supervision and monitoring is essential throughout treatment to minimize serious risks associated with injectable hydromorphone use. ADVERSE EFFECTS In the six-month trial, adverse events occurred in 48% of patients taking hydromorphone; 3% of patients experienced serious adverse effects. MOST COMMON: Immediate postinjection reaction, injection site pruritus, somnolence (all 16% incidence). MOST SERIOUS: Opioid overdose requiring naloxone (2% incidence). 8

Jardiance (empagliflozin tablets), Boehringer Ingelheim.

EXPANDED INDICATION Now indicated

in adults with type 2 diabetes mellitus as an add-on therapy in combination with linagliptin and metformin. (Previously approved only for use as a monotherapy or in combination with metformin, metformin and a sulfonylurea, pioglitazone [alone or with metformin], or basal or prandial insulin [alone or with metformin]. Also approved as add-on combination therapy in patients with established cardiovascular disease.) REVISED INDICATION The wording of the indication for use in patients with established cardiovascular disease has been revised as follows: Indicated as an adjunct to diet, exercise and standard care therapy to reduce the incidence of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease. (The words specifying that the drug is intended for patients with type 2 diabetes “who have inadequate glycemic control” have been removed.) DOSAGE Recommended starting dose is 10 mg once daily, with or without food. Dose can be increased to a maximum of 25 mg once daily.

Keytruda (pembrolizumab for infusion), Merck.

NEW INDICATIONS 1) Monotherapy for

adults with locally advanced unresectable or metastatic urothelial carcinoma. Intended for patients who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1, or in adults who are not eligible for any platinumcontaining chemotherapy regardless of PD-L1 status. 2) Monotherapy for adults with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer whose tumours have progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan. 3. Monotherapy for adults with unresectable or metastatic MSI-H or dMMR endometrial cancer in women whose tumours have progressed following prior therapy and who have no satisfactory alternative treatment options. Received a Notice of Compliance with conditions for these new indications, pending the results of additional clinical trials to verify the

JULY/AUGUST 2019 [Vol.6 No.6]

drug’s clinical benefit. (Also indicated for the treatment of several other conditions— consult product monograph.) DOSAGE (for all 3 new indications): 200 mg administered by IV infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Lynparza (olaparib tablets), AstraZeneca.

EXPANDED INDICATION Maintenance

treatment of adults with advanced BRCAmutated high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) to first-line platinum-based chemotherapy. (Originally approved for maintenance treatment of adults with platinum-sensitive relapsed [PSR] BRCAmutated high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response [complete or partial] to platinum-based chemotherapy. Also approved as monotherapy for the maintenance treatment of adults with PSR BRCA wild type high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer, and for treatment of metastatic breast cancer.) DOSAGE Two 150 mg tablets twice daily (total 600 mg/day). Dose reductions may be required to manage adverse effects or drug interactions. More new and expanded indications, as well as Health Canada advisories can be found in the online version of this issue at CanadianHealthcareNetwork.ca

NEW GENERICS

• Apo-Amphetamine XR Capsules (mixed salts amphetamine 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg extendedrelease capsules), Apotex. Generic alternative to Adderall XR.

NOT ALL PROBIOTICS ARE THE SAME.

IBS SYMPTOM RELIEF SUCH AS: ABDOMINAL DISCOMFORT, GAS & BLOATING

ONLY ALIGN® CONTAINS THE PATENTED PROBIOTIC STRAIN BIFIDOBACTERIUM 35624™ GENUS

SPECIES

SUBSPECIES

Biﬁdobacterium

longum

Strain Designation

STRAIN DESIGNATION

35624™ 35624

Although some store brands compare themselves to Align, none contain the same strain. Only Align contains the patented purestrain probiotic Biﬁdobacterium 35624™, which helps to relieve and manage symptoms of Irritable Bowel Syndrome.

RECOMMENDED BY GASTROENTEROLOGISTS

X MORE THAN ANY OTHER PROBIOTIC*

CAUTION: Keep out of reach of children. In case of accidental ingestion, contact your doctor or a Poison Control Centre. Do not use if you are experiencing nausea, fever, vomiting, bloody diarrhea, or severe abdominal pain. Do not use if you have an immune-compromised condition (e.g., AIDS, lymphoma, patients undergoing longterm corticosteroid treatment). Consult a doctor if symptoms of digestive upsets do not improve, or persistently worsen. To ensure this product is right for your patients, always advise the patient to read and follow the label. * Among gastroenterologists who recommended a brand of probiotic in a ProVoice 2017 survey. © 2018 P&G

PRACTICE EXPERTS

OUR PHARMACIST EXPERTS SHARE INFORMATION AND IDEAS TO SUPPORT YOUR DAILY PRACTICE

THERAPEUTIC ISSUES

JILLIAN REARDON, ACPR, PharmD, RPh, is a clinical

pharmacist and lecturer at the Pharmacists Clinic, Faculty of Pharmaceutical Sciences, University of British Columbia.

What’s the diff?

Update on C. difficile treatment and prevention Clostridium difficile (C. diff) is an opportunistic infection, proliferating when normal gut flora is disrupted.(1) C. diff infection (CDI) should be suspected in patients with new onset diarrhea (≥ 3 unformed stools in 24 hours not explained by other causes) and is confirmed by stool culture.(1) Fever and abdominal pain may also be present.(1) Of note, C. diff recently underwent a name change when the US Centers for Disease Control and Prevention reclassified Clostridium difficile to Clostridioides difficile (which continues to be abbreviated as C. difficile or C. diff).(2)

immunosuppression and gastrointestinal surgery. The incidence of CDI is rising in community-dwelling individuals without recent hospitalizations.(1)

Initial management

The most recent CDI treatment guidelines, published in 2018 by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America, mark a significant departure from previous treatment recommendations.(1) While the first step in CDI treatment remains discontinuation of the offending antibiotic(s), oral metronidazole is no longer recommended first line for nonsevere CDI infections in adults.(1) This is based on randomized controlled trials demonstrating superior cure rates with oral vancomycin compared to

Given the notable departure from using metronidazole first line in the most recent IDSA guidelines, it may be necessary to educate prescribers regarding current evidence-based treatment approaches. Antibiotic exposure is the most significant modifiable risk factor for CDI. Although CDI can occur after just one dose, risk increases with duration of therapy and use of multiple antibiotics.(1) Clindamycin is by far the antibiotic associated with the greatest risk of CDI, increasing risk by 20-fold.(1) Fluoroquinolones, cephalosporins and carbapenems are also considered high risk, with exposure increasing the risk of CDI by two- to six-fold.(3) The risk of CDI is highest within the first four weeks after antibiotics are started, but CDI can occur up to 12 weeks after antibiotic discontinuation.(3) Other important risk factors for developing CDI include age > 65, hospitalization, chronic kidney disease, 10

oral metronidazole (87% versus 78%, respectively p < 0.0008) and higher sustained cure rates at one month (73% versus 63%, respectively p < 0.003).(1,4) Fidaxomicin, a unique oral antibiotic with a narrow spectrum of activity and minimal systemic absorption, has demonstrated comparable cure rates to oral vancomycin and lower rates of recurrence one month after treatment in nonsevere and severe infections; however, its routine use is typically cost prohibitive.(1,5,6) If patients are unable to receive vancomycin or fidaxomicin due to cost, availability or intolerance, oral metronidazole can be used. A 10-day treatment course should be sufficient for any agent, but can be extended to 14 days

JULY/AUGUST 2019 [Vol.6 No.6]

in patients with incomplete symptom resolution.(1)

Recurrent infections

One in four patients will have a recurrence of CDI after being treated with oral vancomycin.(1) Evidence is sparse to inform the best approach to managing recurrences. Typically, oral vancomycin is retried followed by a slow taper (e.g., vancomycin 125 mg qid for 10–14 days, then 125 mg bid for 1 week, then 125 mg daily for 1 week, then 125 mg every 2–3 days for another 2–8 weeks).(1) Fidaxomicin can also be used in cases of recurrence, although no head-to-head trials exist to inform relative effectiveness to vancomycin.(1) Metronidazole is not recommended for recurrent CDI.(1) Subsequent recurrences may be managed similarly or with the addition of rifaximin after completing vancomycin. Fecal microbiota transplantation can be considered in patients with multiple recurrences of CDI when appropriate antibiotics have failed.(1)

Prevention

Antimicrobial stewardship and infection control are the cornerstones of prevention.(1) A review of 31 randomized controlled trials found probiotics (Saccharomyces boulardii or Lactobacillus species) to be effective in reducing the incidence of CDI in patients taking antibiotics (1.5% incidence of CDI with probiotics versus 4% for placebo or no treatment; relative risk 0.40, 95% confidence interval 0.30– 0.52). Benefit was greatest in those with an elevated baseline risk of developing CDI.(6) Probiotics have not been shown to hasten recovery in those with established CDI or to prevent recurrences.(1) Proton pump inhibitors (PPIs) have been associated with CDI in epidemiologic studies. While insufficient evidence

exists to justify stopping PPIs as a means to prevent CDI, discontinuation should be considered in patients without compelling indications for continued PPI use.(1)

PRACTICAL DIABETES

SHELLEY DIAMOND, BScPhm, is a pharmacist

and co-founder of www.diabetescarecommunity.ca, an extensive online resource for Canadians living with diabetes, their families and healthcare professionals.

Pharmacist’s role

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Pharmacists in all settings can practise antibiotic stewardship by ensuring medications with higher risk of causing CDI (e.g., clindamycin, fluoroquinolones, cephalosporins) are used appropriately, especially in at-risk patients such as the elderly and those with frequent antibiotic and/or hospital exposures. Inform patients with CDI to expect symptom resolution within three days of starting vancomycin or fidaxomicin (or 5 days with metronidazole) and emphasize the importance of completing the full antibiotic course to optimize chance of cure.(1) Educate patients and household contacts on the need to properly wash hands with soap and water; alcohol-based hand sanitizers may be insufficient to kill C. diff spores and prevent infection spread.(1) Given the notable departure from using metronidazole first line in the most recent IDSA guidelines, it may be necessary to educate prescribers regarding current evidence-based treatment approaches. Patients receiving prolonged vancomycin tapers for CDI recurrences may require close follow-up to support adherence and monitor effectiveness. Consider recommending short-term use of probiotics in patients at risk of CDI who are starting on high-risk antibiotics, and maintain vigilance in deprescribing PPIs in patients without a clear indication for ongoing acid-suppression.(1,7) REFERENCES 1. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66(7): e1-48. 2. Centers for Disease Control and Prevention. Clostridioides difficile (C. diff). December 17, 2018. https://www.cdc.gov/ cdiff/index.html (accessed May 9, 2019). 3. Deshpande A, Pasupuleti V, Thota P, et al. Community associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013;68:1951-61. 4. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014;59:345-54. 5. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281-9. 6. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31. 7. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2017; 12:CD006095.

Prediabetes—an indicator for change What is prediabetes?

Blood glucose levels that are higher than normal, but do not meet the conventional criteria for diabetes, are commonly referred to as prediabetes. Most people with prediabetes are older and have a higher body mass index, including more central fat distribution and an elevated waist-to-hip ratio. They also often have dyslipidemia and hypertension.(1)

How is prediabetes defined?

In the 2018 Canadian diabetes guidelines, prediabetes is defined as an impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or a glycated hemoglobin (A1C) of 6.0%–6.4%.(2) In comparison, the American Diabetes Association (ADA) uses different values to diagnose prediabetes, including an A1C of 5.7%–6.4%.(3)

Significance of prediabetes

Having an impaired fasting glucose, an impaired glucose tolerance or an A1C of 6.0%–6.4% may mean that individuals are at increased risk for developing diabetes and its associated complications. There are, however, differences in the subcategories of the definitions (IFG, IGT or A1C), in terms of outcomes, although the literature is not consistent on direct associations. It is suspected that IGT may

be more strongly associated with cardiovascular disease outcomes than IFG, and A1C may be more strongly associated with cardiovascular disease outcomes than either IFG or IGT. It is known that people with both IFG and IGT have a higher risk for developing diabetes, as well as cardiovascular disease, than those with either IFG or IGT alone.(2)

Controversy over “the prediabetes label”

Not all people with prediabetes will go on to develop diabetes. In fact, many people who are diagnosed with IFG or IGT will revert back to normal blood glucose levels over time. However, all individuals with prediabetes are at increased risk for cardiovascular disease (although not all are at higher risk for microvascular disease).(4-6) People with prediabetes would therefore benefit from cardiovascular risk factor modification, such as management of cholesterol, hypertension and hyperglycemia, lifestyle advice and smoking cessation. The ADA definition of prediabetes has a lower threshold compared to that used in Canada. Critics suggest that many people labelled as having prediabetes do not go on to develop diabetes and, therefore, the term prediabetes is an “over-classification.” They also contend that the broader ADA

[Vol.6 No.6] JULY/AUGUST 2019

definition expands the number of people diagnosed to extremely large numbers, which would be a burden on the healthcare system. Others feel that a diagnosis of prediabetes provides an opportunity to educate more people at higher risk, and allows for earlier interventions in order to reduce cardiovascular disease.

Help patients understand that prediabetes is a serious diagnosis

The higher A1C levels used by Canadian guidelines for defining prediabetes (compared to the ADA) means that a higher percentage of these individuals will likely develop diabetes down the road. Several clinical studies have shown that a substantial number of individuals with prediabetes will later develop diabetes, with an average annual risk of approximately 5%–10% compared with < 1% in those with normoglycemia.(7) The combination of a FPG of 6.1–6.9 mmol/L and an A1C of 6.0%–6.4% is predictive of 100% progression to type 2 diabetes over a five-year period.(8) A diagnosis of “not having diabetes now, but perhaps in the future” may not be concrete enough for individuals to grasp the importance of a prediabetes diagnosis.

In order to make this more relatable, you can look at the issue on a more personal level. By doing so, you may be able to better understand the patient’s values and goals, and thereby make something abstract seem much more concrete. Ask the patient questions about their future, such as “Do you want to continue to be active with your children or grandchildren?” or “Do you want to be around for longer in a healthier state to be with your loved ones?” This discussion will help you to understand the patient’s longer-term goals. The patient may be more willing to take your recommendations of seeing a dietitian for the purpose of weight management or looking into a gym membership or community programs. You may also want to contact the patient’s physician to discuss starting metformin, which has been shown to slow the progression from prediabetes to diabetes by approximately 30%.(2) Its impact on reducing cardiovascular complications is unclear at this time; however, it has been shown to reduce the risk of myocardial infarction in overweight individuals. Individuals who may benefit the most include those less than 60 years of age with significant obesity, as well as women who have a history of

REFERENCES 1. Haghighatdoost F, Amini M, Feizi A, et al. Are body mass index and waist circumference significant predictors of diabetes and prediabetes risk: results from a population based cohort study. World J Diabetes 2017;8:365-73. 2. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2018;42(suppl 1):S1-325. http://guidelines.diabetes. ca/cpg (accessed April 10, 2019). 3. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018. Diabetes Care 2018;41(suppl 1):S13-27. 4. Huang Y, Cai X, Mai W, et al. Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis. BMJ 2016;355:i5953. 5. Warren B, Pankow JS, Matsushita K, et al. Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol 2016;5:34-42. 6. Shaw JE, Zimmet PZ, Alberti KG. Point: impaired fasting glucose: the case for the new American Diabetes Association criterion. Diabetes Care 2006;29:1170-2. 7. Gerstein H, Santaguida P, Raina P, et al. Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic review and meta-analysis of prospective studies. Diabetes Res Clin Pract 2007;78:305-12. 8. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.

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1. Voltaren Emulgel Product Monograph. GlaxoSmithKline Consumer Healthcare. June 2, 2017. 2. Duteil L, Queille C, Poncet M, et al. Objective assessment of topical corticosteroids and non-steroidal anti-inflammatory drugs in methyl-nicotinate-induced skin inflammation. Clin Exp Dermatol 1990;15:195-199. Trademarks are owned by or licensed to the GSK group of companies. ©2019 GSK group of companies or its licensor.

JULY/AUGUST 2019 [Vol.6 No.6]

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Fight pain and inflammation without a pill1

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gestational diabetes.(2) The diagnostic criteria for prediabetes have changed over time and prediabetes definitions differ among the World Health Organization, the ADA and Diabetes Canada. Regardless of the criteria, early intervention is essential in order to delay progression to diabetes and its complications. You can make a difference!

ce August 2019

Approved for

Answer online at eCortex.ca

Continuing Education L E S S O N

1.25 CEUs Canadian Council on Continuing Education in Pharmacy

Approved for 1.25 CE units by the Canadian Council on Continuing Education in Pharmacy • CCCEP #1329-2019-2814-I-P • Please consult this course online at eCortex.ca for expiry dates

Learning Objectives

Upon successful completion of this learning activity, pharmacists will be better able to: 1. Explain the mechanism of action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) 2. Review existing and emerging efﬁcacy data for available GLP-1 RAs and their role in managing type 2 diabetes 3. Implement practical strategies around dispensing GLP-1 RAs 4. Counsel a patient beginning or continuing treatment with GLP-1 RAs

Exploring the practical use of GLP-1 RAs in type 2 diabetes By Michael Boivin, B.Sc., Phm, RPH, CDE, CTE antihyperglycemic therapy. Over the last several years—most recently in June 2019 in Canada—new data have been published on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in type 2 diabetes.

Instructions 1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. Answer online at eCortex.ca. 2. To pass, a grade of at least 70% (5 out of 7) is required. 3. Complete the required feedback form for this lesson online at eCortex.ca. Please consult this course online at eCortex.ca for expiry dates.

DISCLOSURE The author discloses that in the past he has received funds from the company sponsoring this learning activity, for previous consulting services. He has also received funds from other commercial entities for membership on advisory boards, speaking engagements or other consulting services. One of the expert reviewers discloses membership on the sponsoring company’s advisory board, and has in the past received payment to deliver presentations for the company. Both expert reviewers disclose the receipt of funds for advisory board memberships and/ or speaking engagements on behalf of other commercial entities, including competitors to the sponsoring company. The provider declares no real or potential conﬂict with the sponsor of this lesson.

Answer online at eCortex.ca

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Approximately one in three Canadians (11 million) live with prediabetes or diabetes. The number of people with diabetes will increase significantly over the next decade. People with diabetes are at increased risk of blindness, cardiovascular disease, chronic kidney disease and amputations. Notably, people with diabetes have an average lifespan that is five to 15 years shorter than the lifespan of a person without diabetes.(1) Optimal management reduces a person’s risk of developing complications from diabetes.(2) Unfortunately, only about half of this patient population is meeting glycemic targets and only 13% are reaching targets for hemoglobin A1C, blood pressure and low-density lipoprotein (LDL) cholesterol.(3) Thus, a significant proportion of patients with diabetes are at risk of developing complications. Pharmacists can play a key role in helping people with diabetes meet targets through working with them and their primary care prescribers to individualize

Incretin agents Figure 1 reviews endogenous incretins and their impact on blood glucose. GLP-1 RAs are known as incretin agents. Currently, two classes of incretin agents are available: dipeptidyl peptidase (DPP)-4 inhibitors, also known as gliptins, and GLP-1 RAs. DPP-4 inhibitors block the breakdown of endogenous GLP-1, producing physiologic levels of GLP-1. GLP-1 RAs activate the receptor in the β-cells of the pancreas and are resistant to breakdown by DPP-4, resulting in pharmacologic levels of GLP-1. GLP-1 RAs lead to a ﬁve-fold increase in GLP-1 RA activity, while DPP-4 inhibitors lead to a two-fold increase.(4) GLP-1 RAs Pharmacists should take into account a number of factors when considering GLP-1 RAs for patients. Table 1 reviews key considerations when counselling patients on these agents. Table 2 summarizes the GLP-1 RAs currently available in Canada. Key differences between GLP-1 RAs There are several key differences between the current GLP-1 RAs. These differences pertain to reduction in A1C and weight, cardiovascular (CV) outcomes and combination therapy. Fortunately, new headto-head trials demonstrate the relative difference in efﬁcacy between medications in this class.

Supported by educational funding from Novo Nordisk Canada Inc.

Continuing Education L E S S O N

Exploring the practical use of GLP-1 RAs in type 2 diabetes

CE2

TA B L E 2

Endogenous Incretin System(4)

FIGURE 1

Endogenous incretins secreted by L-cells of GI tract in response to food

TA B L E 1

August 2019

↑ Insulin secretion ↓ Glucagon secretion

↓ Blood glucose ↑ Satiety ↓ Hunger

Enzyme DPP-4 breaks down endogenous incretins

Properties of GLP-1 RAs

Answer online at eCortex.ca

Current GLP-1 RAs in Canada

Medication

Brand

Dulaglutide

Trulicity®

Exenatide twice daily

Byetta®

Exenatide once weekly

Bydureon®

Liraglutide

Victoza®

Lixisenatide

Adlyxine™

A1C lowering when added to metformin(5–7)

• 1.0-1.8%

Semaglutide

Ozempic®

Risk of hypoglycemia(6)

• Negligible (increased risk when added to insulin)

TA B L E 5

Signiﬁcant weight reduction

(5–11)

Summary of Comparison Trials

• 2.8-6.5 kg mean reduction

A1C reduction

Dosing options(5,6,8–11)

• Subcutaneous, daily or weekly

Place in therapy(5,9–11)

• Combination with lifestyle change in patients for whom metformin is inappropriate • Add-on with metformin, metformin/sulfonylurea, metformin/insulin

• Dulaglutide weekly = liraglutide daily • Liraglutide daily > exenatide weekly • Semaglutide weekly > exenatide weekly • Semaglutide weekly > dulaglutide weekly

Most common adverse effects(6)

• Nausea, vomiting, diarrhea • Rare cases of acute gallstone disease

Contraindications(6)

• Contraindicated with personal/family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

TA B L E 3

Cardiovascular Outcome Trials with GLP-1 RAs

LEADER(13) Liraglutide 1.8 mg daily

• Liraglutide was associated with: - 13% ↓ primary outcome (CV death, myocardial infarction [MI], & stroke) - 22% ↓ death from CV disease - 15% ↓ death from any cause • Superior for MACE versus placebo (p=0.01 for superiority)

SUSTAIN-6(14) Semaglutide 0.5 mg or 1.0 mg weekly

• Semaglutide was associated with: - 26% ↓ primary outcome (CV death, MI, & stroke) - Rates of CV death were similar to placebo - 39% ↓ non-fatal stroke • Superior for MACE versus placebo (p=0.02 for superiority)

EXSCEL(15) Exenatide 2 mg weekly

• Exenatide was associated with: - Non-inferiority to placebo in reducing the primary outcome (CV death, MI, stroke) - Non-signiﬁcant ↓ in the risk of death • Non-inferior for MACE versus placebo

ELIXA(16) Lixisenatide 10-20 µg daily

• Lixisenatide was associated with: - Non-inferiority to placebo in reducing the primary outcome (CV death, MI, stroke, hospitalization from unstable angina) • Non-inferior for MACE versus placebo

REWIND(17) Dulaglutide 1.5 mg weekly

• Dulaglutide was associated with: - 12% ↓ primary outcome (CV death, MI, stroke) - Non-signiﬁcant ↓ in MI and CV death - 24% ↓ in risk of non-fatal stroke Superior for MACE versus placebo (p=0.026 for superiority)

MACE: Major adverse cardiovascular event (composite of CV death, myocardial infarction and stroke)

TA B L E 4

Key Comparison Trials for GLP-1 RAs

Dulaglutide 1.5 mg weekly versus liraglutide 1.8 mg daily (AWARD 6)(18)

Dulaglutide is non-inferior to once-daily liraglutide for mean A1C reduction (-1.42% versus -1.36%, p < 0.0001 for non-inferiority), body weight reduction (-2.9 kg versus -3.61 kg) and safety proﬁle

Liraglutide 1.8/daily versus exenatide 2 mg weekly (DURATION 6)(19)

Greater reductions in A1C with liraglutide versus exenatide (-1.48% compared to 1.28%) not meeting the non-inferiority criteria

Semaglutide 1.0 mg weekly versus exenatide 2.0 mg weekly (SUSTAIN 3)(20)

Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving A1C (-1.5% compared to -0.9%) and reducing body weight (-5.6 kg compared to -1.9 kg) and had comparable safety proﬁles (p < 0.0001 for superiority)

Semaglutide 0.5/1.0 mg weekly versus dulaglutide 0.75/1.5 mg weekly (SUSTAIN 7)(21)

At low and high doses, semaglutide was superior to dulaglutide in improvement of glycemic control and reduction of body weight. (p < 0.0001 for superiority) • Low dose, 0.5 mg versus 0.75 mg: A1C, -1.5% compared to -1.1%; weight reduction, -4.6 kg compared to -2.3 kg • High dose, 1.0 mg versus 1.5 mg: A1C, -1.8% compared to -1.4%; weight reduction, -6.5 kg compared to -3.0 kg)

Weight reduction • Semaglutide weekly > exenatide weekly • Semaglutide weekly > dulaglutide weekly TA B L E 6 Combination Trials of GLP-1 RAs and SGLT2is

SUSTAIN 9(22) • Addition of semaglutide 1.0 mg once weekly or placebo to treatment with an SGLT2i for at least 90 days • The addition of semaglutide led to a significant reduction in A1C (-1.5%) and body weight (-4.72 kg) • ETD of semaglutide versus placebo in A1C (-1.42%) and body weight (-3.81 kg); both p < 0·0001) • Generally, well tolerated AWARD 10(23) • Addition of dulaglutide 0.75 mg, 1.5 mg QW or placebo to treatment with an SGLT2i for at least 90 days • Reduction in A1C versus placebo: -1.34%, 1.5 mg/week; -1.21%, 0.75 mg/week • Generally well tolerated DURATION 8(24) • Addition of exenatide 2 mg QW or placebo with dapagliflozin 10 mg daily or exenatide QW plus placebo or dapaglifozin plus placebo to metformin monotherapy • Reduction in A1C was -2.0% for exenatide and dapagliflozin group, -1.6% in the exenatide group and -1.4% in the dapagliflozin group • The dual treatment regimen was well tolerated, with the expected safety profile for this combination ETD: Estimated treatment difference

CARDIOVASCULAR OUTCOME TRIALS

Since 2008, new diabetes medications must have CV outcome data prior to approval.(12) Table 3 provides an overview of outcomes from GLP-1 RA cardiovascular outcome trials. The Diabetes Canada Clinical Practice Guidelines recommend that people with type 2 diabetes taking metformin who are not meeting glycemic targets and who have clinical cardiovascular disease

Continuing Education L E S S O N

Exploring the practical use of GLP-1 RAs in type 2 diabetes

Answer online at eCortex.ca

TA B L E 7

August 2019

CE3

Summary of Characteristics for Counselling Patients on GLP-1 RAs Dulaglutide (Trulicity®) weekly(9)

Exenatide (Byetta®/ Liraglutide Bydureon®) daily/weekly(10,25) (Victoza®) daily(11)

Lixisenatide (Adlyxine®) daily(26)

Semaglutide (Ozempic®) weekly(5)

Initial dose

0.75 mg weekly

Weekly: 2 mg weekly Daily: 5 µg BID

0.6 mg daily

10 µg daily

0.25 mg weekly

Maximal dose

1.5 mg weekly if required

Weekly: 2 mg weekly Daily: 10 µg BID

↑ 1.2 mg daily after 1 week. Can ↑ to 1.8 mg daily if required

↑ 20 µg daily starting at day 15

↑ 0.5 mg weekly after 4 weeks. Can ↑ to 1.0 mg weekly after 4 weeks, if required

Dosing schedule

Weekly

Daily (Byetta® Twice) Weekly (Bydureon® weekly)

Daily

Weekly

Dosing in chronic kidney disease(6)

No dosage adjustment if eGFR > 15 mL/min

No dosage adjustment if eGFR > 50 mL/min (use with caution with eGFR 30-50 mL/min)

No dosage adjustment if eGFR > 15 mL/min

No dosage adjustment if eGFR ≥ 30 mL/min

No dosage adjustment if eGFR > 30 mL/min Use caution if eGFR <30 mL/ min. Not recommended for use in patients with end-stage renal disease (eGFR < 15 mL/min)

Pen needle size

5 mm 29G

7 mm 23G

4 mm 32G

Not included in packages

4 mm 32G

Packaging

4 single-dose preﬁlled pens

Daily: 1.2 mL prefilled pen, 5 µg/dose, 2.4 mL prefilled pen, 10 µg/dose (30-day supply) Weekly: 4 single-dose prefilled pens

3 mL preﬁlled multidose, disposable pen (6 mg/mL) to deliver 0.6 mg, 1.2 mg or 1.8 mg daily

Packs contain pens designed to deliver 10 µg or 20 µg

Pre-ﬁlled, multi-dose, disposable pen containing 1.5 mL or 3.0 mL (1.34 mg/mL) For 0.25 mg or 0.5 mg OW doses, use 1.5 mL pen For 1 mg OW dose, use 3 mL pen

Managing adverse effects

Gastrointestinal – Commonly associated with nausea and, occasionally, vomiting.(4) This is normally at the initiation of therapy and can be mitigated by following the recommended titration schedules. Hypoglycemia – Minimal risk.(27) Initiation of GLP-1 RA may require insulin or insulin secretagogue dose reduction.

Missed doses

If a dose is missed, it should be administered ASAP if there are at least 3 days until the next scheduled dose

(note: large gauge = smaller diameter)

TA B L E 8

Factors when Considering GLP-1 RA Therapy(6)

A1C reduction

Hypoglycemia risk

Weight reduction

Weekly: If a dose is missed, it should be administered ASAP within 3 days after the missed dose Daily: if a dose is missed, it should be skipped

• GLP-1 RAs can reduce A1C by 1.0-1.8% • This is a greater reduction than with many other therapies, such as DPP-4 inhibitors • GLP-1 RAs are not commonly associated with an increase in hypoglycemia risk • Use of GLP-1 RAs in conjunction with basal insulin or sulfonylureas may increase risk of hypoglycemia • GLP-1 RAs can help an overweight or obese person (~90% of people with type 2 diabetes) reduce their weight • Weight gain is seen with insulin, insulin secretagogues and thiazolidinediones

Cardiovascular • Liraglutide can be considered in patients with clinical risk CVD to further reduce their risk of a MACE • Empagliﬂozin and canagliﬂozin can also be considered in people with clinical CVD • New research has shown that semaglutide or dulaglutide could be considered for MACE risk reduction(14,28) Regimen simplicity

• Many of these agents are administered once weekly, which can simplify dosing and improve adherence

consider the addition of liraglutide to reduce the risk of major adverse cardiovascular events (MACE).(6) At the time of writing the clinical practice guidelines, semaglutide was not yet approved in Canada and CV outcome data for dulaglutide were not published.

If a dose is missed, it should be skipped

TA B L E 9

If a dose is missed, it should be injected within the hour prior to the next meal

If a dose is missed, it should be administered ASAP within 5 days after the missed dose

Role of the Pharmacist to Support Patients Starting a

GLP-1 RA Injection training

• For many people with diabetes, a GLP-1 RA could be the ﬁrst injectable therapy • Pharmacists can use their scope of practice to ensure the patient can effectively and safely administer a GLP-1 RA

Counsel on therapy expectations

• A discussion of the beneﬁts for A1C and weight reduction can help to engage patients on the rationale for using this medication • Monitoring of glucose levels to evaluate therapy and ensure safety (e.g., hypoglycemia in patients using insulin or insulin secretagogues)

Mitigate • Nausea and vomiting are the most common adverse adverse effects effects, which normally occur during the initial titration phase and tend to dissipate over time • Many times, these effects can be mitigated by appropriate titration and with continued use Managing other issues

• Pharmacists can explain why adherence is important, and how to manage missed doses

REDUCTION IN A1C AND WEIGHT

A number of comparison studies have been conducted for GLP-1 RAs (Tables 4 and 5). Although all GLP-1 RAs reduce both A1C and weight, some agents lead to a greater reduction in both A1C and weight. These factors should

be considered when selecting a GLP-1 RA agent. COMBINATION THERAPY

Each of the current GLP-1 RAs in Canada is approved for use in combination with metformin, metformin/sulfonylurea, and

Continuing Education L E S S O N

Exploring the practical use of GLP-1 RAs in type 2 diabetes

CE4

August 2019

metformin/basal insulin.(5,9–11) Although off-label, interest is also growing in combining a GLP-1 RA with a sodium-glucose co-transporter 2 inhibitor (SGLT2i). Table 6 reviews the published trials of combination SGLT2i and GLP-1 RA. Although not currently indicated, this combination may be considered by some physicians due to the additional A1C and weight reductions compared to either agent alone. Summary of GLP-1 RA characteristics The new evidence provides pharmacists with some guidance on how a speciﬁc GLP-1 RA can be selected for a person with type 2 diabetes. Table 7 summarizes the characteristics of GLP-1 RAs, to help pharmacists counsel their patients who are starting these agents. Role of the pharmacist with GLP-1 RAs Pharmacists can play a pivotal role in helping patients with diabetes reach glycemic targets to decrease their risk of diabetes complications. Pharmacists can help educate and support patients on GLP-1 RAs who are not reaching glycemic targets or who are starting a GLP-1 RA. PATIENTS NOT REACHING GLYCEMIC TARGETS

The Diabetes Canada guidelines recommend metformin as the initial antihyperglycemic agent for people with type 2 diabetes. For patients with an A1C > 1.5% above target, the guidelines encourage clinicians to add metformin and an additional agent at diagnosis. If a patient does not reach glycemic targets, the clinician should consider adding additional agents so that glycemic targets (typically ≤ 7.0%) are reached in three to six months.(6)

The guidelines strongly encourage healthcare providers to individualize antihyperglycemic selection.(6) Pharmacists should consider discussing the addition of a GLP-1 RA based on specific factors (Table 8). Key Point: GLP-1 RAs are an option that can be considered for most patients with type 2 diabetes. Their positive efficacy and safety profi le indicate that they can be considered early and late in the course of the disease. To select a specific GLP-1 RA that is most appropriate for the patient, pharmacists can draw from the comparison trials summarized in Tables 4 and 5. PATIENTS STARTING ON A GLP-1 RA

For any patient starting a GLP-1 RA, it is important for pharmacists to proactively offer counselling, education and support to ensure that the patient can get the most from this agent. For many of these patients, a GLP-1 RA could be their ﬁrst injectable therapy, and their concerns over self-injection may discourage adherence. New patients may also have second thoughts about needing “another drug,” and pharmacists can share information about how these drugs are able to signiﬁcantly improve glycemic levels—and in turn lower the risk of complications from diabetes. Table 9 summarizes the role of the pharmacist with patients starting a GLP-1 RA. Making it happen in practice All pharmacists are encouraged to actively engage people with diabetes to ensure their disease is managed according to current Diabetes Canada guidelines. Small interventions, education and support can have a dramatic difference on outcomes.

Answer online at eCortex.ca

GLP-1 RAs are one option that can be considered for people with type 2 diabetes. By having access to the latest evidence, pharmacists can educate patients and recommend this class of agents for patients who can beneﬁt the most. KEY LEARNING POINTS

1. Many people with type 2 diabetes are not meeting glycemic targets recommended by clinical guidelines. 2. GLP-1 RAs can be considered in type 2 diabetes for patients currently using metformin or other antihyperglycemic agents. 3. There is evidence that liraglutide, semaglutide and dulaglutide can reduce adverse cardiovascular outcomes in people with diabetes and clinical cardiovascular disease. 4. In head-to-head trials, semaglutide has been shown to offer superior A1C and weight reduction compared to exenatide weekly and dulaglutide. Dulaglutide and liraglutide offer comparable A1C reduction. 5. New evidence supports the safety and efﬁcacy of combining SGLT2 inhibitor and GLP-1 RA therapy. 6. Pharmacists can play a key role in educating and counselling patients on GLP-1 RAs who are not meeting A1C targets or who are starting this therapy. References for this CE lesson are available online at www.ecortex.ca.

Find the questions for this CE lesson online at www.ecortex.ca.

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Faculty: Exploring the practical use of GLP-1 RAs in type 2 diabetes ABOUT THE AUTHOR

REVIEWERS

Michael Boivin is a clinical pharmacist consultant and educator, and president of CommPharm Consulting in Barrie, Ontario. He has developed more than 100 accredited continuing education programs on the management of diabetes and has trained hundreds of pharmacists to help them prepare for the certiﬁed diabetes educator exam.

All lessons are reviewed by pharmacists for accuracy, currency and relevance to current pharmacy practice.

Answer online at eCortex.ca

CE Project Manager: Karen Welds CE Designer: Shawn Samson

This lesson is published by EnsembleIQ: 20 Eglinton Ave. West, Suite 1800 Toronto, ON M4R 1K8 Phone: 877.687.7321 Fax: 888.889.9522 CE queries: email canadianhealthcarenetwork@halldata.com

No part of this CE lesson may be reproduced, in whole or in part, without the written permission of the publisher.

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5 TIPS

PEARLS YOU CAN USE IN YOUR PRACTICE NOW

LAUNCHING SEXUAL HEALTH SERVICES IN COMMUNITY PRACTICE

ANDREW SCHONBE, BScPhm, RPh

ecently, we have seen drastic changes in access to sexual health education in some regions,(1) expanding social media use, the rise of the #MeToo movement, increasing rates of sexually transmitted infections (STIs) and resistant STIs in some communities.(2) As a result, the need for improved access to sexual health education and resources is more timely than ever before.

Pharmacies and pharmacists are highly accessible in the community and are in a prime position to address gaps in sexual health education and promote risk reduction. Pharmacists can launch comprehensive sexual health programs and services in their communities to address important topics including consent, online safety, STIs and LGBTQ+ (lesbian, gay, bisexual, transgender and queer) health. These types of programs can favourably alter the perception of pharmacists, gain media attention for pharmacy services, support collaboration with other professionals, and position your pharmacy as a progressive health and wellness resource. This article provides five tips to help pharmacies introduce sexual health programs and services for their communities.

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Host education sessions in the pharmacy

Invite parents and youth to regular presentations hosted at your pharmacy. As some topics may be outside of a pharmacistâ€™s scope, collaborate with

community partners and invite subject matter experts to be guest speakers. For example, invite a local police officer to give a talk on online safety. For topics related to consent, a representative from a local sexual assault centre may be available to provide insight. Caution should be taken when scheduling events with regards to holidays or conflicting local events; select a day of the week

when parents and teens will be more available. The number of attendees and the overall success can be maximized by cross-promoting the event with the speakerâ€™s organization, reaching out to local schools, calling your patients to invite them to attend, creating an online attendance check-in on social media, garnering media attention in advance, and live streaming or recording for future posting.

Provide resources to the community

Set up an in-store table or section with literature on various sexual health-related topics for the public. Many resources are accessible for free (with free shipping) through a multitude of organizations. CATIE, CyberTip and Rainbow Health

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Ontario are good resources to consider. Review all materials beforehand to ensure age appropriateness and that the information is consistent with your messaging. It is also important to ensure the pharmacy team is familiar with the content and has brushed up on sexual health in preparation to receive questions. For references the pharmacy team can use, refer to Health Canada and your provincial public health resources. Patient educational materials and information on sexual health topics should also be posted on a dedicated section of your website and on any social media channels your pharmacy uses, to maximize exposure and access. Use instore signage and bag-stuffers to direct patients to your online resources.

Organize on-site sexual health testing Provide on-site anonymous sexual health testing days (for STIs) at your pharmacy by collaborating with your local public health unit. This greatly improves testing access in the community and promotes a space for those seeking greater confidentiality. A counselling room may provide enough space depending on testing requirements.

Depending on your facilities, a public health nurse may be able to provide rapid HIV testing, urine collection, blood work and select swabs. I suggest allowing for both appointments and drop-in services or testing. Appointment scheduling can be managed by the pharmacy team and ensures the nurse will have a baseline of patients to see during the visit.

Incorporate LGBTQ+ services

Individuals identifying as LGBTQ+ can face discrimination and unique obstacles in accessing healthcare.(3) To address this concern, your team can take part in diversity training to designate the pharmacy as a “Safer Space.” Displaying Safer Space signage alerts your community that you provide a welcoming and inclusive environment. Local LGBTQ+ organizations may offer training or can connect you with an organization that does. In addition to Safer Space signage, you can also display notices to alert patients that the pharmacy welcomes any specific requests they may have. For example, transgender individuals may face misgendering and misuse of pronouns, which can be extremely distressing.(4) It is important to proactively

collect information and institute policies to navigate these types of concerns. Consider continuing education topics such as medications used during the gender-confirming process, and health needs that may be more common among the men who have sex with men (MSM) population. This will help support your ability to better understand and meet the needs of these patient populations. It may also affect pharmacy decisions to regularly stock relevant types of medication.

Provide HIV prevention services

Access to HIV prevention therapy is, unfortunately, a challenge for some who seek the required care.(5) Patients in my practice have reported a lack of awareness in the healthcare community and that they still face stigma in 2019 while seeking medication options. Community pharmacies can support patients by familiarizing themselves with HIV preexposure prophylaxis (PrEP) and post-exposure prophy laxis (PEP) therapies. It is advisable to regularly maintain the required medications in-stock and ensure local physicians, hospitals and clinics are aware that your pharmacy provides access.

Due to the highly sensitive requirement that PEP is provided as soon as possible, it is ideal to have the product on hand rather than waiting for it to be ordered. Staying updated with HIV-related topics, such as the undetectable = untransmittable (U=U) campaign,(6) will further strengthen the quality of service your practice offers. (U=U defines that an individual with an undetectable viral load cannot transmit HIV sexually to a partner). The pharmacy can also support STI prevention in general by distributing free condoms—especially to teens where cost may be a barrier. Try partnering with a local HIV organization to supply free condoms (both internal and external) for the pharmacy to provide to those in need. Upon request, youth could then access free condoms along with information on their proper use, STI testing and STI risks to consider.

SUMMARY

Pharmacists can position themselves as leaders in promoting sexual health and wellness in the community, through partnership with local resources and instituting the important services described in this article. ANDREW SCHONBE (andrew@expressaidpharmacy.ca) is a community pharmacist–owner specializing in youth, addiction and LGBTQ+ health in Barrie, ON. He is also a faculty member of Georgian College’s regulated pharmacy technician program.

REFERENCES: 1. Martin N. Barrie pharmacist launches monthly sexual health sessions to bridge education gap. https://www.cbc.ca/news/canada/toronto/barrie-pharmacist-sex-ed-classes-1.4837326 (accessed January 27, 2019). 2. Ubelacker S. Gonorrhea, other STIs on rise in Canada: public-health experts. May 29, 2018. https://www.theglobeandmail.com/life/health-and-fitness/article-gonorrheaother-stis-on-rise-in-canada-public-health-experts/ (accessed January 4, 2019). 3. Ontario HIV Treatment Network. Facilitators and barriers to health care for lesbian, gay and bisexual (LGB) people. March 2014. http://www.ohtn.on.ca/Pages/Knowledge-Exchange/Rapid-Responses/Documents/RR79.pdf (accessed January 4, 2019). 4. McNeil J, Bailey L, Ellis S, et al. Trans Mental Health Study 2012. https:// www.gires.org.uk/wp-content/uploads/2014/08/trans_mh_study.pdf (accessed January 4, 2019). 5. CATIE. HIV in Canada: a primer for service providers. https://www.catie.ca/en/hiv-canada/7/7-1/ (accessed January 22, 2019). 6. Dieffenbach CW, Eisinger RW, Facui AS. HIV viral load and transmissibility of HIV infection. Undetectable equals untransmittable. JAMA 2019 [published online January 10, 2019]. https://jamanetwork.com/journals/jama/fullarticle/2720997 (accessed January 14, 2019).

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† A finger prick test using a blood glucose meter is required during times of rapidly changing glucose levels when interstitial fluid glucose levels may not accurately reflect blood glucose levels, or if hypoglycemia or impending hypoglycemia is reported or the symptoms do not match the system readings. ‡ The reader can scan through clothing with a thickness up to 4 mm. §The FreeStyle LibreLink app is compatible with Near-field Communication (NFC) enabled iPhone 7 and higher running iOS 11 or higher. ¶ The reader can capture data from the sensor when it is within 1-4 cm of the sensor. ** The FreeStyle LibreLink app and the FreeStyle Libre reader have similar but not identical features. The FreeStyle Libre sensor communicates with the FreeStyle Libre reader that started it or the FreeStyle LibreLink app that started it. A sensor started by the FreeStyle Libre reader will also communicate with the FreeStyle LibreLink app, provided that the FreeStyle LibreLink app is used to scan the sensor within an hour of the sensor starting up.

†† For a complete glycemic picture, scan once every 8 hours. FreeStyle, Libre, and related brand marks are trademarks of Abbott in various jurisdictions. Product images are for illustrative purposes only. © 2019 Abbott | ADC-13155

HELPING PATIENTS WITH CANCER TO QUIT SMOKING SHIRIN ABADI, BSc(Pharm), ACPR, PharmD, DPLA, MBA, FCSHP, RPh

TOBACCO USE, INCLUDING CIGARETTE SMOKING,

is the greatest preventable cause of death, as it kills more than seven million people every year globally.(1) One in five deaths in Canada is attributed to cigarette smoking.(2) In Canada, the incidence of smoking has been on the decline over the past few decades, from about 50% in 1965 to 13% in 2015.(3) Despite this decline, the health-economic cost associated with smoking in Canada is about 16.2 billion dollars per year.(2,4) Cigarette smoking is a significant contributor to cancer-related mortality and also increases all-cause mortality and cancer recurrence.(5-7) Furthermore, cigarette smoking reduces the response rate to cancer treatment, while increasing treatmentrelated toxicities.(5-7) This article reviews the benefits of tobacco smoking cessation in patients with cancer, the harms associated with continued tobacco smoking in patients with cancer, the use of pharmacotherapeutic interventions to help cancer patients quit smoking, and how pharmacists can assist patients with their quit attempts.

Benefits of smoking cessation on cancer mortality

Smoking cessation can reduce cancer death rate by 30%–40%, which is as good as or better than many cancer treatments currently available on the market.(5-8) For example, in a prospective cohort study of 388 patients diagnosed with lung cancer, the median overall survival of patients was significantly better (by 9 months) for those who stopped smoking upon diagnosis, compared to those who continued to smoke (hazard ratio [HR]=1.79; 95% confidence interval [CI], 1.14–2.82).(9) 20

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Additionally, in a retrospective cohort study of 2,882 patients with lung cancer, all-cause mortality was significantly reduced in patients who quit smoking upon diagnosis compared to those who continued to smoke (HR=0.82; 95% CI, 0.74–0.92).(10) Furthermore, in a prospective observational study in 20,691 women with localized or invasive breast cancer, there was a significantly greater mortality rate from breast cancer, respiratory cancer, respiratory disease and cardiovascular disease in patients who were smokers at one year prior to their cancer diagnosis, compared to those patients who never smoked.(11) In addition, women who continued to smoke after their diagnosis also had a significantly greater morality rate from breast cancer than those who never smoked (HR=1.72; 95% CI, 1.13–2.60).(11) Women who quit smoking after their diagnosis had a significantly lower mortality rate associated with respiratory cancer compared to patients who continued to smoke (HR=0.39; 95% CI, 0.16–0.95).(11)

Smoking cessation can reduce cancer death rate by 30%–40%, which is as good as or better than many cancer treatments currently available on the market. Harms of continued smoking in cancer patients

Pharmacokinetic studies have demonstrated that cigarette smoking can significantly reduce the bioavailability of some cancer medications, including erlotinib and irinotecan, thus putting patients at a higher risk for cancer progression, recurrence and death.(12,13) This is likely due to cytochrome P450 and glucuronyl transferases enzyme induction by polycyclic aromatic hydrocarbons that are produced from cigarette smoking; these enzymes are responsible for the metabolism of certain cancer medications.(14) In the case of docetaxel and other highly protein-bound chemotherapy agents, cigarette smoking may upregulate alpha-1-acid-glycoprotein and protein binding, thus reducing the free levels of these drugs and making them less effective.(15) In addition, continued cigarette smoking may increase the risk of complications and mortality associated with radiation

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CLINICAL FEATURE

TABLE 1

Smoking cessation agents for patients with cancer are similar to those used for the general population, although product choice may be influenced by the type of cancer (see section on Pharmacist’s role). Smoking cessation pharmacotherapy has demonstrated efficacy in maintaining abstinence from cigarette smoking at six months compared to placebo (Table 1).(22-33) Combination therapies, including the nicotine patch with other nicotine replacement products or bupropion sustained-release (SR), are more effective than monotherapy in achieving abstinence.(16,23,25-28) Some literature also suggests that combination therapy with bupropion SR and varenicline can lead to increased effectiveness, although it may also lead to a greater risk of side effects, such as anxiety and depression.(29)

Abstinence Rates for Smoking Cessation Agents(27,28) ABSTINENCE RATE AT 6 MONTHS*

NONPRESCRIPTION NRT Nicotine gum

19%

Nicotine lozenge

20%

Nicotine inhaler

25%

Nicotine mouth spray Nicotine patch**

FIRST-LINE PRESCRIPTION THERAPY

Bupropion sustained release Varenicline

16% 24%

ABSTINENCE RATE AT 6 MONTHS* 24% (29% when combined with nicotine patch) 33%***

Dosing and tips for using nicotine replacement therapy (NRT)

NRT–nicotine replacement therapy * Abstinence rate at 6 months with placebo is 7%–13%.(27,28) Abstinence rates with pharmacological agents may improve with longer duration of therapy.(27.28) ** Combining the nicotine patch with short-acting NRTs (e.g., gum) may increase the abstinence rate at 6 months to 30%.(27) *** With varenicline 1 mg orally twice daily.(27)

Dosing of nicotine replacement products depends on the average number of cigarettes smoked by an individual in a day. Since there are 20–25 cigarettes per pack, it is important to clarify the number of cigarettes that the patient is using.

TABLE 2

Nicotine Patch Dosing(23,26) NUMBER OF CIGARETTES/ DAY*

NICOTINE PATCH DOSE**

≥ 10 < 10 (or patient weighs < 45 kg and/ or has coronary heart disease)

NICOTINE PATCH

21 mg/day x 6 weeks, then 14 mg/day x 2 weeks, then 7 mg/day x 2 weeks 14 mg/day x 6 weeks, then 7 mg/day x 2 weeks

* Each cigarette contains 1–3 mg of nicotine.(26) ** Nicotine patches are currently available in 7 mg, 14 mg and 21 mg sustained-release 24-hour formulations, or 5 mg, 10 mg and 15 mg sustained-release 16-hour formulations.

therapy and surgery, due to increased infection rates, pulmonary and cardiovascular complications, impaired wound-healing, decreased response to therapy, longer hospitalization and compromised quality of life.(16)

Cigarette smoking cessation interventions

Table 2 provides an outline of how to dose the nicotine patch. For greater success, patch use should begin seven days prior to the quit date. The patch should be applied to a dry, clean nonhairy area of the body, and the application site rotated daily to minimize skin irritation.(26,27) If the patient experiences insomnia, it would be reasonable to remove the patch at

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Given the many adverse effects of cigarette smoking on patients with cancer, it is never too late for them to consider quitting, particularly once they are better informed about the negative consequences of continuing to smoke tobacco. Studies have demonstrated that informed patients who are diagnosed with cancer might be more motivated to quit smoking.(17,18) Up to onethird of patients diagnosed with cancer are able to successfully quit smoking, particularly those whose cancers are associated with smoking, those with other comorbidities and those with a higher body mass index.(18-20) Studies have demonstrated that counselling and pharmacotherapy for smoking cessation are more effective than either intervention alone.(19,20) With regards to counselling, longer and more frequent sessions are associated with greater success rates.(20)

Exploring the practical use of GLP-1 RAs in type 2 diabetes By Michael Boivin, B.Sc., Phm, RPH, CDE, CTE Upon successful completion of this learning activity, pharmacists will be better able to: 1. Explain the mechanism of action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) 2. Review existing and emerging efﬁcacy data for available GLP-1 RAs and their role in managing type 2 diabetes

3. Implement practical strategies around dispensing GLP-1 RAs

Pharmacotherapy to promote cigarette smoking cessation

4. Counsel a patient beginning or continuing treatment with GLP-1 RAs

The main goal of pharmacotherapy to promote smoking cessation is to treat nicotine withdrawal symptoms, which can occur within 30 minutes after the last cigarette or dose of nicotine. Withdrawal symptoms include restlessness, irritability, anxiety, agitation, insomnia, depression, poor concentration, increased appetite and intense nicotine cravings.(21)

Supported by educational funding from Novo Nordisk Canada Inc.

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TABLE 3

Short-Acting NRTs: Dosage & Instructions for Use(23,26) SHORT-ACTING NRT*

DOSE**

INSTRUCTIONS FOR USE***

Nicotine gum (2 mg, 4 mg sugar-free pieces)a

1 piece/hr prn cravings (up to 20 pieces/day)

“Bite, bite, park” method: bite into the gum a couple of times until a peppery taste is released, then park between cheek and jaw until no further taste, then repeat process for about 30 minutes.

Nicotine lozenge (1 mg, 2 mg, 4 mg sugar-free pieces)b

1 piece/hr prn cravings (up to 15 pieces/day)

Suck on lozenge until flavour is released, then park lozenge between cheek and gum until flavour dissipates, then repeat process. Do not chew or swallow lozenge!

Nicotine inhaler (4 mg/cartridge)c Nicotine mouth spray (1 mg/spray)

1 inhaler/hr prn cravings (up to 16 cartridges/day) 1–2 sprays/30 min prn cravings (up to 64 sprays/day)

Gently draw air into the mouth through the inhaler and puff it into cheeks, hold for a few seconds, before breathing out. Do not inhale deeply! Prime spray (when using device for the first time or after 2 or more days of nonuse), then hold spray close to the mouth, without touching lips. Press down on top of spray to release mist, hold spray in mouth for a few seconds before swallowing. Repeat process once more in 1 minute, if cravings still present.

NRTs–nicotine replacement therapies * May be used in combination with the nicotine patch. ** Titrate dose to response, i.e., absence of withdrawal symptoms. *** No food or drink for 15 minutes prior to or during product use to prevent any interference with nicotine absorption. a. Use 4 mg gum for individuals who smoke more than 21 cigarettes per day. b. 1 mg lozenge = 2 mg gum; use 2 mg lozenge for individuals who smoke more than 21 cigarettes per day; use 4 mg lozenge for individuals who have cravings within 30 minutes upon waking. c. 4 mg nicotine is delivered from a 10 mg cartridge. Each cartridge usually lasts for about 20 minutes.

bedtime. The patch should be removed prior to undergoing an MRI (magnetic resonance imaging) scan, as its aluminum backing may lead to thermal burns.(26) Compared to the nicotine patch, other nicotine replacement products are short-acting.(26,27)

SHORT-ACTING NRTS: GUM, LOZENGE, INHALER, MOUTH SPRAY(26-28)

Nicotine from short-acting NRTs is absorbed through the lining of the mouth. The onset of action is about 20 minutes for the gum, lozenge and inhaler. The mouth spray is the fastest-acting NRT, with an onset of action of one minute.(26,27) Table 3 provides a summary of the dose and instructions for use for short-acting NRTs. Nicotine withdrawal symptoms typically respond to NRT within the first three weeks, but the habitual/psychological/ behavioural symptoms may linger longer. Therefore, NRTs may be continued for up to 12 weeks or longer, while the dose is being tapered, as a longer duration of therapy may improve abstinence rates.(27) Patients must be advised about the appropriate technique for using NRTs (Table 3). The nicotine inhaler has the advantage of looking and feeling like a cigarette. The word “inhaler” is a misnomer, as nicotine absorption via this device occurs through the lining of the mouth, similar to the gum and the lozenge. Table 4 provides examples of side effects associated with the use of NRTs.

Prescription products for smoking cessation

Bupropion SR and varenicline have demonstrated effectiveness for smoking cessation in randomized controlled trials.(29-31) Bupropion binds noradrenergic and dopaminergic receptors, whereas varenicline is a partial agonist at the nicotinic receptors, mimicking the effects of nicotine in the brain, while inhibiting the binding of nicotine from exogenous sources (e.g., cigarettes) to the receptors.(26,27) Table 5 provides information about the dosage, potential side effects, contraindications and precautions for these products. While bupropion SR is more effective when combined with NRT, more extensive studies are needed to justify the combined use of varenicline and NRT.(24-32) While varenicline is the most effective 22

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TABLE 4

Nicotine Replacement Therapy Side Effects(23,26) NICOTINE FORMULATION Oral formulations Patch

Any NRT (Oral and/or Patch)

SIDE EFFECTS* Mouth/throat irritation/pain, dry mouth, cough, tingling sensation in mouth, hiccups, heartburn/ indigestion, upset stomach, flatulence Skin irritation, insomnia, nightmares/ vivid dreams Headaches, nausea, tachycardia, hypertension, vasoconstriction

* Examples only; refer to reliable references to access a comprehensive list.

FIGURE 1

Five A’s of Tobacco Smoking Cessation(34)

1| 2| 3| 4| 5|

ASK patients about their tobacco use: not just once, but ideally at every visit. The more patients are asked about their smoking habit, the more likely they will consider quitting. ADVISE tobacco users to quit, by explaining the benefits on their health and finances.

ASSESS readiness to make a quit attempt and ask patients if they would be interested to receive more information about available resources. ASSIST with the quit attempt, by providing patients with suggestions for pharmacotherapy and referral to counselling services. ARRANGE for follow-up care, to make sure patients are succeeding with their attempt to quit smoking.

single pharmacological agent available, its use together with counselling may further improve its effectiveness. Given that bupropion SR is also effective for the treatment of depression, its use may be favoured in this patient population. Second-line medications with moderate efficacy that may be considered for smoking cessation include nortriptyline and cytisine (a natural health product sold in Canada under the

TABLE 5

First-Line Prescription Agents for Smoking Cessation: Dosages, Potential Side Effects, Contraindications and Precautions(23,26) PRESCRIPTION AGENTS*

Bupropion sustained release

Varenicline

DOSE

POTENTIAL SIDE EFFECTS**

CONTRAINDICATIONS & PRECAUTIONS**

150 mg po once daily x 3 days, followed by 150 mg po bid x 7–12 weeks (space doses by at least 8 hours to minimize seizure risk)

Headache, dizziness, seizure, insomnia, agitation, tremor, tinnitus, dry mouth, anorexia, nausea, vomiting, constipation

Contraindications: hypersensitivity, seizures, head trauma, anorexia; use with monoamine oxidase inhibitors, linezolid, methylene blue or thioridazine

0.5 mg po once daily x 3 days, then 0.5 mg po bid x 4 days, then 1 mg po bid x 12 weeks, with food to reduce risk of nausea

Insomnia, abnormal dreams, mood changes, aggression, taste disturbance, nausea, constipation, flatulence, vomiting, hyperglycemia

Contraindications: hypersensitivity

Precautions: mood instability, suicidal ideation, cardiovascular events, hepatic impairment, excessive alcohol, antidepressants, tamoxifen, CYP2D6 substrates, meds & comorbidities that decrease seizure threshold Precautions: suicide ideation, hostility, agitation, central nervous system depression, sleep walking, seizures, cardiovascular events, renal impairment; use with alcohol, quinolones or trimethoprim

* Start 7 days prior to quit date. ** Examples only; refer to reliable references to access a comprehensive list.

brand name Cravv).(23) Clonidine has limited efficacy for smoking cessation and is therefore not currently recommended.(23) The safety of electronic cigarettes is uncertain, given the lack of long-term studies and information about the health effects of vaporized chemicals such as propylene glycol.(23,27) There is also insufficient reliable evidence to support the use of nutritional supplements, acupuncture and hypnosis.(16) Therefore, their use for smoking cessation cannot be recommended at this time.(16,23,27)

While varenicline is the most effective single pharmacological agent available, its use together with counselling may further improve its effectiveness.

NRTs can be used long-term, particularly if they help patients reduce or continue to abstain from smoking. For patients using bupropion SR or varenicline for smoking cessation, pharmacists can monitor for response to therapy and adverse effects, including sudden mood changes, agitation, suicidal ideation and seizures, as well as drug interactions. Patients should be advised to reduce caffeine intake by 50% when quitting smoking, due to decreased caffeine clearance.(35) Otherwise, they may experience symptoms such as anxiety, irritability and insomnia, which mimic nicotine withdrawal

Pharmacist’s role

The 5 A’s of tobacco smoking cessation provide a framework for pharmacists to assist patients to quit smoking (Figure 1).(34) Pharmacists can play an important role when advising patients with cancer about the benefits of cigarette smoking cessation on cancer- and treatment-related outcomes; the best ways to use smoking cessation pharmacotherapies; and medication side effects (Tables 3-5) and how to manage them. Pharmacists can also help patients select the most appropriate product. For example, for patients who are undergoing cancer therapies that have skin-related toxicities or for those who have pre-existing skin conditions, the use of the nicotine patch may not be advisable, as it may exacerbate skin-related side effects. The use of oral NRTs may not be advisable in patients with oral and/or head and neck cancers undergoing radiation therapy or those who are experiencing mucositis/stomatitis, as they may further exacerbate the patient’s symptoms. For patients who have experienced recent cardiovascular events, including angina, myocardial infarction or arrhythmia, or those requiring revascularization surgery, pharmacists should advise them to use caution when considering the use of nicotine (via cigarettes or NRTs), as it may impede oxygen delivery to organs and tissues, and delay wound healing.(23,26)

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symptoms. Pharmacists should follow up with patients within two weeks of their quit date to inquire about tobacco use, withdrawal symptoms, psychiatric symptoms, caffeine/alcohol/ other drug use, side effects of medications, and the need for dose adjustment. If patients are unsuccessful during their first cessation attempt, pharmacists should reassure them that it may take several quit attempts in order to achieve success. For patients who are not yet ready to quit smoking, pharmacists should encourage them to reduce the number of cigarettes smoked, and inform them of free smoking cessation support (https://www.helpthemquit.ca/treatment/costs-coverage).(36)

Summary

Cigarette smoking is a significant risk factor for cancer and other medical conditions, such as respiratory and cardiovascular diseases. Smoking cessation in patients with cancer is associated with a reduction in cancer-related mortality, all-cause mortality and treatment-related toxicity, and an improvement in cancer treatment response. Effective prescription and nonprescription therapies, free counselling services and assistance with drug coverage are available to assist patients with smoking cessation. SHIRIN ABADI (sabadi@bccancer.bc.ca) is a clinical pharmacy specialist and the pharmacy clinical and education coordinator at BC Cancer, in Vancouver, B.C. and a clinical professor at the University of British Columbia. Shirin has reviewed the literature on smoking cessation pharmacotherapy in patients with cancer and has given presentations on this topic. THE AUTHOR ACKNOWLEDGES MS. FRANCES FOLKMAN CUSANO, BSC(PHARM), ACPR, PHARMACY CLINICAL PRACTICE LEADER AT THE TOM BAKER CANCER CENTRE IN CALGARY, AB, FOR SHARING HER EXPERTISE ON THIS TOPIC. REFERENCES 1. World Health Organization. WHO report on the global tobacco epidemic, 2017: monitoring tobacco use and prevention policies. https://apps.who.int/iris/bitstream/hand le/10665/255874/9789241512824-eng.pdf;jsessionid=CAFFE5C21078170194642AB123014B 39?sequence=1 (accessed January 8, 2019). 2. Canadian Cancer Society. Smoking causes 1 in 5 of all deaths, costs $6.5 billion in healthcare in Canada each year: study. October 16, 2017. www.cancer.ca/en/about-us/for-media/mediareleases/national/2017/cost-of-tobacco/?region=on#ixzz5ebcOVxYl (accessed January 8, 2019). 3. University of Waterloo. Tobacco use in Canada: historical trends in smoking prevalence. https://uwaterloo.ca/tobacco-use-canada/adult-tobacco-use/smoking-canada/historicaltrends-smoking-prevalence (accessed January 8, 2019). 4. The Conference Board of Canada. Smoking costs Canadian economy more than $16 billion in 2012. https://www.conferenceboard.ca/press/newsrelease/2017/10/16/smoking-costscanadian-economy-more-than-$16-billion-in-2012 (accessed January 8, 2019). 5. US Department of Health and Human Services. The health consequences of smoking–50 years of progress: a report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014. 6. Warren GW, Alberg AJ, Kraft AS, et al. The 2014 Surgeon General’s report: the health consequences of smoking-50 years of progress. Cancer 2014;120: 1914-6. 7. Balogh EP, Dresler C, Fleury ME, et al. Reducing tobacco-related cancer incidence and mortality: summary of an institute of medicine workshop. Oncologist 2014;19:21-31.

8. Thun MJ, Jemal A. How much of the decrease in cancer death rates in the United States is attributable to reductions in tobacco smoking? Tobacco Control 2006;15:345-7. 9. Dobson Amato KA, Hyland A, Reed R, et al. Tobacco cessation may improve lung cancer patient survival. J Thorac Oncol 2015;10:1014-9. 10. Koshiaris C, Aveyard P, Oke J, et al. Smoking cessation and survival in lung, upper aerodigestive tract and bladder cancer: cohort study. Br J Cancer 2017;117:1224-32. 11. Passarelli MN, Newcomb PA, Hampton JM, et al. Cigarette smoking before and after breast cancer diagnosis: mortality from breast cancer and smoking-related diseases. J Clin Oncol 2016;34):1315-22. 12. Hamilton M, Wolf JL, Rusk J, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006;12:2166-71. 13. Van der Bol JM, Mathijssen RHJ, Loos WJ, et al. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 2007;25:2719-26. 14. O’Malley M, King AN, Conte M, et al. Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol 2014;9:917-26. 15. Petros WP, Younis IR, Ford JN, et al. Effects of tobacco smoking & nicotine on cancer treatment. Pharmacotherapy 2012;32:920-31. 16. National Comprehensive Cancer Network. Smoking cessation (version 1.2018). https:// www.nccn.org/professionals/physician_gls/pdf/smoking.pdf (accessed April 4, 2019). 17. Westmaas JL, Newton CC, Stevens VL, et al. Does a recent cancer diagnosis predict smoking cessation? An analysis from a large prospective US cohort. J Clin Oncol 2015;33:1647-52. 18. Westmaas JL, Alcaraz KI, Berg CJ, et al. Prevalence and correlates of smoking and cessationrelated behavior among survivors of ten cancers: findings from a nationwide survey nine years after diagnosis. Cancer Epidemiol Biomarkers Prev 2014;23:1783-92. 19. Stead LF, Koilpillai P, Fanshawe TR, et al. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev 2016;3:1-118. 20. Lancaster T, Stead LF. Individual behavioural counselling for smoking cessation. Cochrane Database Syst Rev 2017;3:CD001292. 21. West R, Ussher M, Evans M. Assessing DSM-IV nicotine withdrawal symptoms: a comparison and evaluation of five different scales. Psychopharmacology 2006;184:619-27. 22. Herman AI, Sofuoglu M. Comparison of available treatments for tobacco addiction. Curr Psychiatry Rep 2010;12:433-40. 23. Rigotti N. Pharmacotherapy for smoking cessation in adults; July 10, 2018. UpToDate. Riverwoods, IL; Wolters Kluwer Health. https://www.uptodate.com/ (accessed January 12, 2019). 24. Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence; 2008 update. Rockville: U.S. Department of Health and Human Services; May 2008. https:// www.aafp.org/dam/AAFP/documents/patient_care/clinical_recommendations/ TreatingTobaccoUseandDependence-2008Update.pdf (accessed January 19, 2019). 25. Smith SS, McCarthy DE, Japuntich SJ, et al. Comparative effectiveness of 5 smoking cessation pharmacotherapies in primary care clinics. Arch Intern Med 2009;169:2148-55. 26. The RxFiles. Tobacco/smoking cessation pharmacotherapy. www.RxFiles.ca (accessed January 19, 2019). 27. Petrasko K, Reeve C. Smoking cessation. In: Arman L, Campbell M, Dandachi F, et al, eds. Compendium of therapeutics for minor ailments. Ottawa, ON: Canadian Pharmacists Association; 2018. p. 57-83. 28. Canadian Agency for Drugs and Technologies in Health. Nicotine replacement therapy for smoking cessation or reduction: a review of the clinical evidence. January 16, 2014. https:// www.ncbi.nlm.nih.gov/books/NBK195714/pdf/Bookshelf_NBK195714.pdf (accessed February 20, 2019). 29. Vogeler T, McClain C, Evoy KE. Combination bupropion SR and varenicline for smoking cessation: a systematic review. Am J Drug Alcohol Abuse 2016;42:129-39. 30. Hurt RD, Sachs DPL, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195-202. 31. Hays JT, Ebbert JO, Sood A. Efficacy and safety of varenicline for smoking cessation. Am J Med 2008;121(4 Suppl):S32-42. 32. Ebbert JO, Hays JT, Hurt RD. Combination pharmacotherapy for stopping smoking: what advantages does it offer? Drugs 2010;70:643-50. 33. Cahill K, Stevens S, Perera R, et al. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013;31(5):CD009329. 34. Canadian Pharmacists Association. Quit. The 5 A’s approach. https://www.pharmacists.ca/cpha-ca/assets/File/membership/The%205As%20Approach.pdf (accessed January 26, 2019). 35. Swanson JA, Lee JW, Hopp JW, et al. The impact of caffeine use on tobacco cessation and withdrawal. Addict Behav 1997;22(1):55-68. 36. HelpThemQuit.Ca. Cost of nicotine replacement therapy. https://www.helpthemquit.ca/ treatment/costs-coverage (accessed April 4, 2019).

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JULY/AUGUST 2019 [Vol.6 No.6]

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

Approved by CCCEP for

1.00 CEU CCCEP # 1329-2019-2713-I-P

This lesson has been approved for 1.00 CEU by the Canadian Council on Continuing Education in Pharmacy. For CE expiry dates go to www.ecortex.ca.

LESSON

Managing Bipolar Disorder By Colette Raphael, RPh, B.Pharm, BCPP, MHA, CHE

Upon successful completion of this learning activity, pharmacists will be able to 1. Describe the signs, symptoms and diagnostic criteria for bipolar disorder (BD). 2. Review the guiding principles that form the basis of the new Canadian Network for Mood and Anxiety Treatments (CANMAT) BD guidelines published in 2018. 3. Describe the pharmacological treatment of BD, including first-, and second-line options available, based on the CANMAT guidelines. 4. Review drug safety and monitoring of selected agents for BD.

INSTRUCTIONS

1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. For immediate results answer online at eCortex.ca. 2. To pass this lesson, a grade of at least 70% (11 out of 15) is required. If you pass, your CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces require individual pharmacists to notify them.)

ANSWERING

For immediate results, answer online at eCortex.ca CanadianHealthcareNetwork.ca

Answer online at

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LEARNING OBJECTIVES

Introduction

Bipolar disorder (BD), formerly known as manic-depressive disorder, is a chronic, recurrent, disabling condition with significant morbidity and mortality. Currently, there is no cure for BD. The prevalence rate is estimated at 1.2%. It occurs equally in men and women with a mean age of onset between 17 and 21 years.(1) BD causes shifts in mood, energy and activity levels that are extreme enough to affect the ability to carry out day-to-day tasks.

Diagnosis

The diagnostic criteria for BD (Table 1) and the subtypes (Table 2) are defined in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).(2) The subtypes of BD involve evident changes in mood, energy and activity levels. These moods range from being elevated (mania), to being depressed (depression) or normal (euthymia). Less severe manic periods are known as hypomanic episodes.

Clinical course

As indicated by Griswold and Pessar, â€œThe clinical presentations of BD are broad and include mania, hypomania, depression and psychosis.â€? Moreover, BD is frequently associated with comorbid conditions such as substance use and anxiety disorders. Distinguishing the symptoms of true mania from secondary causes can therefore be difficult.(3) According to one report, 69% of patients who seek treatment in the first year of onset are misdiagnosed.(4) The nature of misdiagnosis is often from an initial presentation of depression (60%), when no evaluation for past hypomanic or manic symptoms is performed. Other psychiatric misdiagnoses include anxiety disorder (26%), schizophrenia (18%) and personality disorder (17%).(5) Misdiagnosis and inappropriate treatment exacerbate outcomes with more episodes, rapid cycling (at least 4 separate mood episodes within a single year), reduced quality of life and suicide.

[Vol.6 No.1] JANUARY/FEBRUARY JULY/AUGUST 2019 2019

CE 11

LESSON

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

TABLE 1 Diagnostic criteria for bipolar disorder(2) MANIC EPISODE

A - Elevated, expansive or irritable mood with increased goaldirected activity or energy for at least 1 week (or any duration if hospitalization is necessary) with significant distress B - ≥ 3 of the following symptoms (4 if mood is mostly irritable) • Inflated self-esteem • Decreased need for sleep • Talkative • Flight of ideas • Distractibility • Increased goal-directed activity • Involvement in activities with high potential of detrimental outcomes

HYPOMANIC EPISODE

Similar to manic episode except that the abnormally elevated mood period lasts at least 4 consecutive days rather than 7 Also, the episode is not severe enough to significantly impair functioning

C - Mood disturbance may cause marked impairment in functioning D - The episode is not attributable to the effects of a substance (e.g., drug of abuse, medication) or caused by a medical condition (e.g., hyperthyroidism) Note: Criteria A-D constitute a manic episode. Minimally one lifetime manic episode is required for the diagnosis of bipolar I disorder.

MAJOR DEPRESSIVE EPISODE

Α - ≥ 5 of the following symptoms have been present for at least 2 weeks (at least one of the symptoms is either depressed mood or loss of interest or pleasure) • Depressed mood • Decreased interest or pleasure • Changes in weight/appetite • Changes in sleep • Psychomotor retardation or agitation • Fatigue or loss of energy • Feelings of worthlessness or inappropriate guilt • Decreased concentration or indecisiveness • Recurrent thoughts of death B - The symptoms result in significant distress in daily functioning C - The symptoms are not attributable to the effects of a substance (e.g., drug of abuse, medication) or caused by a medical condition (e.g., hypothyroidism) Note: Criteria A-C constitute a major depressive episode (MDE). MDEs are common in bipolar I disorder but are not required for the diagnosis of bipolar I disorder.

Table 1 is adapted from the Diagnostic and Statistical Manual of Mental Disorders, fifth ed.(2)

Patients with BD spend approximately 30% of their life in a depressive state.(6) BD is a chronic, lifelong illness with frequent relapses. A new analysis of patients from the Systematic Treatment Enhancement Program for BD (STEPBD) study showed that patients who had more than five illness episodes had a significantly higher chance of relapse than those who had fewer episodes.(7) Even with treatment, subsyndromal symptoms of depression or mania may persist; which may lead to greater morbidity and increase risk of recurrences.(8) An increase in the frequency of episodes is common, with each subsequent episode becoming harder to treat.(9)

Suicide risk

Suicidal ideation and risk must be regularly monitored because patients with BD have a higher risk of suicide attempts compared with those with other psychiatric diagnoses and the general population. A high percentage of patients will attempt suicide. Worldwide, about 43% of patients

CE 2

TABLE 2 Bipolar disorder subtypes(2) BIPOLAR I DISORDER

BIPOLAR II DISORDER

• A hypomanic or depressive episode may occur before or after the manic episode

• No history of a full manic episode

• Diagnosis can be made after at least one manic episode

• Occurrence of one hypomanic episode and at least one major depressive episode

Table 1 is adapted from the Diagnostic and Statistical Manual of Mental Disorders, fifth ed.(2)

with BD report suicidal ideation, 21% a suicide plan, and 16% a suicide attempt within the past year.(9) A thorough assessment for suicide risk during all clinical interactions is recommended.(9) The factors associated with increased suicidality attempt include younger age of illness onset, female sex, a diagnosis of bipolar II disorder, comorbid anxiety disorder, comorbid substance use, presence of an eating disorder and comorbid personality disorder.(9) The association between various treatments and suicide risk has been reviewed by the International Society for Bipolar Disorders (ISBD) Task Force and others, which suggest that lithium and, to a lesser

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extent, anticonvulsants may contribute to preventing suicide attempts and deaths.(9)

Treatment guidelines

The goals of therapy are to control the symptoms of acute episodes, prevent recurrences, provide supplementary care for comorbidities related to psychiatric conditions (e.g., anxiety, substance use) or medical conditions (e.g., endocrine/ metabolic disorders) and minimize functional impairments.(10) There are three main components to BD treatment: pharmacotherapy, psychotherapy and psychoeducation. Given the importance of pharmacotherapy in the treatment of BD, this lesson primarily

Answer online at

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

focuses on this component with the aim of targeting acute mania, acute bipolar depression and maintenance therapy. The Canadian Network for Mood and Anxiety Treatments (CANMAT) in collaboration with the ISBD recently published the latest (2018) iteration of the bipolar treatment guidelines. The previous edition was issued in 2005, with subsequent updates in 2007, 2009, and 2013.(9) The CANMAT 2018 guidelines incorporate significant advances in the field of BD, including updates to diagnosis and management, as well as new research into pharmacological treatments. The guidelines provide clear recommendations for first-, second- and third-line treatments, with consideration given to levels of evidence for efficacy (See Tables 3 and 4 online), safety and monitoring. This lesson summarizes the first- and second-line treatment recommendations. Readers are encouraged to refer to the guidelines for third-line treatments and treatments that are not recommended.

TABLE 5 Five main steps in managing bipolar disorder(9)

Acute treatment guidelines

TABLE 7 Difficulties in diagnosing and treating bipolar depression(9)

ACUTE TREATMENT Table 6 summarizes management of acute manic episodes. In manic episodes of BD, pharmacotherapy is selected to rapidly control behavioural symptoms, restore sleep, and stabilize mood. The goal of initial treatment is to reduce agitation, aggression and impulsivity to prevent harm to self or others.(11) In general, the first-line options in acute manic episodes include lithium, divalproex or second-generation antipsychotics, which are considered mood stabilizers and often used to treat concomitant psychotic symptoms. Antidepressants should be tapered and discontinued when possible.(9) The first-line options in acute major depressive episodes include lithium, lamotrigine, quetiapine and lurasidone. Antidepressants should not be used as monotherapy but rather concurrently with a mood stabilizer to minimize the risk of a switch to mania.(9)

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LINE OF TREATMENT

Step 1 Step 2

LESSON

EVIDENCE LEVEL

Review general principles and assess medication status Initiate or optimize therapy and check adherence

Step 3

Add-on or switch therapy (alternate first-line agents)

Step 4

Add-on or switch therapy (second-line agents)

Step 5

Add-on or switch therapy (third-line agents)

TABLE 6 Management of acute manic episodes(9) First-line: MONOTHERAPIES First-line: COMBINATION THERAPIES Second-line

TREATMENTS FOR ACUTE MANIC EPISODES (EVIDENCE LEVEL*) Lithium (L1) Quetiapine (L1) Divalproex (L1) Asenapine (L1)

Aripiprazole (L1) Paliperidone (> 6mg/day) (L1) Risperidone (L1)

Quetiapine + Li/DVP (L1) Aripiprazole + Li/DVP (L2)

Risperidone + Li/DVP (L1) Asenapine + Li/DVP (L2)

Olanzapine (L1) Carbamazepine (L1) Olanzapine + Li/DVP (L1) Lithium + DVP (L3)

Ziprasidone (L1) Haloperidol (L1) ECT (L3)

DVP–divalproex (encompasses sodium valproate, valproic acid and divalproex sodium); ECT–electroconvulsive therapy; Li–lithium. *Evidence level: L1, L2, L3 (see Table 4 available online for definitions of level of evidence ratings) Table 6 is adapted from Yatham et al. 2018

Initial diagnosis

Bipolar disorder is often unrecognized and misdiagnosed

Depression

Predominant symptomatic phase in all subtypes

Comorbidities

Chronic condition Phenotypes

Common, may hinder diagnosis

Need for long-term symptom stability

Bipolar I vs. bipolar II, rapid cycling, mixed features specifier

TABLE 8 Management of acute depressive episodes in BD(9) First-line treatments

Second-line treatments

ACUTE BIPOLAR I (EVIDENCE LEVEL*)

ACUTE BIPOLAR II (EVIDENCE LEVEL*)

Divalproex (L2) SSRIs/bupropion (adj) (L1) ECT (L4) Olanzapine + fluoxetine (L2)

Lithium (L2) Lamotrigine (L2) Bupropion (adj) (L2) ECT (L3) Sertraline (in pure depression (non-mixed) (L2) Venlafaxine (in pure depression (non-mixed) (L2)

Quetiapine (L1) Lurasidone + Li/DVP (L1) Lithium (L2) Lamotrigine (L2) Lurasidone (L2) Lamotrigine (adj) (L2)

Quetiapine (L1)

adj–adjunctive; DVP–divalproex (encompasses sodium valproate, valproic acid and divalproex sodium); ECT–electroconvulsive therapy; Li–lithium; SSRI–selective serotonin reuptake inhibitor. *Evidence level: L1, L2, L3, L4 (see Table 4 available online for definitions of level of evidence ratings). Table 8 is adapted from Yatham et al. 2018

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CE 3

LESSON

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

GENERAL PRINCIPLES OF MANAGING ACUTE MANIA(9) The first step prior to initiating pharmacological treatment in patients newly diagnosed with BD is to conduct a medical evaluation and a psychiatric evaluation to rule out symptoms associated with other conditions (e.g., endocrine disorder, substance use). Then, if the presentation is mania, the next steps are to discontinue antidepressants, review the course of illness, review previous treatment responses, evaluate adherence, initiate or optimize monotherapy, and lastly add-on and/or switch therapy (first-, second- or third-line). Table 5 summarizes the main five steps in the management of BD. GENERAL PRINCIPLES OF MANAGEMENT OF ACUTE BIPOLAR DEPRESSION The depressive polarity in BD accounts for up to 60% of the time that patients spend unwell(5) and is often more prevalent and more incapacitating than manic states. Depressive episodes should be treated aggressively given the high risk (upward of 70%) of suicide attempts and deaths in patients with BD that occur during this phase.(9) The same conventional principles (steps) used in the management of acute mania also apply to the management of acute bipolar depression (see Table 5). TREATMENT CHALLENGES IN BIPOLAR DEPRESSION As previously noted, misdiagnosis and delayed diagnosis of BD are common and depression occurring in the context of BD is even harder to detect. Table 7 lists the many difficulties in diagnosing and treating bipolar depression. BDI and BDII are distinct disorders (see Table 2 for diagnostic criteria). The diagnosis of BDII is usually stable over time although there is a risk of conversion to BDI early in the illness, which implies that BDII may be a risk factor or prodrome of BDI in some patients.(9) While hypomania is, by definition, less acute than mania, the disability associated

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TABLE 9 Risk factors for recurrence(9) • Younger age of onset

• More (and more frequent) previous episodes

• Rapid cycling

• Comorbid substance use

• Psychotic features

• Comorbid anxiety

Additionally, poor adherence and/or nonadherence may be a factor for apparent nonresponse to treatment; this may result in unnecessary dose increases, medication switches and adjunctive medications. Table 9 is adapted from Yatham et al. 2018

TABLE 10 Maintenance treatment of bipolar disorder(9) THERAPIES FOR PREVENTION OF MANIA (EVIDENCE LEVEL*)

First-line treatments

Lithium (L1) Quetiapine (L1) Divalproex (L3) Lamotrigine (L2) Asenapine (L2)

Quetiapine + Li/DVP (L1) Aripiprazole + Li/DVP (L2) Aripiprazole (L2) Aripiprazole IM once monthly (L2)

Second-line treatments

Olanzapine (L1) Risperidone LAI (L1) Risperidone LAI (adj) (L2) Carbamazepine (L2)

Paliperidone (> 6 mg/day) (L2) Lurasidone + Li/DVP (L4) Ziprasidone + Li/DVP (L2)

First-line treatments

Lithium (L1) Quetiapine (L1) Divalproex (L2) Lamotrigine (L1) Asenapine (L2)

Quetiapine + Li/DVP (L1)

Second-line treatments

Olanzapine (L1) Risperidone LAI (adj) (L4) Carbamazepine (L2)

Lurasidone + Li/DVP (L3)

THERAPIES FOR PREVENTION OF DEPRESSION (EVIDENCE LEVEL*)

THERAPIES FOR PREVENTION OF ANY MOOD EPISODE (EVIDENCE LEVEL*)

First-line treatments

Lithium (L1) Quetiapine (L1) Divalproex (L1) Lamotrigine (L1) Asenapine (L2)

Quetiapine + Li/DVP (L1) Aripiprazole + Li/DVP (L2) Aripiprazole (L2) Aripiprazole IM once monthly (L2)

Second-line treatments

Olanzapine (L1) Risperidone LAI (L1) Risperidone LAI (adj) (L2) Carbamazepine (L2)

Paliperidone (> 6 mg/day) (L2) Lurasidone + Li/DVP (L3) Ziprasidone + Li/DVP (L2)

adj–adjunctive; DVP–divalproex (encompasses sodium valproate, valproic acid and divalproex sodium); IM-intramuscular; LAI–long-acting injectable; Li–lithium. *Evidence level: L1, L2, L3, L4 (see Table 4 available online for definitions of level of evidence ratings). Table 10 is adapted from Yatham et al. 2018

with BDII is comparable to that associated with BDI. The rates of attempted and completed suicide are similar in both BDI and BDII.(9) Because the treatment of BDII has been understudied compared to BDI, with few large, methodologically rigorous clinical trials, there are fewer first-line treatment recommendations. Table 8 synopsizes the

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pharmacological management of acute depressive episodes in BD.

Maintenance treatment guidelines

The goal of maintenance therapy is to prevent future problematic mood episodes, reduce sub-syndromal symptoms and improve the quality of

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PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

LESSON

TABLE 11 Monitoring parameters for selected* bipolar disorder medications(9,11,12) PARAMETER

LITHIUM

DIVALPROEX

CARBAMAZEPINE

LAMOTRIGINE

Renal function

Baseline and every 6 months; more often if there is evidence of deterioration or patient is on other medications such as ACE inhibitors, diuretics or NSAIDs

Baseline

Baseline and annually

Baseline

Not required

Baseline, 2 weeks after initiation or dose change, then biannually to annually

Baseline, every 2 weeks for 2 months, then quarterly to biannually

Baseline and annually

Electrocardiogram (ECG)

Baseline and annually if there are risk factors for or existing cardiovascular disease

Not required

Baseline

Not required

Complete blood count (CBC) with differential

Baseline and annually

Baseline, 2 weeks after initiation or dose change, then biannually to annually

Baseline, every 2 weeks for 2 months, then quarterly to biannually

Baseline

Drug serum level

Every 3-6 months after therapeutic range has been established. More often if non-adherence is suspected or if clinically indicated.

Only if there is evidence of ineffectiveness, poor adherence or toxicity

Not required

Serum electrolytes

Baseline and annually

Not required

Pregnancy test (in women of childbearing age)

Baseline, and if suspicion of pregnancy

Baseline, at 2 weeks, then annually

Baseline, and if suspicion of pregnancy

Weight, serum calcium, urine output, diet (e.g., significant change in sodium intake such as low salt diet, which can increase lithium concentration)

Weight, ammonia if suspicion of hyperammonemia

Weight, rash development, HLA-B*1502 if of Asian descent

Weight, rash development

Thyroid function (TSH)

Liver function

Other

Baseline and every 6 months, more often if evidence of deterioration

Not required

Baseline and annually

Not required

ACE–angiotensin-converting enzyme; HLA–human leucocyte antigen; NSAID–nonsteroidal anti-inflammatory drug *Note: In addition to these four classic, selected mood stabilizers, multiple second-generation antipsychotics (SGAs) (with or without lithium or divalproex) are approved for acute mania, acute depression, or maintenance therapy. Monitoring parameters for SGAs in bipolar disorder are the same as in psychotic disorders. Readers are encouraged to review the monitoring parameters for SGAs in the CANMAT 2018 guidelines and/or other relevant resources.

life. Many agents recommended for the management of acute episodes have prophylactic efficacy and, generally, those that were found effective in the acute phase should be continued during the maintenance phase.(9) Medication changes are influenced by the most recent episode polarity (i.e. mania or depression), polarity of the index episode or the more frequently presenting pole of illness. Pharmacotherapy is usually indefinite due to the recurrent nature of the disorder.(10) Risk factors for recurrence are summarized in Table 9. The general approach to maintenance treatment is the same as for acute

Answer online at

treatment (see Table 5). Maintenance treatments for BD are outlined in Table 10.

Monitoring parameters in BD

A comprehensive medical history including assessment of the body mass index (BMI) and baseline laboratory investigations should be completed prior to initiating pharmacological treatment for BD and at regular interval thereafter.(9,11,12) Table 11 lists parameters that need monitoring for some commonly used medications. Note that monitoring frequency assumes that the patient is exhibiting no clinically substantial changes or concerning symptoms. More frequent evaluation

should be considered on a patient-specific basis. Additionally, “Not required” assumes that the patient is stable without major comorbidity or drug interactions.(11) MONITORING OF DRUG SERUM LEVELS FOR LITHIUM, DIVALPROEX, CARBAMAZEPINE, AND LAMOTRIGINE Therapeutic levels have not been established for carbamazepine, divalproex or lamotrigine in BD; target serum levels are based on those used in the treatment of seizure disorders.(9,11) Serum levels for these agents are usually performed to rule out nonadherence to treatment or when toxicity is suspected.(9,11)

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CE 5

LESSON

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

TABLE 12 Selected significant drug-drug interactions involving lithium, divalproex, carbamazepine and lamotrigine(11) MEDICATIONS INTERACTIONS

DVP

CBZ

Lamotrigine

CLINICAL CONCERNS

COMMENTS

Li levels are increased

The MA is not clearly understood; NSAIDs inhibit prostaglandin synthesis leading to decreased renal blood flow and facilitation of sodium and Li reabsorption and increased Li serum concentration. NSAIDs can increase Li serum concentrations between 16-60% depending on the specific agent. Concomitant use is not recommended. Aspirin and sulindac may not influence Li levels.

ACE inhibitors/ARBs

Li levels are increased

ACE inhibitors decrease sodium reabsorption resulting in sodium loss, cause volume depletion, and a dose-related decrease in GFR leading to compensatory increase in Li reabsorption and increased Li serum concentration. ARBs increase urinary sodium excretion and can cause volume depletion, leading to increased Li reabsorption and increased Li serum concentration. ACE inhibitors and ARBs can increase Li levels by 30-40%. This interaction is delayed and may not be seen for 3-5 weeks. Consider alternative antihypertensive agent that does not interact with Li when possible.

Diuretics

Li levels are increased by thiazides and decreased by mannitol

Thiazide diuretics increase Li levels by 25-40% and should be avoided. Loop diuretics may promote Li clearance in a clinically insignificant manner, however, over-diuresis with a loop diuretic can lead to toxicity. Osmotic diuretics (e.g., mannitol) increase Li clearance 40%. Potassium-sparing diuretics have limited effects on Li concentration.

Methylxanthines

Li levels may be decreased

In one single-dose pharmacokinetic study involving caffeine 300 mg, Li was reduced by ~30%. Theophylline reduces Li levels by > 30-60% in a dose dependent manner.

Other

Pharmacodynamic drug interactions between Li and other agents have been described. Most interactions are related to an increased risk of neurotoxicity. These reports are mostly limited to case reports.

Li is described as a risk factor for neuroleptic malignant syndrome when used with antipsychotics. Li has been rarely associated with serotonin syndrome. Non-dihydropyridine calcium channel blockers and antipsychotics have been associated with increasing the risk of Li-induced neurotoxicity, but this is likely rare.

Carbapenem antibiotics

Doripenem, ertapenem, imipenem/ cilastatin, and meropenem reduce DVP levels

The MA is not fully understood, but reductions of DVP levels can be significant and subtherapeutic within 24 hours. Administering additional DVP may not overcome this interaction. Risk of withdrawal seizure may be increased by a carbapenem’s independent risk for inducing seizures.

Lamotrigine

DVP increases the AUC of lamotrigine about 2-fold

Interaction occurs via a phase II glucuronidation metabolic pathway. When adding DVP to lamotrigine, a 50% reduction of lamotrigine is required. When lamotrigine is added to DVP, reduce the initial starting dose to 12.5 mg daily or 25 mg every other day.

Phenytoin

Complex interaction that is unpredictable

DVP may cause an initial decrease in total phenytoin levels; while free levels remain unaltered. Drug levels may normalize after several weeks. Phenytoin may double DVP clearance.

Ritonavir

Increased clearance of DVP

Ritonavir elevates levels of glucuronosyltransferases causing increased clearance and decreased serum concentration of DVP.

Warfarin

Increased effects of warfarin may be seen

DVP displaces warfarin from albumin-binding sites. More frequent INR monitoring may be required. Bleeding risk may be enhanced in the setting of DVP-induced thrombocytopenia and concomitant warfarin therapy.

CYP450 3A4 and 1A2 substrates

3A4 and 1A2 substrates will be induced by CBZ, decreasing that drug’s concentration and potential effectiveness

Examples of 3A4 substrates: Alprazolam, aripiprazole, brexpiprazole, citalopram, lurasidone, quetiapine, simvastatin, tacrolimus, oral contraceptives. Examples of 1A2 substrates: Asenapine, clozapine, olanzapine.

CYP450 3A4 inhibitors/inducers

Substrate of 3A4; inhibitors and inducers of 3A4 may affect CBZ levels

Inhibitors: Azole antifungals, cimetidine, fluoxetine, grapefruit juice. Inducers: Rifampin, phenobarbital, phenytoin.

Antidepressants

Decreased effectiveness via induction of many antidepressants; higher doses may be required.

Associated with serotonin syndrome; this is rare and mainly theoretical. Contraindicated within 14 days of MAOI use.

Antiretrovirals

Decreased effectiveness of various agents

Contraindicated with delavirdine and other non-nucleoside reverse transcriptase inhibitors. Induces many other antiretrovirals from other classes such as maraviroc and lopinavir. Careful screening of drug interactions between CBZ and any antiretroviral should be conducted.

Antipsychotics

Induction of antipsychotic medication and reduced effectiveness

Contraindicated with lurasidone. Examples: The AUC and/or serum levels are significantly reduced with aripiprazole (70%), haloperidol (60%), olanzapine (50%), quetiapine (80%), and risperidone (50%).

Clozapine

Decreased serum concentrations, enhanced myelosuppressive effects

Clozapine should be avoided with other medications that carry the risk of agranulocytosis, including CBZ.

Apixaban/ dabigatran/ rivaroxaban/warfarin

Decreased serum concentrations of apixaban, dabigatran, rivaroxaban, and warfarin

Warfarin requirements may be greater; carefully monitor INR. CBZ should be avoided with concomitant novel oral anticoagulants; warfarin is preferred.

Hormonal contraception

Decreased serum concentrations via 3A4 induction

Breakthrough bleeding and pregnancies have occurred. Alternative or backup contraceptive methods are recommended. Hormonal contraception with higher doses may decrease this risk.

Estrogen-containing products

Lamotrigine levels are reduced by up to 50%

Therapeutic drug monitoring may be warranted, and higher lamotrigine dosing may be required.

VPA

See DVP/Lamotrigine interaction

NSAIDs

See DVP/Lamotrigine interaction.

Li–lithium; DVP–divalproex (encompasses sodium valproate, valproic acid and divalproex sodium); CBZ-carbamazepine; ACE–angiotensin-converting enzyme; ARB-angiotensin II receptor blockers; NSAID–nonsteroidal anti-inflammatory drug; AUC-Area under the curve; CYP-Cytochrome P450; INR-International normalized ratio; MAOI-monoamine oxidase inhibitor; MA-Mechanism of action; GFR- Glomerular filtration rate

CE 30 6

JULY/AUGUST JULY/AUGUST 2019 2019 [Vol.6 No.6]

Answer online at

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

As for lithium, it is suggested to verify serum levels before steady state to avoid toxicity. The target serum level for lithium in acute treatment is 0.8-1.2 mEq/L (0.4- 0.8 mEq/L in older adults) while in maintenance treatment, serum levels of 0.6- 1 mEq/L may be sufficient.(9)

Summary

BD is a serious mental illness with significant morbidity and mortality. Its management is complex and includes minimizing the number and severity of mood episodes and improving functioning. Pharmacists, as medication experts, can play a pivotal role in applying current treatment approaches, reviewing and monitoring the pharmacological treatments and collaborating with other healthcare professionals to provide quality care and assist patients affected by BD. Tables 3, 4 available online at www.ecortex.ca. Additionally online find, Table 13 on selective significant adverse effects involving lithium and divalproex, as well as Table 14 on adverse effects involving carbamazepine and lamotrigine. REFERENCES 1. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey initiative. Arch Gen Psychiatry 2011;68:241-51. 2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed (DSM5). Arlington, VA: American Psychiatric Publishing; 2013. 3. Griswold KS, Pessar LF. Management of bipolar disorder. Am Fam Physician. 2000;62(6):1343-53, 1357-8. 4. Knežević V, Nedić A. Influence of misdiagnosis on the course of bipolar disorder. Eur Rev Med Pharmacol Sci 2013;17:1542-5. 5. National Depressive and Manic-Depressive Association (DMDA) Constituency Survey (2001). Living with bipolar disorder: how far have we really come? https://secure2.convio.net/dabsa/pdfs/bphowfar1.pdf. 6. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530-7. 7. Bowden CL, Perlis RH, Thase ME, et al. Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP‐BD). CNS Neurosci Ther 2012;118:243-9. 8. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994;31:281-94. 9. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 2018;20:97-170. 10. Canadian Pharmacists Association. Bipolar disorder. RxTx Compendium of Therapeutic Choices 2018. https://www.e-therapeutics.ca/search. 11. College of Psychiatric and Neurologic Pharmacists. Bipolar disorder. Psychiatric Pharmacotherapy Review. 2018-2019. 12. Clinical Practice Guidelines. Management of bipolar disorder in adults. Malaysia Health Technology Assessment Section. 2014.

Answer online at

LESSON

QUESTIONS

Answer online at www.eCortex.ca, Quick Search CCCEP #1329-2019-2713-I-P Mr. Smith has bipolar disorder and has been a patient of your pharmacy for several years. Mr. Smith uses divalproex sodium 500 mg twice daily as a mood stabilizer. The following 3 questions refer to this case. 1. During Mr. Smith’s last visit at the pharmacy, you notice that he seems more “hyper” than usual. His speech is rapid and he would not let you interrupt. You suspect a relapse into a manic episode. Which of the following symptoms would also be indicative of a manic episode? a. b. c. d.

Increased need for sleep Recurrent thoughts of death Racing thoughts Inappropriate guilty feelings

2. Considering his current symptoms, you review his pharmacotherapy regimen and confirm adherence to treatment. Which of the following regarding treatment with divalproex sodium in bipolar disorder is true? Divalproex sodium…

a. Is effective in the treatment of mania b. Is not effective in preventing manic episodes c. Requires much higher doses than when used for seizure disorders d. Requires serum concentration monitoring to optimize efficacy 3. Mr. Smith returns 3 months later and has relapsed into a severe depressive episode despite being adherent to his treatment. Which of the following could be an appropriate course of action? a. Stop divalproex sodium and start an SSRI b. Continue the divalproex sodium and add on an SSRI c. Decrease the dose of divalproex sodium and reevaluate d. Discontinue divalproex sodium and start aripiprazole 4. Lithium is safe to use for the management of acute mania and acute depression in BD because of its lack of interactions with other drugs. a. True b. False

5. Which of the following is associated with lamotrigine? a. b. c. d.

Hyponatremia Thrombocytopenia Stevens-Johnson syndrome Lack of interactions

6. BT, recently diagnosed with bipolar disorder, presents to your pharmacy with his first prescription of lithium. Which of the following regarding lithium is true? Lithium… a. Is an old agent and is no longer considered first-line b. Has not been shown to reduce rates of suicide c. Is first-line for the management of bipolar II d. Is effective in preventing manic and depressive episodes 7. BT has been on lithium for the past 4 weeks and is doing well. He stops by your pharmacy to inform you that his family doctor will call in a prescription for an ankle pain. What medication would be the most appropriate to control BT’s pain?

a. Duloxetine 60 mg once daily b. Celecoxib 200 mg 2 times daily for 7 days for pain c. Naproxen 500 mg 2 times daily until pain is resolved d. Sulindac 200 mg 2 times daily as needed for pain 8. Gwendolyn is a 28-year-old patient with BD, admitted to the hospital for depressed mood and suicidality. The patient experienced a major depressive episode at the age of 15 but does not recall taking any medications at that time. Gwendolyn’s first and only manic episode occurred at the age of 21 and was treated with olanzapine. However, the patient attributed the self-discontinuation of the medication 3 months prior to her admission to weight gain and fatigue.

[Vol.6 JULY/AUGUST No.6] JULY/AUGUST 2019 2019

CE 7 31

LESSON

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Bipolar Disorder

Medical evaluation and laboratory tests revealed no abnormalities. Based on CANMAT guidelines, what would be the best initial treatment option for this patient?

a. b. c. d.

a. Restart olanzapine and add fluoxetine b. Start quetiapine with a target dose of 800 mg daily c. Start lithium 300 mg twice daily titrated based on serum concentration d. Start aripiprazole 15 mg daily

Colette Raphael is a Board Certified Psychiatric Pharmacist with many years of clinical experience in mental health and addiction and an Accreditation Specialist currently working at the Centre for Addiction and Mental Health (CAMH) in Toronto. Ms. Raphael is also a Teaching Associate with the University of Toronto, Faculty of Pharmacy.

a. True b. False

14. Which of the following is not a goal of therapy in BD? a. Control the symptoms of acute episode b. Prevent recurrences c. Cure BD at once d. Minimize functional impairments

Ammonia Liver function tests HLA-B*1502 variant Thyroid function tests

This lesson is published by EnsembleIQ: 20 Eglinton Ave. West, Suite 1800, Toronto, ON, M4R 1K8 Phone: 877.687.7321 Fax: 888.889.9522 CE queries: email ecortex@canadianhealthcarenetwork.ca No part of this CE lesson may be reproduced, in whole or in part, without the written permission of the publisher.

11. According to CANMAT guidelines, which of the following is considered the most appropriate first-line treatment for a patient with bipolar disorder currently in a major depressive episode? a. b. c. d.

CE CLINICAL EDITOR Lu-Ann Murdoch, RPh, BScPhm, ACPR

CE MANAGING EDITOR Vicki Wood, Toronto, Ont. vwood@ensembleiq.com

a. True b. False

Paroxetine Alprazolam Lamotrigine Erythromycin

CE PROJECT MANAGER Rosalind Stefanac

CE DESIGNER Nancy Peterman, Toronto, Ont.

15. In acute depressive episodes, antidepressants should be tapered and discontinued when possible:

10. Divalproex sodium has a potentially serious drug-drug interaction with which of the following medications?

a. b. c. d.

AUTHOR By Colette Raphael, RPh, B.Pharm, BCPP, MHA, CHE

Depression Anxiety disorder Schizophrenia Personality disorder

13. Suicide is one of the leading causes of death in BD:

9. Baseline laboratory screening before starting divalproex sodium should include which of the following? a. b. c. d.

THIS MONTH MANAGING BIPOLAR DISORDER

12. The most frequent misdiagnosis in BD is:

Lithium monotherapy Bupropion monotherapy Carbamazepine monotherapy Aripiprazole and an antidepressant

E THIS C IS N LESSO ! FREE

LESSON

P H A RM ACY P R ACT I CE + BUS I N ES S N AT I ONA L CO NT INUING EDUC AT IO N P RO GR A M

*REFERENCE ONLY:

JULY/AUGUST 2019 • 1.00 CEU • 1329-2019-2713-I-P Managing Bipolar Disorder For CE expiry dates, please go to www.ecortex.ca

1. 2. 3. 4. 5.

a a a a a

b b b b b

cd cd cd

Please submit your answers online

6. 7. 8. 9. 10.

a a a a a

b b b b b

c c c c c

d d d d d

11. 12. 13. 14. 15.

FOR IMMEDIATE RESULTS, ANSWER ONLINE AT www.eCortex.ca

a a a a a

bcd bcd b bcd b

> To find this lesson, enter the CCCEP number (1329-2019-2713-I-P) in the Keyword box. If you have any questions please email: ecortex@canadianhealthcarenetwork.ca 8

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Chec many kmoout re

CCCEP-ap pro CE lesson ved s online!

COVER: THE INNOVATORS

any pharmacists would prefer not to spend time figuring out third party drug coverage for patients. But at Specialty Rx Solutions and SRx Pharmacies, helping patients get reimbursed for prescription medications is part of the comprehensive services targeted at improving outcomes for patients with chronic diseases. The new and growing national pharmacy chain was launched about five years ago when Adesh A. Vora looked at various specialty areas of patient care and realized there were many gaps in providing exceptional pharmaceutical care. “Marginalized patients and those who are chronically ill are often non-compliant with their drug treatments and require more attention and care,” he says. “Retail pharmacy can be a very demanding workplace for pharmacists where volume has become the priority over patient care,” he adds. “But we feel we have created a model that allows us the time needed to support those patients in need with better outcomes. Pharmaceutical companies are now interested in partnering with us to deliver unique new drugs that require that extra attention to details.” By now, Vora, who is president and CEO of the new chain, has opened pharmacies in Alberta, British Columbia, Manitoba and Saskatchewan under the name SRx Pharmacy. In Ontario, there are now six SpecialtyRx Solutions Pharmacies with more slated to open soon.

“ Our objective is to make sure our patients on prescription medications receive all the support they need for a successful treatment outcome.”

SPECIALTY PHARMACIES FOCUS ON PATIENTS WITH CHRONIC DISEASES BY SONYA FELIX • PHOTOGRAPHY BY COLIN WAY Calgary SRx Pharmacy Team (ABOVE LEFT TO RIGHT) Sonal Raythatha, clinical Pharmacist; Brittany Larmand, pharmacy technician; Betty Lau, pharmacy technician; Robyn Fulton, clinical Pharmacist and Stephanie Gysel, clinical Pharmacist, pharmacy Manager

Heading east, he recently opened a Spécialite Rx Solutions in Quebec and plans to expand further east in the near future. Filling care gaps With the focus on chronic disease management, pharmacy staff identify gaps in care and do what they can to fill those gaps, says Stephanie

Gysel, pharmacy manager of SRx Pharmacy in Calgary, which opened in 2016. Pharmacists and registered pharmacy technicians, who perform the final check on prescriptions and engage in sterile and non-sterile compounding, practice to their full scope to provide the best possible patient care. “Every single patient at our

pharmacy, whether filling a prescription for a specialty medication or simply an antibiotic, gets the same high level of care,” says Gysel. “We only get paid for the services we can charge the province, but we feel it is the right thing to do.” The model Vora devised for helping Canadians with chronic diseases stresses collaboration with other healthcare professionals. His executive team includes a nurse practitioner and a registered nurse. “If we do not work in better collaboration with doctors, nurses and other healthcare providers, combine the synergies of various healthcare providers, we collectively as a team are failing the patient,” he explains. The company’s collaborative goals include increasing efficiencies, reducing errors and discrepancies in the current healthcare system, and providing access to a topnotch panel of consultants. At the Calgary SRx Pharmacy, the pharmacy team works collaboratively

[Vol.6 No.6] JULY/AUGUST 2019

with specialist clinics that don’t often have enough nursing or pharmacy staff. “We’re a resource for them,” explains Gysel. “We do patient teaching, followups and monitor lab work collaboratively with the patients’ health care team. Our objective is to make sure our patients on prescription medications receive all the support they need for a successful treatment outcome.” Filling health care gaps adds significant cost-savings to the provincial and federal governments as well as private insurance plans, Gysel says. “For example, with our Hepatitis C patients, they receive regular follow-up care from our pharmacists, ensuring compliance, resolving potential drug interactions and providing all the support they need to complete a $60,000 drug therapy effectively, thus reducing potential drug wastage and improving patient outcomes.”

Time to do patient teaching and follow-ups is crucial to ensure patients receive needed support for a successful treatment outcome, says Stephanie Gysel (above right), with a patient. BELOW: SRx Pharmacy in Calgary.

With many new specialty drugs carrying high price tags, patients may be overwhelmed and stressed over how to pay for treatment. “As we know, there is sometimes very little funding for marginalized patients, such as those with Hepatitis C, addictions and

JULY/AUGUST 2019 [Vol.6 No.6]

mental health concerns. There are also many chronic diseases that do not receive a ton of funding, such as inflammatory bowel disease or rheumatology, in comparison to diabetes and cardiovascular diseases.” To help address the cost

factor, SRx Pharmacy liaises with individual manufacturer patient support programs and patients to ensure patients receive coverage for the mediations they need, Gysel explains. “We will also assist patients in enrolling in Alberta Blue Cross Non-Group coverage if they require.” SRx Pharmacy also has an affiliated infusion clinic, where patients can go to receive infusions for medications such as biologic drugs. “The nurses work with patients to ensure their infusions are given at a time convenient for their life schedule, including evenings and weekends,” Gysel says. “Our business is growing and we get great feedback from patients,” she says. “It’s very rewarding—every day, I feel we make a difference in someone’s life. I leave every day feeling good about my job.” Sonya Felix is a BC-based writer specializing in pharmacy and benefits issues

FINDING YOUR NICHE:

DEALING WITH ADDICTION

PROVIDING HOPE WHEN PATIENTS HIT ROCK BOTTOM

Top: Getty Images; Photo: courtesy of Rich Rego

BY ROSALIND STEFANAC

t’s no secret that Canada is in the midst of an opioid crisis. According to a 2019 national government report on Apparent Opioid-related Deaths in Canada, one life lost every two hours in 2018 was related to opioids, and 94% of these deaths were unintended. In fact, for the first time in four decades, life expectancy has plateaued in Canada, largely due to opioid misuse. With statistics like these, you would think that every pharmacy in the country would be providing services to help patients facing opioid addiction issues, but that’s clearly not the case. Those pharmacists distributing treatments such as methadone and naloxone say stigma and misconceptions about the type of patients who have addictions are some of the factors still preventing more people from getting involved. “When we do educational sessions in the community and hear that pharmacists aren’t offering methadone or naloxone, it can mean patients are having to drive 40 minutes a day for treatment and that’s just not right,” says Kelly Grindrod, an associate professor at the University of Waterloo’s School of Pharmacy. For the last four years, Grindrod has been working as a clinical pharmacist as part of a primary care team at the Kitchener Downtown Community Health

“A lot of people misunderstand addiction as not being a disease state. But this is not a lifestyle choice and these patients are often facing many multi-faceted issues that include mental health and trauma.”

Talking to patients and creating those trusting relationships is a key part of the job, says Pharmacist Rich Rego with a patient in downtown Calgary.

Centre, which treats vulnerable patients often dealing with addictions. Prior to that Grindrod also worked in hospital and community settings in downtown Vancouver, where patients with similar issues were the norm. “Sure, there are patients who are difficult, but the vast majority are ones you form [professional] relationships with because you see them

every day and that’s so rewarding,” she says. “When I was working with methadone, we saw patients stabilize, find housing and even have their first child.” Calgary pharmacist Rich Rego, who has been specializing in addiction care for the last 12 years, says seeing patients thrive is the best part of his job. “The success stories are what keeps me going,” says Rego, who owns two pharmacies and runs Alberta’s first clinic focused on injectable opioid agonist (iOA) treatment for opioid use disorder. “Just the other day a girl we looked after had a baby and came back to thank us—when you do get those success stories months or even a year later, you realize what an impact you’ve had.” For Rego, specializing in addictions has also opened doors to teaching opportunities, speaking engagements and even an on-camera role in a high-profile 2018 documentary called Painkiller about Canada’s opioid crisis (www.telus. com/en/health/personal/painkiller). “I wasn’t looking for those opportunities but they found me because of my expertise,” he says, noting that his real education still comes from the day to day interaction with patients. “They’re my ultimate teachers.” Rego says he is always willing to share insights and advice with pharmacists interested in providing services for addiction patients. In an effort to get more pharmacists across Canada involved in this critical

[Vol.6 No.6] JULY/AUGUST 2019

“It’s all about patient empowerment. We allow them to see that they have the will and ability to get off these substances and we coach them through that.” patient care area, Grindrod is part of group working on a national naloxone and harm reduction education program for pharmacists to launch in 2020. (Pharmacists can contact her directly [kgrindrod@uwaterloo.ca] for further details.) “In a smaller rural community especially, you can connect with the local public health nurse and paramedic and you might even become the main distributor of naloxone in the area,” she says. “Or you can just be a pharmacist with a handful of patients that need this care and that can be so impactful too.” In addition to being professionally rewarding, helping patients with addictions can make good business sense too. Pharmacy owner John Girgis first started offering specialized services for patients with addictions in his Liberty Village Pharmacy in Toronto about 10 years ago and they now make up about

20% of the clientele. He has since spun off variations of the program in all four of his pharmacy locations. “A lot of people misunderstand addiction as not being a disease state,” he says. “But this is not a lifestyle choice and these patients are often facing many multi-faceted issues that include mental health and trauma.” Girgis got certified in psychiatric and pain management through the U.S. and aligned himself with pain management physicians in the area to formulate a program that would be as effective as possible for patients with addiction-related issues. Part of that includes an opioid risk tool assessment to determine if a patient might be at risk for addiction. “We do a lot of out-of-the-box compounding too, with different concentrations to help alleviate withdrawal that comes with stopping opioids,” he says. Given the sensitive nature of this disease state, Girgis doesn’t advertise his addiction services. Referrals come through physicians and nurse practitioners or patient word of mouth. “It’s all about patient empowerment,” he says. “We allow them to see that they have the will and ability to get off these substances and we coach them through that.”

RESOURCES FOR ADDICTION CARE The Centre for Addiction and Mental Health (https://www.camh.ca/en/ education/continuing-education)

Canadian Society of Addiction Medicine (https://csam-smca.org/) Canadian Centre on Substance Use and Addiction (https://www.ccsa.ca/) National Institute on Drug Abuse (https://www.drugabuse.gov/)

STUDY: Allowing Pharmacists to Directly Dispense Opioid Antidote Can Cut Opioid Overdose Deaths (https://www.rand.org/news/ press/2019/05/06.html)

Toward the heart

(https://towardtheheart.com/)

ROSALIND STEFANAC is a Toronto writer specializing in healthcare and pharmacy topics.

How do I specialize?

Organizations like the Centre for Addiction and Mental Health offer some great continuing education courses on addiction for pharmacists and other healthcare providers. Additionally, the Canadian and American societies of addiction medicine have educational resources for healthcare professionals. Before starting to offer addiction services in your own workplace, consider getting more frontline experience by lending your time to local outreach programs or a primary healthcare team who deals with vulnerable clients. Ensure your pharmacy is well equipped to provide care for patients facing addiction issues by offering methadone/ naloxone programs and having private counselling spaces; be aware of other resources you can refer patients to in the community and connect with other healthcare providers who can refer people to you. Pharmacists specializing in this area say it can be useful to get further certification in pain education and psychiatric care, available through the U.S.

JULY/AUGUST 2019 [Vol.6 No.6]

Classified

We are more than our name implies. Check out our new website. www.oconnell.ca

CLASSIFIED ADVERTISING

a great place to work Advance your pharmacy career with Save-On-Foods. We are a Western Canadian company with over 130 pharmacies in over 50 communities across BC, Alberta, Saskatchewan, Manitoba, and the Yukon. We’re looking for pharmacy professionals who share a passion for healthy living and for delivering quality patient-centred care to our customers.

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Our pharmacists have opportunities to be involved with health screenings, vaccinations and travel health, medication management services, prescribing, and other clinical programs where possible in their province. A career at Save-On-Foods is an opportunity to: • Work in a friendly, professional and supportive work environment • Enjoy flexibility, stability and great compensation packages • Develop your leadership skills, expand your scope of practice and advance your career

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pharmacy

[Vol.6 No.6] JULY/AUGUST 2019

BACK TALK

CREATIVE THOUGHTS AND SMART IDEAS FOR PHARMACY OWNERS AND MANAGERS

BIZ TALK

DEREK DESROSIERS, BSc(Pharm), RPEBC, RPh, has accrued more than 36 years of

experience as a community pharmacist, pharmacy manager and pharmacy owner. He was also CEO of a regional pharmaceutical wholesale company and banner program, and recently, director of pharmacy practice support at the BC Pharmacy Association. Feedback and topic ideas are welcome at Derek@dessonconsulting.com.

HOW TO GAUGE EMPLOYEE ENGAGEMENT Do you ever wonder how your employees feel about their job and your business, and if they are performing at the top of their game? Employee engagement is crucial for a successful and growing business. In order to engage your employees, you first need to know how they feel about their jobs, coworkers, management and the overall culture within the company. 38

An employee climate survey can unveil important information to help you modify and execute your strategic plan. A good employee survey should be conducted by a third party. Employees are more willing to participate in a survey, and more candid, when they know management will not be able to identify them. Furthermore, it’s important

JULY/AUGUST 2019 [Vol.6 No.6]

to reinforce that there will be no negative repercussions to anyone as a result of survey responses. Some of the best surveys, involve a series of statements that staff members rate on a five-point scale from ‘strongly disagree’ to ‘strongly agree.’ If conducted online, these types of surveys are easy for employees to complete and generally do not take much time. Ensure that employees have the opportunity to offer clarification in open-ended comment boxes. Aggregate results can be tabulated and presented first to management, then to staff at an employee meeting. Doing so lets them know that you are taking their concerns seriously. Results can usually be put into several larger categories, which may include: pride in the organization, training, salary/wage administration, communication, management and overall job satisfaction. Giving employees an opportunity to voice their concerns and opinions is the most important first step in ensuring that they are engaged in the business.

An engaged staff will almost always lead to positive outcomes such as increased sales, customer satisfaction, improved customer retention and improved profitability. A company with a positive, enthusiastic culture is much less likely to experience issues related to employee dissatisfaction. Many a business has failed or performed poorly because the employees were disinterested, unengaged and, in a way, actually sabotaging the business. Management is often blind to the issues underlying disengagement. An employee climate survey can uncover problems.

Act upon what you learn Your next step is to address the key issues identified in the employee climate survey. You also need to continuously keep staff engaged by soliciting their opinions, compensating them appropriately, ensuring their workload is appropriate, and having the right people with the right skills in the right job. Providing incentives (not necessarily financial) is another way to keep staff engaged in the business and performing at their best. The bottom line is that if you know and understand how your staff feel, and you make every effort to keep them engaged in the business, you will reap the benefits personally and financially over the long term.

Illustration by Spencer Flock

An employee climate survey can uncover problems.

d e R e oWR c HAnge Fo

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