Pharmacy Practice + Business - June 2020 by ensembleiq

What can you offer your patients for clinically proven pain relief at the source? Voltaren (diclofenac diethylamine gel) reaches into inflamed soft tissues and joints to relieve pain and inflammation associated with acute injury.1,2

Diclofenac Emulgel formulation NNT = 1.8 In the 2015 Cochrane review* of topical NSAIDs, diclofenac Emulgel formulation had an NNT of 1.8. The “ideal treatment” would have an NNT of 1.0.3,4† NNT = number needed to treat. * The review included randomized, double-blind, active or placebo-controlled trials in which treatments were administered to adults with acute pain resulting from strains, sprains or sports or overuse-type injuries.3 †Reflects a hypothetical scenario where all the patients in the treatment group have benefitted but no one has in the control arm.4

Flip to discover

Voltaren’s reach into inflamed soft tissues and joints after topical administration.

Voltaren contains diclofenac*, which penetrates through the skin and reaches inflamed tissues1,2 Formulated for absorption of diclofenac through the skin.2

Accumulates under the skin and releases diclofenac into underlying tissues.1,2

In literature, absorption of various NSAIDs, including diclofenac, occurs to a depth of at least 3-4 mm through the underlying dermis and subcutaneous tissue.1,2,5

Voltaren Extra Strength contains oleyl alcohol which increases the permeation of diclofenac through the skin.2

Diclofenac concentration in the synovial tissue and synovial fluid can be up to 20x the plasma concentrationâ&#x20AC; after topical application to hand and knee joints.1,2

*Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) for topical use. â&#x20AC; As demonstrated in vitro in human rheumatoid synovial microsomes.

Voltaren is clinically proven to reduce pain and inflammation at the site of application1,2 In a clinical study by Duteil L, et al. published in the Journal of Clinical & Experimental Dermatology (1990), Voltaren demonstrated:

84%

inhibition of inflammation in the first 4 hours after 1 application6

75%

inhibition of inflammation 48 hours after 1 application1,6

Recommend Voltaren to your patients with acute, localized pain.

Voltaren (diclofenac diethylamine gel, 1.16% w/w and 2.32% w/w) is indicated for the relief of pain associated with acute, localized muscle or joint injuries such as sprains, strains and sports injuries. This is typically as an adjunct to other measures such as rest for the relief of discomfort associated with such injuries. Voltaren Emulgel Back & Muscle Pain and Voltaren Emulgel Joint Pain Regular Strength (diclofenac diethylamine gel 1.16% w/w) are indicated for use in adults and adolescents 16 years of age and older. Voltaren Emulgel Extra Strength and Voltaren Emulgel Joint Pain Extra Strength (diclofenac diethylamine gel 2.32% w/w) are indicated for use in adults between 18 to 65 years. Voltaren should not be used for more than 7 days for muscle and joint injuries unless recommended by a doctor. Please consult the Product Monograph for information to assist in the benefit-risk assessment. Always direct the patient to read the label. The Product Monograph is available upon request by calling 1-888-788-8181. References 1. Voltaren Emulgel Product Monograph. GlaxoSmithKline Consumer Healthcare Inc. March 4, 2020. 2. Voltaren Emulgel Extra Strength Product Monograph. GlaxoSmithKline Consumer Healthcare Inc. March 4, 2020. 3. Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD007402. 4. Health Knowledge. Numbers needed to treat (NNTs) - calculation, interpretation, advantages and disadvantages. [Internet]. 2018. Available from: https://www.healthknowledge.org.uk/public-health-textbook/research-methods/ 1a-epidemiology/nnts. Accessed April 16, 2020. 5. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J. Pharmacol. Exp. Ther 1994; 268 (1):144-151. 6. Duteil L, Queille C, Poncet M, Ortonne JP, Czernielewski J. 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. ÂŠ2020 GSK group of companies or its licensor.

PM-CA-VOLT-20-00017

Contents JUNE/JULY 2020 [VOL.7 NO.5]

EDITOR’S MESSAGE

THE BUZZ

Pharmacists in the big game / BY VICKI WOOD

What pharmacists are talking about on CanadianHealthcareNetwork.ca

DRUG NEWS

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

16 19 25

PRACTICE EXPERTS Geriatric Issues

/ BY MATHILDA PRINSLOO

PRACTICE EXPERTS Travel Health

/ BY SHERILYN HOULE

5 TIPS

Recognizing and managing immune checkpoint inhibitor tox-ICI-ties / BY PIERRE THABET & JASON WENTZELL

28 35

CLINICAL FEATURE

Understanding Lyme disease: Answers to 14 key questions about diagnosis and management / BY VICTORIA COX

PAGES 21-24

COVER STORY

Covid-19 heroes: Pharmacists truly stepped up. Thank you!

CE LESSON

Exploring acute migraine treatments for adults (1.0 CEU) MADE POSSIBLE BY ARALEZ PHARMACEUTICALS CANADA INC.

/ BY SONYA FELIX

INNOVATOR PROFILE

51 52

CLASSIFIEDS

Skip Dr. Google—Ask a Pharmacist / BY ROSALIND STEFANAC

PAGES 43-50

Employment opportunities and services

CE LESSON Managing patients with chronic kidney disease

BACK TALK

Strategy: Unusual times can spur business creativity / BY PAVITHRA RAVI / ILLUSTRATION BY SPENCER FLOCK

www.CanadianHealthcareNetwork.ca /

(1.25 CEUs)

@Ppr_plus

@PharmacyPracticePlusBusiness [Vol.7 No.5] JUNE/JULY 2020

Recommend FeraMAX® for your IDA patients. Pharmacist survey on iron supplements FeraMAX®

48%

Palafer®

22%

Eurofer

Proferrin®

Wampole

Responses less than 2% not shown; n=746 gave a valid response with an OTC brand name; Results may total >100% due to multiple brand recommendations

•

For the ﬁfth year in a row, FeraMAX® is the #1 recommended iron supplement by Pharmacists (48%) and Physicians (47%) in a national survey†

•

Recognized by the Society of Obstetricians and Gynecologists of Canada

Recommend with conﬁdence. References: † Pharmacy Practice+ and Profession Santé 2020 / The Medical Post and Profession Santé 2020 – Survey on OTC Counselling and Recommendations Palafer® is a registered trademark of Beecham Laboratories Inc. Proferrin® is a registered trademark of Colorado Bio Labs, Inc. Total Completed Surveys: • Pharmacists: 1,426 (including 574 Quebec pharmacists) • Physicians: 654 (including 289 Quebec physicians)

Editor’s Message

VICKI WOOD

vwood@ensembleiq.com

PHARMACISTS IN THE BIG GAME

bench-warmer. “Put me in, coach,” he pleads. Grudgingly—since he has no other option—the coach does. And in the end, the kid comes through with a touchdown and wins the game. Well, COVID-19 certainly put you in the game, pharmacists. You geared up (as best you could). You adjusted your hours and your pharmacy layouts. You learned the new rules and then you had to create new systems for patients and staff. As our cover story states, you truly stepped up, often as the only healthcare providers open in communities that were shuttered, when the rules of the game were confusing and the statistics alarming. Pharmacy students, also eager to help, supported the effort in hundreds of practical ways. Across the country, students such as the Pharm AgainstCOVID-19 group got busy sourcing and delivering PPE donations, volunteering as support staff and using social media to bust myths and raise awareness of pharmacists’ importance to their communities. This summer, although the pandemic is by no means behind us, we wanted to take the time to celebrate and recognize the efforts of both community and hospital pharmacists who did us all proud by showing up to deliver not only their usual level of patient care, but also calm reassurance, fact-based information and a friendly face to the rest of us in these troubled times. From those of us whose only job was to stay home, thank you.

In mid-March, when most of Canada went into semi-lockdown as a measure to help stem the spread of COVID-19, how many of us expected that we would enter the summer of 2020 still battling this fierce and unusual virus? If someone had told me on March 13 (the day our province, Ontario, began to close to non-essential activities) that I would not be able to step within two metres of my adult children, see my sister or my parents or best friends (or even get a haircut) for the next three months, it would have been extremely hard to prepare for the time ahead. Yet, taking it day by day, people managed. We pitched in to help in any way that we could, and mostly, we stayed home to avoid making the situation worse. But for pharmacists, it was showtime. The pandemic suddenly turbo-charged the implementation of concepts that the profession has been asking to take on for years. Prescribing, renewals, minor ailment assessment? Done. You stepped up at a time when doctors and walk-in clinics were reducing personal visits and hospitals became hot zones of potential virus transmission. The situation reminds me of that old football trope we all have somewhere in our collective memories. You know the one (it originated with the 1925 movie, The Freshman): the scrawny kid has been warming the bench all season, relegated to waterboy. He’s been begging, to no avail, for a chance to play, but the coach won’t listen. Then in the final quarter of the championship game, all the star players are injured and there’s no one left but our PHARMACY PRACTICE + BUSINESS SENIOR VICE PRESIDENT, CANADA 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 CREATIVE DIRECTOR Nancy Peterman

PRODUCTION MANAGER Lisette Pronovost

DIRECTOR OF MARKETING Alex Voulu

Special thanks to Mayur Tailor and Emil Diab of Pharm AgainstCOVID-19 for supplying many of the photos for our cover story. @Ppr_plus @PharmacyPracticePlusBusiness

ACCOUNT MANAGER, QUÉBEC Nancy Dumont ndumont@ensembleiq.com

CONTINUING EDUCATION/ PROJECT MANAGER/PROOFREADER Rosalind Stefanac SALES COORDINATOR Kalli Sagos SENIOR DIRECTOR, DIGITAL ksagos@ensembleiq.com CANADA & SPECIAL PROJECTS Valerie White COLUMNISTS AND CONTRIBUTING/CONSULTING SENIOR DIRECTOR EDITORS AUDIENCE STRATEGY Derek Desrosiers, BSc(Pharm), Lina Trunina RPEBC, RPh; Shelley Diamond, ltrunina@ensembleiq.com BScPhm; Sherilyn Houle, BSP, PhD; Sandra Knowles, BScPhm; BRAND DIRECTOR Lu-Ann Murdoch, BScPhm; Nardine Martin Rissin Nakhla, PharmD; Carlene Oleksyn, mrissin@ensembleiq.com BSP Pharm, CTH; Vikas Parihar, SENIOR ACCOUNT MANAGERS, BScBiochem, BScPharm, PharmD; TORONTO Jillian Reardon, BSc(Pharm), ACPR, Norman Cook PharmD, RPh; Rosalind Stefanac; ncook@ensembleiq.com Karen Welds Scott Tweed stweed@ensembleiq.com

CORPORATE OFFICERS CHIEF EXECUTIVE OFFICER Jennifer Litterick CHIEF FINANCIAL OFFICER Jane Volland

CHIEF INNOVATION OFFICER Tanner Van Dusen CHIEF HUMAN RESOURCES OFFICER Ann Jadown

EXECUTIVE VICE PRESIDENT, EVENTS & CONFERENCES Ed Several SENIOR VICE PRESIDENT, CONTENT Joe Territo

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: 2000, rue Peel, Bureau 760, Montréal, Quebec, H3A 2W5. 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 © 2020 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.7 No.5] JUNE/JULY 2020

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1. ALG is the benchmark for residual value projections in North America, publishing residual values for all vehicles in the United States and Canada. For more information, visit www.alg.com. 2. Safety ratings are awarded by the Insurance Institute for Highway Safety (IIHS). Please visit www.iihs.org for testing methods.

THE BUZZ

The first word is yours

Here’s what pharmacists are talking about on CanadianHealthcareNetwork.ca this month:

Preliminary discussions underway for pharmacies to test for COVID-19 AND Before we do more—such as COVID-19 testing—we need tools, time and protection

In early June, the news broke that Ontario premier Doug Ford was in early discussions with pharmacy companies about the possibility of bringing COVID-19 testing to pharmacies; an approach being widely implemented in the US. In response, pharmacist/blogger Brandon Tenebaum argued that before any more expanded scope is pursued, pharmacy must address the issues that are already causing pharmacists stress in the workplace: lack of time, lack of adequate staffing and the autonomy to provide services in a professionally responsible manner.

YOUR COMMENTS “ There is absolutely nothing in this for the individual pharmacist. Increased personal risk, more liability, more work, another tedious technical task like sticking needles into people, little or no compensation, more stress…etc. Who needs this?” “ Is a diagnostic test whose result offers no opportunity for a therapeutically actionable decision by a pharmacist in our lane at all? I believe not, but others may see it differently. Is our accessibility our greatest asset or does that asset itself cause opportunities for distraction from more helpful patient related activities? Tough internal discussions to be had, by pharmacists as well as by pharmacies. Ideally, discussions to be had prior to external advocacy. Not after.”

“ I’m not surprised we are at a stage to have these discussions. I think it’s great and reminds all levels of government and public of the value of our profession. However, the reality is most of us are busy retail stores where inviting a potentially positive Covid-19 patient in for a swab is not reasonable and very high risk. Not to mention the added mental strain of having potentially positive patients wandering our stores would have on staff.” “ COVID testing should not be any part of expanded scope discussion. This has nothing to do with our knowledge and clinical skills, and would we helping our patients? No! It’s a service that should be offered in a lab or dedicated testing site and we don’t have time for this. Pharmacists are accessible, let’s not give up our patient care time for something that doesn’t belong in pharmacy.”

“ I think that it’s important to recognize that most pharmacists are female. The pandemic has shown the emotional burden of caring lies with women, as so many roles bleed into each other: mother, childcare, teacher, and oh yeah, pharmacist. We need to think outside of the pharmacy box (literally) to consider flexible models for women who make up the bulk of the pharmacy workforce. Goodbye lowquality, high-volume care. Hello meaningful interactions with patients that help optimize medication management. That is the only way forward.”

Don’t forget to check out current news, blogs and expert columns!

[Vol.7 No.5] JUNE/JULY 2020

THE BUZZ

continued

YOUR COMMENTS “ For any pharmacist out there that wishes that pharmacies revolved around pharmacists instead of the other way around, consider the implications of a patient’s ability to “transact” safely at multiple pharmacies based on convenience and inventory supply. Safely, in the continuity of care meaning, due to an effective and complete centralized database/patient record.”

WHAT CAN A PIZZA COMPANY TEACH US ABOUT PRESCRIPTION MANAGEMENT DURING COVID-19? In this blog lamenting the disconnected, outdated state of Canada’s health and medication information systems, Dr. Jonathan Marcus suggests that healthcare could take a lesson from fast-food industry leaders, such as Domino’s, and implement systems that provide real-time inventory, patient management and medication tracking.

“ The idea of creating a central data base of all medications ‘available in a jurisdiction’ is just plain fantasy. The mechanics of assembling all the data would be hampered first by the business confidentiality rights of wholesales. Why would any wholesale want to provide data on its inventory to an outside agency?” “ The Domino’s model is that the pizza crust is there, ingredients are there and all the staff are there to turn out pizzas. Just order the pizza. First come, first served, unless preordered. The pharmacist’s role is much more than filling drugs.” “ I agree that Dr. Marcus’ model is a bit simplistic, although I like the creativity he’s tapping into. Prescription management is much more complex than suggested, and should really be investigated by a multidisciplinary team that examines existing models, like BC’s.”

AND THE LAST WORD IS YOURS

Don’t forget to check out current news, blogs and expert columns! 10

JUNE/JULY 2020 [Vol.7 No.5]

Shutterstock

“I love this conceptual thinking. Keep it going Dr. Marcus. Of course, every potential solution introduces new problems, but we solve them until some version of the concept works.”

Inspiring business learning

ave The t e a D

NOVEMBER 7, 2020

NOVEMBER 28, 2020

FEBRUARY 6, 2021

VANCOUVER

MONTRÃ&#x2030;AL

THE INTERNATIONAL CENTRE

JW MARRIOTT PARQ

CENTRE MONT-ROYAL

PharmacyU.ca

TORONTO

Drug News

A review of new launches, new indications, new dosage forms and Health Canada advisories

NEW PRODUCTS

Cabenuva: first monthly injectable for HIV cabotegravir 200 mg/mL and rilpivirine 300 mg/mL extended-release injectable suspensions, ViiV Healthcare.

SUPPLIED Cabenuva is supplied as 2 mL

and 3 mL dosing kits. The 2 mL kit contains: one 400 mg/2 mL single-dose vial of cabotegravir extended-release injectable suspension and one 600 mg/2 mL single-dose vial of rilpivirine extendedrelease injectable suspension. The 3 mL kit contains one 600 mg/3 mL single-dose vial of cabotegravir extended-release injectable suspension and one 900 mg/3 mL single-dose vial of rilpivirine extendedrelease injectable suspension. Each 2 mL and 3 mL dosing kit also contains two syringes, two vial adaptors, and two needles for intramuscular (IM) injection (23-gauge, 1½ inch). INDICATIONS A complete regimen for the treatment of HIV-1 infection, to replace the current antiretroviral regimen in adults who are virologically stable and suppressed (HIV-1 RNA < 50 copies/mL). ACTION Cabotegravir inhibits HIV integrase. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. DOSAGE Dosing consists of three distinct phases: 1. an oral lead-in with Vocabria (cabotegravir tablets) taken together with oral rilpivirine tablets (described in section on Vocabria below); 2. initiation injections of cabotegravir and rilpivirine (3 mL); and 3. continuation injections with cabotegravir and rilpivirine (2 mL). Initiation injections (3 mL dosing kit): Start injections on the final day of oral cabotegravir and rilpivirine lead-in. Give a single 3 mL (600 mg) IM injection of cabotegravir and a single 3 mL (900 mg) IM injection of rilpivirine. Continuation injections (2mL dosing kit): Should be started one month after the initiation injections. Recommended continuation injection doses are a single 2 mL (400 mg) 12

IM injection of cabotegravir and a single 2 mL (600 mg) IM injection of rilpivirine administered once monthly. Patients may be given the injections up to seven days before or after the date of the scheduled monthly 2 mL injection dosing visit. Before starting cabotegravir and rilpivirine injections, patients must agree to the required monthly injection dosing schedule and be counselled about the importance of adhering to scheduled dosing visits to help maintain viral suppression, and reduce the risk of viral rebound and potential development of resistance with missed doses. Consult product monograph for advice on how to manage missed doses. ADMINISTRATION Cabotegravir and rilpivirine injections should be administered IM at separate gluteal sites at the same visit. The ventrogluteal site is recommended. Consider the patient’s body mass index (BMI) to ensure that the needle is long enough to reach the gluteus muscle. Longer needles (not included in the dosing kit) may be required for patients with higher BMI (> 30 kg/m2) to ensure that injections are administered IM rather than subcutaneously (SC). ADVERSE EFFECTS MOST COMMON: Injection site reactions, including localized pain/discomfort (79%), nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%); most are mild to moderate and decrease over time. Pyrexia, fatigue and headache (5%–8%). MOST SERIOUS: Depressive disorders have been reported with rilpivirine-containing products. Hepatotoxicity, severe skin and hypersensitivity reactions. Serious post-injection reactions (dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, changes in blood pressure) within minutes after injection of rilpivirine; may be associated with inadvertent (partial) intravenous administration and begin to resolve within a few minutes. DRUG INTERACTIONS Contraindicated in combination with anticonvulsants

JUNE/JULY 2020 [Vol.7 No.5]

CLINICAL EDITOR

LU-ANN MURDOCH RPh, BScPhm, ACPR

(carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antimycobacterials (rifabutin, rifampin), systemic dexamethasone (more than a single-dose) and St John’s wort. If a macrolide or ketolide antibiotic is needed (clarithromycin, erythromycin or telithromycin), consider azithromycin instead. Consult product monograph for more detailed information on drug interactions. COMMENT First long-acting injectable complete antiretroviral regimen for treatment of HIV. Rybelsus: first oral GLP-1 receptor agonist semaglutide 3 mg, 7 mg and 14 mg tablets, Novo Nordisk.

INDICATIONS An adjunct to diet and

exercise to improve glycemic control in adults with type 2 diabetes. Indicated as a monotherapy when metformin is considered inappropriate due to intolerance or contraindications. Also indicated in combination with other agents: metformin; metformin + a sulfonylurea; metformin + an SGLT2 inhibitor; basal insulin; metformin ± insulin/basal insulin. ACTION An oral glucagon-like peptide-1 (GLP-1) receptor agonist. DOSAGE Starting dose is 3 mg once daily. After 30 days, increase to a maintenance dose of 7 mg once daily. After at least 30 days on the 7 mg daily dose, the dose can be increased to 14 mg once daily if additional glycemic control is needed. This gradual dose escalation is designed

to reduce gastrointestinal symptoms. No dosage adjustment is required in hepatic or renal impairment. ADMINISTRATION Must be taken on an empty stomach at least 30 minutes before the first food, beverage or other oral medications of the day. Waiting less than 30 minutes will likely reduce semaglutide absorption. Take with no more than half a glass of water (120 mL); larger volume will likely decrease the amount of semaglutide absorbed. Swallow tablets whole; do not split, crush or chew. Note that each tablet also contains 300 mg of salcaprozate sodium (SNAC), which enhances the absorption of semaglutide. ADVERSE EFFECTS MOST COMMON: Gastrointestinal disorders (nausea, diarrhea, vomiting); most occur during dose escalation and are mild or moderate in severity. MOST SERIOUS: Hypoglycemia is more frequent when semaglutide is used in combination with a sulfonylurea or insulin. Risk of thyroid C-cell tumours; contraindicated in patients with a personal or family history of medullary thyroid carcinoma. Contraindicated in patients with multiple endocrine neoplasia syndrome type 2. PR interval prolongation; use with caution in patients with pre-existing conduction system abnormalities or a history of rhythm disturbances (e.g., tachyarrhythmia). Acute pancreatitis, serious hypersensitivity reactions (including anaphylaxis), acute renal failure and worsening of chronic renal failure. DRUG INTERACTIONS Semaglutide delays gastric emptying, which may influence the absorption of other oral medications; wait at least 30 minutes before taking other oral medications. Use caution if co-administering drugs that increase heart rate or prolong the PR interval. STORAGE Store in the original blister packaging to protect from moisture and light. COMMENT First oral GLP-1 agonist to be marketed in Canada. Novo Nordisk also markets a once-weekly SC injectable dosage form of semaglutide (Ozempic) in Canada. Vocabria: oral lead-in for Cabenuva HIV therapy cabotegravir 30 mg tablets, as cabotegravir sodium, ViiV Healthcare.

INDICATIONS Approved for use in

combination with rilpivirine tablets as a complete regimen for short-term

treatment of HIV-1 infection in adults who are virologically stable and suppressed (HIV-1 RNA < 50 copies/mL). Intended for use as an oral lead-in to assess tolerability of cabotegravir before initiating Cabenuva (cabotegravir and rilpivirine extended-release injectable suspensions) and for oral bridging therapy for missed Cabenuva injections. ACTION Cabotegravir is an HIV integrase inhibitor. DOSAGE As specified above (see section on Cabenuva), a lead-in with oral cabotegravir plus oral rilpivirine is required before starting cabotegravir and rilpivirine extended-release initiation injections. The recommended dosage of oral cabotegravir is one 30 mg tablet, taken together with one 25 mg tablet of rilpivirine, once daily with a meal. This regimen should be continued for about one month (at least 28 days) to assess the patient’s tolerability to cabotegravir. The final oral doses of cabotegravir and rilpivirine should be taken on the same day that cabotegravir and rilpivirine extendedrelease initiation injections are started. Also, if a patient plans to miss a scheduled cabotegravir and rilpivirine injection visit by more than seven days, oral cabotegravir and rilpivirine may be used once daily to replace up to two consecutive planned missed monthly injection visits. ADVERSE EFFECTS See Cabenuva above. DRUG INTERACTIONS Contraindicated in combination with anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) and rifampin. Administer antacids at least two hours before or four hours after taking oral cabotegravir. Consult product monograph for more detailed information on drug interactions.

OTHER NEW PRODUCTS Cablivi

Fulphila pegfilgrastim 10 mg/mL solution for SC injection; 6 mg/0.6 mL single-dose syringe, Mylan.

INDICATIONS To decrease the incidence

of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive antineoplastic drugs. DOSAGE Single 6 mg SC injection, administered once per cycle of chemotherapy. Administer no sooner than 24 hours after the administration of cytotoxic chemotherapy. COMMENT Second biosimilar to Neulasta (Amgen), following Lapelga (Apotex).

NEW DOSAGE GUIDELINES Maviret

(glecaprevir/pibrentasvir tablets), AbbVie.

New shorter duration of therapy for some treatment-naïve patients infected by hepatitis C virus. For genotypes 1, 2, 4, 5 or 6, the recommended duration of treatment is eight weeks in patients without cirrhosis (this is unchanged) and eight weeks (formerly 12 weeks) in patients with cirrhosis. For patients with genotype 3, the duration of treatment is unchanged—eight weeks in patients without cirrhosis and 12 weeks in those with cirrhosis.

NEW INDICATIONS

caplacizumab for injection, powder for solution; 11 mg/vial, Sanofi Genzyme.

Biktarvy

INDICATIONS Treatment of adults with

acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. DOSAGE First day of treatment: 11 mg bolus intravenous (IV) injection at least 15 minutes before a plasma exchange, followed by an 11 mg SC injection after completion of plasma exchange on that day. Subsequent days of treatment during plasma exchange: 11 mg SC injection daily

following plasma exchange. Treatment after plasma exchange period: 11 mg SC injections once daily for 30 days following the last daily plasma exchange. COMMENT First therapeutic agent specifically approved in Canada for treating acquired thrombotic thrombocytopenic purpura, a lifethreatening blood-clotting disorder.

bictegravir/emtricitabine/tenofovir alafenamide tablets, Gilead Sciences.

EXPANDED INDICATION Now indicated

as a complete regimen for the treatment of HIV-1 infection in adults and children weighing ≥ 25 kg with no known resistance to the individual components. (Originally approved only for use in adults.) DOSAGE Adults and children weighing ≥ 25 kg: One 50 mg/200 mg/25 mg tablet taken orally once daily, with or without food.

[Vol.7 No.5] JUNE/JULY 2020

dapagliflozin tablets, AstraZeneca.

with high-dose inhaled corticosteroids (patients ≥ 18 years of age) or mediumto-high-dose inhaled corticosteroids (patients 6–17 years of age) and an additional asthma controller(s) (e.g., LABA) and have a blood eosinophil count of ≥ 150 cells/μL at initiation of treatment with mepolizumab OR ≥ 300 cells/μL in the past 12 months. (Originally indicated for this use in adults only. Also indicated as an add-on to corticosteroids for the treatment of adults with eosinophilic granulomatosis with polyangiitis.) DOSAGE Severe eosinophilic asthma: Adults and adolescents (≥ 12 years of age)—100 mg SC once every four weeks. Children (6–11 years of age)—40 mg SC once every four weeks. Note: only the lyophilized powder formulation can provide the recommended 40 mg dose for children six to 11 years of age.

NEW INDICATION An adjunct to diet,

Tecentriq

(Drug News continued)

Brivlera brivaracetam tablets, UCB Pharma.

EXPANDED INDICATION Adjunctive

therapy in the management of partialonset seizures in patients four years of age and older with epilepsy who are not satisfactorily controlled with conventional therapy. (Originally indicated only for use in adults.) DOSAGE Children ≥ 4 years and adolescents: Starting dose and therapeutic dosage range varies according to body weight. Consult product monograph for details. Forxiga

exercise and standard of care therapy to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and cardiovascular risk factors or established cardiovascular disease. DOSAGE To reduce the risk of hospitalization due to heart failure: Recommended dosage is 10 mg once daily. Keytruda pembrolizumab for infusion, Merck.

NEW INDICATION Monotherapy first-

line treatment of adults with metastatic nonsmall cell lung carcinoma or stage III disease where patients are not candidates for surgical resection or definitive chemoradiation. Intended for patients expressing PD-L1 as determined by a validated test, with no EGFR or ALK genomic tumour aberrations. (Also approved for several other indications; consult product monograph for details.) DOSAGE 200 mg administered as an IV infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression. Nucala mepolizumab for SC injection, GlaxoSmithKline.

EXPANDED INDICATION Add-on

maintenance treatment for adults, adolescents and children (≥ 6 years) with severe eosinophilic asthma. Intended for patients who are inadequately controlled 14

atezolizumab for injection, Hoffmann-La Roche.

NEW INDICATION For use in

combination with nab-paclitaxel and carboplatin for the first-line treatment of adults with metastatic nonsquamous nonsmall cell lung cancer (NSCLC) who do not have EGFR or ALK genomic tumour aberrations. (Also indicated for use in the treatment of locally advanced or metastatic breast cancer, locally advanced or metastatic urothelial cancer, and other types of NSCLC; consult product monograph for details.) DOSAGE Metastatic nonsquamous NSCLC: Induction phase—1200 mg administered by IV infusion, followed by nab-paclitaxel and carboplatin every three weeks for four or six cycles. For each 21-day cycle, atezolizumab, nab-paclitaxel and carboplatin are administered on Day 1. In addition, nab-paclitaxel is administered on Days 8 and 15. Maintenance phase without chemotherapy—1200 mg administered by IV infusion every three weeks.

HEALTH CANADA ADVISORIES

Hemlibra: interference with lab assays (COVID-19) Hemlibra (emicizumab injection) may interfere with certain lab assays used to diagnose coagulopathy/disseminated intravascular coagulation caused by COVID-19 infection. Hoffmann-La Roche has prepared a table listing

JUNE/JULY 2020 [Vol.7 No.5]

common coagulation assays that may be used to diagnose, monitor and manage patients with COVID-19-associated coagulopathy (https://healthycanadians. gc.ca/recall-alert-rappel-avis/hcsc/2020/72779a-eng.php). The table notes which assays are affected by Hemlibra, with potential alternatives provided. If a patient on Hemlibra seeks treatment due to symptoms of COVID-19 infection, send a copy of this table to the treating healthcare provider and advise them to consult the Hemlibra product monograph for further details. In addition, healthcare providers should be made aware of the long half-life of Hemlibra (~30 days), which should be considered during clinical management of the patient. Methadone: avoid switching products if possible Currently, three methadone products are used for substitution treatment for opioid dependence in adults in Canada: Metadol-D, Methadose and Sandoz Methadone. Health Canada has received reports of variable responses by patients being treated for opioid dependence after their methadone product was switched to a different formulation. Some patients who were stable for years developed symptoms of opioid withdrawal after switching. Early withdrawal symptoms can lead to patients failing to remain in their treatment program and returning to problematic opioid use. Therefore, Health Canada advises to avoid switching methadone products, when possible, in patients who are stable on their methadone treatment. Further details about these advisories and safety reviews can be obtained from the MedEffect Canada website: www.canada.ca/en/health-canada/services/drugshealth-products/medeffect-canada.html and www. canada.ca/en/health-canada/services/drugs-healthproducts/medeffect-canada/safety-reviews.html. Lu-Ann Murdoch, RPh, BScPhm, ACPR, is a consulting clinical editor for Pharmacy Practice +Business and drug information consultant for Pharmacist’s Letter.

PATIENTS DON’T HAVE TO LIVE WITH ABDOMINAL DISCOMFORT, GAS OR BLOATING.

‡

TREAT IBS SYMPTOMS WITH ALIGN – THE MOST RECOMMENDED PROBIOTIC‡

OVER 60% OF PATIENTS REPORTED SIGNIFICANT RELIEF FROM IBS SYMPTOMS AFTER 4 WEEKS1† BIFIDOBACTERIUM 35624 REDUCED GLOBAL IBS SYMPTOMS 20% MORE THAN PLACEBO†

% Answering “Yes” at Week 4†

p<0.02

60 50 40

62% 42%

30 20 10

Bifidobacterium 35624 (1 x 108 CFUs) n=90

Placebo n=92

Gluten Free Soy Free Vegetarian

Patients were asked following question: Compared to the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms?1

RECOMMENDED 4X MORE THAN ANY OTHER PROBIOTIC BY GASTROENTEROLOGISTS‡ †A randomized, double-blind, placebo-controlled trial that investigated the efficacy and safety of Bifidobacterium 35624 in 362 female subjects with irritable bowel syndrome (IBS). Study included: 2-week run-in; 4-week treatment; 2-week follow-up period. Dosage range: 1x1010 Bifidobacterium 35624 (1x109 - 1x1011), 1x108 Bifidobacterium 35624 (1x107 - 1x109), 1x106 Bifidobacterium 35624 (1x105 - 1x107), placebo. Primary endpoint was abdominal pain/discomfort at week 4. ‡Among gastroenterologists who recommended a brand of probiotic in a ProVoice 2019 survey. Reference: 1. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated Probiotic Bifidobacterium infantis 35624 in Women with Irritable Bowel Syndrome. Am J Gastroenterol. 2006;101:1581-1590. 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. © 2020 P&G

Practice Experts

GERIATRIC ISSUES

ANEMIA OF CHRONIC DISEASE: A CONTEMPORARY APPROACH Anemia occurs in about 10% of community dwelling elderly people and 48%–63% of nursing home residents.(1-3) Although the prevalence increases with age, anemia is not an inevitable outcome of aging. Hemoglobin < 120 g/L in females and < 130 g/L in males is associated with decline in functionality, increased risk of frailty and poorer survival.(1-3) According to the National Health and Nutritional Examination Survey (NHANES) III, 30% of community dwelling elderly survey participants with anemia had anemia of chronic disease (ACD), another third had nutrition deficient anemias and 30% had unexplained anemia.(4-7) ACD is defined as a mild anemia associated with a chronic inflammatory, infectious or neoplastic illness, and with a characteristic disturbance of iron metabolism.(4,5) Pharmacists should be able to differentiate ACD from iron deficiency anemia in order

MATHILDA PRINSLOO

Our pharmacist experts share information and ideas to support your daily practice

to discourage unnecessary treatment with iron supplements and also promote deprescribing.

BPharm, BCGP, CDE, EPPh

proinflammatory cytokines (e.g., interleukins 1 and 6) and engaging the liver to produce hepcidin, a hormone that regulates iron homeostasis.(4,5,8,9) Hepcidin prevents the release of iron from iron stores, which reduces the amount of iron available in the circulation for the production of hemoglobin, resulting in anemia.(9,10,13)

Diagnosis

Anemia of chronic disease (ACD)

Iron deficiency anemia (IDA)

The diagnosis of ACD is based on clinical presentation, laboratory testing and suspicion of acute or chronic inflammation.(2,14,15) Typical symptoms of iron deficiency anemia (e.g., fatigue, weakness, dyspnea) are not indicative of ACD in older adults. Conjunctival pallor is a reliable sign and skin pallor is a helpful diagnostic clue, but difficult to detect in elderly people.(2,14,15) ACD develops gradually and is characterized by normochromic, normocytic mild anemia: hemoglobin > 100 g/L and a low reticulocyte count.(5,7,16) Iron deficiency anemia, on the other hand, is characterized by microcytic, hypochromic anemia; hemoglobin can be below 100 g/L and the reticulocyte count is also low.(14,17) ACD is usually detected on routine laboratory testing (Table 1) or during investigation for patterns of abnormalities by reviewing previous blood counts.(4) ACD can overlap with iron deficiency anemia; 20%–80% of elderly people with ACD also have iron deficiency anemia.(4,8) A useful diagnostic indicator of the co-extistance of iron deficiency anemia with ACD is a soluble transferrin receptor-ferritin (sTfR– ferritin) value of 1.5–2.(4,14)

Hemoglobin

100–129 g/L in males 100–119 g/L in females

< 130 g/L in males < 120 g/L in females

Points to consider in managing ACD

Serum ferritin

≥ 50 μg/L

< 15 μg/L

C-reactive protein

> 5 mg/L

< 3 mg/L

Transferrin saturation

≤ 20%

< 10%–15%

Total iron binding capacity (TIBC)

Elevated

Decreased

Erythrocyte sedimentation rate (ESR)

Elevated

In normal range

Mean corpuscular volume (MCV)

< 80 fL

ACD—the anemia of inflammation

The etiology of ACD is multifactorial and immune mediated. The hallmark feature is underlying inflammation. Examples of inflammatory processes associated with ACD include acute or chronic infections (e.g., tuberculosis, pneumonia), malignancies and autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel diseases, vasculitis). Various other conditions such as diabetes mellitus, heart failure, chronic obstructive pulmonary disease and chronic kidney disease (eGFR < 60 mL/min/1.73m2) are also associated with ACD.(4,5,8-10) Chronic kidney disease is present in 37%–44% of older adults and, therefore, is an important risk factor for ACD.(11,12) The body’s immune system responds to inflammatory stimuli by releasing

TABLE 1

Indices for differentiating ACD from IDA in the elderly (2,4,5,10,15) Indices

JUNE/JULY 2020 [Vol.7 No.5]

• The main objective is to resolve the underlying cause of ACD. Successful treatment of the underlying cause may completely resolve ACD without the need for iron supplementation. However, this is not always possible. For example, improving blood glucose control in people with diabetes may not lead to the resolution of ACD.(2,5,14,17) • Correction of ACD with iron supplements does not improve the

prognoses of chronic diseases with underlying inflammatory pathogeneses. Symptoms of ACD are usually related to the underlying disease itself.(2,17) • Overtreatment with iron supplements can be hazardous. Hemoglobin > 150 g/L is associated with an increased risk of morbidity and mortality.(5) • Iron supplements should be reserved for people with concomitant iron deficiency.(4,10,17) • Erythropoietin-stimulating agents (e.g., epoetin) are not standard of care in the elderly with ACD, although there are exceptions.(2,4) • Red blood cell transfusion should be reserved for life-threatening anemia (i.e., hemoglobin < 100 g/L).(3,6,10)

Pharmacists can improve clinical outcomes and enhance quality of care

Many elderly people take iron supplements, often multiple times per day, which contributes to pill burden at the expense of quality of life, possible gastrointestinal adverse effects, drug– drug and drug–food interactions, and medication cost.(17,18) Pharmacists can play a key role in assessing the need for iron supplementation and advocate for deprescribing where appropriate. • Order (where allowed under scope of practice) or obtain iron laboratory tests (Hb, TIBC and serum ferritin) and compare with previous results. Lack of response to iron supplements over time may suggest ACD if other causes have been ruled out. • Use laboratory indices to make a differential diagnosis or find evidence to suggest the need for further investigation (e.g., mean corpuscular volume [MCV] > 100 fL indicates vitamin B12 or folate deficiency).(17) • A six- to eight-week trial of oral iron supplementation is often used to rule out iron deficiency anemia.(6) Lack of response may suggest coexisting ACD and iron deficiency anemia and justify a trial of intravenous iron, since hepcidin (which is elevated in ACD) impairs absorption of iron from the gut.(4-6,14) • Suggest deprescribing iron supplements in people with ACD alone. If patients or prescribers are resistant to deprescribing, or iron deficiency anemia has been diagnosed, suggest treatment with “low-dose” iron (about

Overtreatment with iron supplements can be hazardous. Hemoglobin > 150 g/L is associated with an increased risk of morbidity and mortality.

15 mg elemental iron/day). Lowdose iron has been proven effective in elderly patients and causes less gastrointestinal upset compared to higher doses. Examples of “low dose” iron supplementation are:  One-half tablet of ferrous gluconate 300 mg daily or one tablet every other day  1 mL ferrous sulfate 75 mg/mL drops every day  2.5 mL ferrous sulfate 150 mg/5 mL liquid every day or 5 mL every other day.(14,17-20) • Many elderly patients take stimulant laxatives to relieve constipation related to iron supplements. Once iron supplements have been deprescribed, counsel patients to taper laxatives if stools become loose or too frequent. • Food reduces the absorption of iron.(17,18,20) Suggest to elderly patients that they take low-dose iron on an empty stomach or two hours after meals.(18) Vitamin C-containing foods (e.g., citrus, berries, melon) improve the absorption of iron from the gut.(18,20) Encourage patients to consume ironcontaining foods daily. Iron from heme sources is more available compared to iron from non-heme sources.(18) Mathilda Prinsloo is a clinical pharmacist at Senior Care Practice, a fee-for-service Medication Therapy Management service for community dwelling older adults. She is a member of collaborative and interdisciplinary teams at primary health care clinics in Winnipeg, Manitoba. REFERENCES

1. Röbrig G. Anemia in the frail, elderly patient. Clin Interval Aging 2016;11:319-26. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4803240/ (accessed March 3, 2010). 2. Erucic L, Balducci L. Anemia of aging: the role of chronic inflammation and cancer. Semin Hematol 2008;45:242-9. https://pubmed.ncbi.nlm.nih. gov/18809094/ (accessed February 21, 2020). 3. Vittorio EB. Anemia in the elderly population. J Haematol 2014;3(4):95-106. https://www.thejh.org/index. php/jh/article/view/182/131 (accessed March 3, 2020). 4. Camaschella C, Weiss G. Anemia of chronic

disease/anemia of inflammation. Updated January 28, 2020. www.uptodate.com/contents/anemia-ofchronic-disease-anemia-of-inflammation. (accessed February 21, 2020). 5. Price EA. Anemia in the older adult. Updated September 11, 2019. www.uptodate.com/contents/ anemia-in-the-older-adult (accessed February 21. 2020). 6. Goodnough LT, Shier SL. Evaluation and management of anemia in the elderly. Am J Hematology 2014;89:88-96. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4289144/ (accessed February 21, 2020). 7. Patel KV. Epidemiology of anemia in older adults. Semin Hematol 2008;45:210-7. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC2572827/ (accessed March 3, 2020). 8. Weiss G, Goodnough LT. Anemia of chronic disease. NEJM 2005;352:1011-23. 9. Gates BC. Anemia of chronic disease and kidney failure. Updated November 27, 2018. https:// emedicine.medscape.com/article/1389854-overview (accessed February 21, 2020). 10. Ganz T. Anemia of inflammation. N Engl J Med 2019;3812:1148-57. 11. Resnick B, Sabol V, Galik E, et al. The impact of anemia on nursing home residents. Clin Nurs Res 2010;19:113-30. https://pubmed.ncbi.nlm.nih. gov/20185805/ (accessed March 3, 2020). 12. Stevens LA, Li S, Wang C, et al. Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2010;55(3 suppl 2):S23-33. 13. Cook K, Beata A, Lyons I, et al. Anemia’s. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy—a pathophysiologic approach. 8th ed. New York, NY: McGraw Hill; 2011. p.1717-40. 14. Lanier HB, Park JJ, Callaghan R. Anemia in older adults. Am Fam Physician 2018;98:437-42. https:// pubmed.ncbi.nlm.nih.gov/30252420/ (accessed February 21, 2020). 15. Chen BH, Ghandi S. Anemia of chronic disease, making the right call. Can J CME 2004;August:59-62. http://www.stacommunications.com/journals/cme/2004/ August/pdf/059.pdf (accessed March 3, 2020). 16. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States of America, evidence of a high rate of unexplained anemia. Blood 2004;104:2263-8. https://doi.org/10.1182/blood-2004-05-1812. 17. Smith DL. Anemia in the elderly. Am Fam Physician 2000;62:1565-72. https://www.aafp.org/ afp/2000/1001/p1565.html (accessed March 3, 2020). 18. Canadian Pharmacists Association. Iron preparations; oral. Updated November 2017. www.etherapeutics.ca (accessed February 21, 2020). 19. Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much iron? Low dose iron is as effective in octogenarians. Am J Med 2005;118:1142-7. https:// www.amjmed.com/article/S0002-9343(05)00210-X/ fulltext (accessed February 21, 2020). 20. Lindbladt AJ, Cotton C, Allan MG. Iron deficiency in the elderly: how much iron is enough? Can Fam Physician 2015;61:59. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4325864/ (accessed March 3, 2020).

[Vol.7 No.5] JUNE/JULY 2020

BETTER TOGE+HER #

1 Dermatologist Recommended Laundry Products

Hypoallergenic. No dyes. No perfumes. Just cleaner*, softer clothes. Tide Free & Gentle, Downy Free & Gentle and Bounce Free & Gentle provide dye and perfume free, dermatologist recommended alternatives for every step of the laundry routine. They are mild on skin while still delivering better cleaning* and outstanding conditioning. REMIND PATIENTS: The laundry routine needs to be

ENTIRE

TIDE AND DOWNY FREE & GENTLE RECOGNIZED BY:

free

THE ONLY LAUNDRY REGIMEN APPROVED BY:

*vs. the next leading free detergent.

Practice Experts

TRAVEL HEALTH

DESTINATION: INFORMATION! NAVIGATING TRAVEL HEALTH RESOURCES While travel is currently severely curtailed because of the COVID-19 pandemic, pharmacists can use this opportunity to better familiarize themselves with travel health resources. When restrictions begin to lift, pharmacists will then be well prepared to resume providing advice under what will likely be even stricter travel regulations. Anyone who has written The International Society of Travel Medicine’s Certificate in Travel Health examination(1) can attest that the content tested is largely based upon the Yellow Book published by the US Centers for Disease Control and Prevention (CDC).(2) As a result, the Yellow Book and the CDC’s website are often the first resources consulted by health professionals new to practising travel medicine. However, these are not the only reputable resources available, and advice provided across various resources can be inconsistent. This article introduces a number of available clinical resources and provides strategies to address conflicting recommendations across them.

CDC’s ‘rainbow’ of resources

The Yellow Book (Health Information for International Travel) includes chapters on conducting pretravel consultations, travel vaccines, and diseases and other health risks associated with travel, among other topics. It is available for purchase in print form, but most of its content is also available for free online (Table 1). The primary use for the Yellow Book is to locate an overview of a specific topic. With the exception of a few chapters discussing popular itineraries/destinations, the Yellow Book generally isn’t a practical choice for compiling a list of potential risks associated with travel to a specific country. For example, it can be consulted for a

SHERILYN HOULE

Our pharmacist experts share information and ideas to support your daily practice

In Canada, travel information is provided through the Public Health Agency of Canada, with the expert assistance of the Committee to Advise on Tropical Medicine and Travel. table comparing the vaccines available to prevent typhoid fever, but will not tell you the degree of risk of typhoid for a traveller to Tanzania.(3) The Pink Book (Epidemiology and Prevention of Vaccine-Preventable Diseases) is a print and online resource focused specifically on US vaccines and the diseases they prevent. While the Yellow Book reviews vaccines available to prevent travel-related conditions, the Pink Book provides additional details on US vaccine composition, immunogenicity, and minimum ages and intervals for vaccines, with information on routine, recommended and travel vaccines. For country-level information on health and safety risks, the CDC Travelers’ Health website allows both travellers and clinicians to search for advice by country, as well as by additional special considerations, such as travelling with children, immune-compromised travellers and extended-stay travellers. Search results include broad recommendations on vaccineand nonvaccine-preventable diseases (with links to the Yellow Book for additional information), and other patient counselling recommendations, such as the prevention of insect bites, food and water precautions, and maintaining personal safety. However, it provides few printable patient education handouts and, as an American resource, vaccine recommendations are consistent with the US Advisory Committee on

BSP, PhD

Immunization Practices (ACIP),(4) with vaccine and drug recommendations largely based on product availability within the United States.

Canadian resources and recommendations

In Canada, travel information is provided through the Public Health Agency of Canada, with the expert assistance of the Committee to Advise on Tropical Medicine and Travel (CATMAT). While there is not a Canadian equivalent to the CDC Yellow Book, CATMAT has published statements that summarize information on a number of health-related considerations among international travellers including recommendations for their prevention and treatment (Table 1).(5) For example, the statement on malaria includes a recently updated appendix on malaria risk and recommended preventive measures by geographical area. Clinicians requiring information on more specialized conditions (e.g., schistosomiasis) or itineraries (e.g., adventure travel) will need to consult the Yellow Book or other references in the absence of a CATMAT statement. The Canadian Immunization Guide (Table 1) represents a Canadian equivalent to the CDC’s Pink Book, based on advice from the National Advisory Committee on Immunization (NACI) for routine vaccines and CATMAT for travel vaccines, reflecting Canadian product availability. Similar to the CDC Travelers’ Health website, the Government of Canada’s Travel Advice and Advisories website (Table 1) also offers country-level information on health and safety risks for travellers, as well as contact information for Canadian consular services for each country. Canadian travellers are encouraged to register their international travel with the government online, to facilitate communication in the event of an emergency or changes in travel advice or advisories for the region(s) visited.(6) Travellers and healthcare professionals can also access a variety of handouts and booklets in electronic format or by ordering free print copies.(7)

[Vol.7 No.5] JUNE/JULY 2020

International websites and paid software

The governments of the United Kingdom(8,9) and Australia(10) also offer searchable country-specific and general travel recommendations similar to the US and Canadian resources (Table 1). Finally, subscription-based travel medicine resources are available from providers such as Shoreland Travax, TropiMed and TravelCare (Table 1). The benefits of paid software programs include the integration of various information sources, high-quality patient education handouts, and malaria risk maps at a finer level of detail; however, cost may limit their use to clinics and pharmacies that perform a larger number of pretravel consultations. A comparison of available software programs, written by a travel medicine physician, considers their ease of use, quality of patient handouts, malaria maps and cost.(11) Readers are encouraged to visit and compare various websites and take advantage of free software program trials to identify their preferred resources.

Maneuvering mixed messages

In my opinion, the golden rule of travel medicine is “No consultation without individualization.” Simply recommending every vaccine or drug mentioned by any resource for a destination does not constitute a pretravel consultation,(12) and

TABLE 1

TABLE 2 S ummary

of hepatitis A and typhoid vaccine recommendations for Jamaica(13-15)

Website (see Table 1)

Hepatitis A

Typhoid

CDC Travelers’ Health (US)

Most travellers

Travel Advice and Advisories, Government of Canada

All travellers

Discuss with healthcare professional if elevated risk

TravelHealthPro (UK)

Those whose activities put them at increased risk

Not listed

CDC–Centers for Disease Control and Prevention

advice may vary across resources. For example, conflicting recommendations for hepatitis A and typhoid vaccination recommendations for Jamaica across websites are summarized in Table 2. These discrepancies may reflect local product availability and cost, the frequency at which recommendations are revisited to consider new evidence and outbreaks, or differing opinions among members of expert advisory committees.(16) The first step to manage these situations is to consult the more detailed documents from CATMAT or the Yellow Book, which often provide a rationale for the broader recommendation provided on that organization’s website. Consider whether the rationale for the overall recommendation is consistent with your patient’s risk factors for exposure and complications from the illness. Also, consider your patient’s likelihood for future travel and

whether vaccination now may provide ongoing benefit. Finally, consider your patient’s level of risk tolerance and ability to pay for the product. Equipped with this information, shared decision-making will allow the patient and clinician to come to an evidence-based and individualized care plan. If at any time you feel unable to provide an individualized recommendation while considering the patient, their destination and their itinerary, referral to another clinician with expertise in travel medicine is your best bet. Sherilyn Houle, BSP, PhD, is an assistant professor, School of Pharmacy, University of Waterloo, ON, and a pharmacist at the International Travel & Immunizations Clinic, Centre for Family Medicine in Kitchener, ON. She has her Certificate in Travel Health from the International Society of Travel Medicine. References are available in the online version of this article. Click on the Pharmacy Practice+Business logo to find this issue.

www.CanadianHealthcareNetwork.ca/pharmacists/

Travel health resources(5)

Resource

Website

North American governments (free) CDC Yellow Book (Health Information for International Travel) (US)

wwwnc.cdc.gov/travel/page/yellowbook-home-2014 (click on “Table of Contents” for free content)

CDC Pink Book (Epidemiology and Prevention of Vaccine-Preventable Diseases) (US)

www.cdc.gov/vaccines/pubs/pinkbook/index.html

CDC Travelers’ Health (US)

wwwnc.cdc.gov/travel

Committee to Advise on Tropical Medicine and Travel (CATMAT) Statements & Recommendations (Canada)

www.canada.ca/en/public-health/services/catmat.html

Canadian Immunization Guide

www.canada.ca/en/public-health/services/canadianimmunization-guide.html

Travel Advice and Advisories, Government of Canada

https://travel.gc.ca/travelling/advisories

International governments (free) TravelHealthPro (National Travel Health Network and Centre) (UK)

https://travelhealthpro.org.uk

Fitfortravel (UK)

https://www.fitfortravel.nhs.uk

Smartraveller (Australia)

https://www.smartraveller.gov.au/

Subscription-based software Shoreland Travax (US)

www.shoreland.com/services/travax

TropiMed (Swiss)

www.tropimed.ch/en/index.html

TravelCare (US)

https://us.travelcare.com/en/software/

CDC–Centers for Disease Control and Prevention

JUNE/JULY 2020 [Vol.7 No.5]

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Approved for

Continuing Education L E S S O N

1.0 CEU Canadian Council on Continuing Education in Pharmacy

Approved for 1.0 CE unit by the Canadian Council on Continuing Education in Pharmacy • CCCEP #1329-2020-3030-I-P • Please consult this course online at eCortex.ca for expiry dates

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Migraines are a common neurologic condition associated with severe unilateral headache, nausea and photophobia and/ or phonophobia.(1) In 2010/11, it was estimated that 2.7 million Canadians were diagnosed with migraine. The prevalence was higher in females than males, and in adults between ages 30 to 49.(2) Migraine is one of the most common chronic illnesses in the world, affecting 14.7% of the global population, more than diabetes, osteoarthritis of the knee and asthma combined.(3) The effects of a migraine can be debilitating, with 39% of individuals having some impairment in their activities, and 54% experiencing severe impairment or requiring bedrest. This resulted in up to 7 million workdays lost annually in Canada.(3-5)

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Migraines are a complex neurological disorder initiated by the trigeminal nerve endings releasing vasoactive inﬂammatory substances that induce vasodilation and inﬂammation.(6-8)

Two major subtypes of migraine are classified by the International Headache Society (IHS): migraine without aura, and migraine with aura. (Table 1).(5,9,44) Migraine without aura is the most common subtype and is characterized by headache attacks lasting 4 to 72 hours. One-third of migraine patients may also experience migraine with aura, which can precede the headache and last up to 60 minutes or longer.(5) Migraines are characterized by multiple phases: the prodrome, headache and postdrome phases; with or without aura.(10) During the prodrome phase, nonheadache symptoms may start before the headache phase.(11-12) These symptoms may include difficulty concentrating, fatigue, memory impairment, mood changes, irritability, food cravings, yawning, neck stiffness, photophobia and phonophobia. They may precede the onset of pain by up to 72 hours.(13) The headache phase occurs when pain is perceived, which presents as an intense unilateral, throbbing sensation and is exacerbated by physical exertion.(13) Hyperexcitability and central sensitization of pain neurons can lead to secondary pain on the scalp, face and neck, and cause difficulty in performing common activities, such as combing hair, shaving, wearing eyeglasses or contact lenses, or even showering.(14-15) Photophobia and phonophobia is also experienced in as many as 80% of patients suffering from migraine.(13) The last phase of a migraine is characterized by the postdrome or recovery phase when non-headache symptoms may persist for one to two days after the headache.(16) Postdrome symptoms include tiredness, reduced appetite and mood changes.(17)

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There are no diagnostic tests for migraine, but rather, the diagnosis is made through the exclusion of serious underlying disorders based on symptoms.(1,5,18) A 3-item migraine screener was developed to quickly screen patients. A positive response on 2 out of 3 questions was found to yield a predictive value of 93% (Table 2).(19)

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TABLE 1

International Headache Society criteria for migraine with and without aura(5,9,44)

Migraine without aura

Migraine with aura

A. At least 5 attacks fulﬁlling criteria B to D

A. At least 2 attacks fulﬁlling criteria B to D

B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)

B. Aura consisting of at least one of the following, but no motor weakness: • Fully reversible visual symptoms including positive features (e.g., ﬂickering lights, spots, lines) and/or negative features (loss of vision) • Full reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness) • Fully reversible dysphasic speech disturbance

C. Headache has at least two of the following characteristics: • Unilateral location • Pulsating quality • Moderate or severe pain intensity • Aggravation by or causing avoidance of routine physical activity

C. At least two of the following: • Homonymous visual symptoms and/or unilateral sensory symptoms • At least one aura symptom develops gradually over ≥ 5 minutes and/or different aura symptoms occur in succession over ≥ 5 minutes • Each symptom lasts ≥ 5 minutes and ≤ 60 minutes

D. During headache, at least one of the following is present: • Nausea and/or vomiting • Photophobia and phonophobia

D. Headache fulﬁlling criteria B to D for migraine without aura begins during the aura or follows aura within 60 minutes

E. Not attributed to another disorder

DIFFERENTIAL DIAGNOSIS AND RED FLAGS

In the absence of signiﬁcant past medical history, it’s important to investigate and rule out potential secondary causes of headache.(20) The mnemonic “SNOOP” can aid pharmacists in identifying red ﬂags that would warrant physician or ER referral (Table 3).(20)

Overview of the acute treatment of migraine attacks The goal of migraine therapy is to promptly relieve pain and associated symptoms of migraine within two hours after treatment.(5) If an individual is not able to be pain-free within two hours, or cannot continue their usual activities reasonably well, another medication can be tried.(5) The 2013 Canadian Headache Society (CHS) guidelines identifies 12 medications as first-line choices following OTC failure, based on what was determined to be high-quality evidence (see Table 4 online), as well as other medications with weaker recommendations.(5) Treatment should be individualized by considering factors such as migraine management history, attack severity, rate and nature of migraine onset and formulations of available medications.(5,22) NSAIDs (including ASA) and triptans are the primary medications for acute migraine treatment.(5,22) Individuals experiencing a moderate to severe migraine are advised to treat with medications earlier when the pain is mild.(5,22) Triptans specifically are generally more effective when taken at the first onset of headache pain, rather than during the aura phase.(5,22-24) Since patients may delay taking their medication, pharmacists should remind them that taking medication at the first sign of an attack will yield better outcomes and may ultimately require using less medication over time.

Pharmacological therapy TRIPTANS

Triptans are strongly recommended for acute treatment of moderate to severe migraine attacks, or for patients who do not respond adequately to NSAIDs, acetaminophen and lifestyle modiﬁcation.(5)

Answer online at eCortex.ca

Adapted from Headache Classiﬁcation Subcommittee of the International Headache, Society. The International Classiﬁcation of Headache disorders.(5,9,44)

TABLE 2

3-item ID Migraine Screener(19)

Item

Yes

You felt nauseated or sick to your stomach when you had a headache

❍ ❍

Light bothered you (a lot more than when you don’t have headaches)

❍ ❍

Your headaches limited your ability to work, study or do what you need to do for at least one day

❍ ❍

Triptans act on serotonin (5-HT) subclass 1B and 1D receptors and prevent neurogenically sterile inflammatory responses around vessels and cause vasoconstriction.(5) Seven triptans are currently available in Canada (Table 4).(5) Meta-analyses and a systematic review of triptans have shown that all currently available triptans are effective as symptomatic treatments for migraine attacks.(5,22,24) Although sumatriptan has the most extensive data to support efficacy, tolerability and safety, other triptans may have advantages based on different pharmacokinetic profi les, migraine frequency, timing of migraines, and patient tolerance to side effects.(22) For severe migraine attacks with early vomiting, selection of orally disintegrating tablets, subcutaneous or intranasal formulations should be considered.(5,22) Individual patient response may vary and finding the most effective triptan may require trial and error. Approximately one-third of patients do not achieve migraine relief with their first oral triptan, and response cannot be predicted.(5)

TABLE 3

Red ﬂags

S - Systemic symptoms or secondary risk factors, such as, fever, weight loss, cancer or HIV. N - Neurological symptoms, such as arm numbness altered consciousness, loss of vision. O - Onset; an abrupt, thunderclap-like onset can indicate an acute bleed requiring emergency care. O - Older than 50 at onset, suggesting temporal arteritis or acute angle-closure glaucoma. P - Previous headache history: has it changed, or is it a new headache?; Positional: does it change upright vs. lying down?; Papilledema: are there visual obscurations? Adapted from Dodick et al.(21)

Patients who ﬁnd their symptoms poorly managed after the initial dose may repeat 2 hours after, with a maximum of two doses within 24 hours.(5,22) In addition, switching from one triptan to another should be considered in patients who poorly respond or are intolerant to one triptan (with a 24-hour wash period advised).(5) The most common adverse reactions caused by triptans include chest discomfort, fatigue, dizziness, paresthesia, drowsiness, nausea and throat symptoms.(20) “Triptan sensation,” experienced by 1-7% of patients in placebo-controlled clinical trials, include burning, tingling or tightness in the face, neck, limbs or chest.(26) Triptans administered by the oral route may be taken with or without food.(20)

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Answer online at eCortex.ca

June 2020

Due to their vasoconstrictive properties, triptans are contraindicated in patients with CV disease, sustained hypertension, pregnancy, migraines with brainstem aura (e.g., symptoms of vertigo, disorientation, diplopia, tinnitus, confusion, speech impediment) and hemiplegic migraines.(22,26) Their use with SSRIs or SNRIs should be cautioned due to increased risk of serotonin syndrome.(5,22) NSAIDS

Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective option for the acute treatment of migraine because of their ability to reduce meningeal inflammation and central sensitization.(27,28) Of all the NSAIDs, acetylsalicylic acid (ASA), ibuprofen, naproxen sodium and diclofenac potassium have high-quality evidence for efficacy in the treatment of acute migraine of all severities.(5,22) For best efficacy, all NSAIDs and ASA should be taken as early as possible after onset of headache, while pain is still mild.(5) • Diclofenac potassium powder in an oral solution (50 mg) as a single dose is recommended for patients with migraines that increase in intensity rapidly, as well as migraines of all severities.(5,22) The buffered solution provides a faster onset of therapeutic effect within 15 minutes as compared to tablet formulations, and may be taken on an empty stomach for faster absorption.(5,22,29,30) Diclofenac potassium immediate release tablets (50 mg) are also available and recommended for acute treatment of migraine of all severities, but has slower onset than the oral solution.(5) A maximum of 100 mg should not be exceeded per day.(5) • Naproxen sodium immediate release formulation (550 mg tablets available in Canada; up to 825 mg) given at onset of pain, and up to twice daily if repeated.(5) The prolonged half-life of naproxen sodium is helpful for patients experiencing prolonged migraine attacks.(5,22,31) Naproxen sodium is preferred over naproxen base for the acute treatment of migraine due to the faster onset of action.(5) A maximum of 1,375 mg should not be exceeded per day.(5) • ASA (975 to 1000 mg tablets or effervescent formulation) given at onset of pain, and up to every 4-6 hours if repeated.(5) The effervescent formulations have a faster onset of action than tablets.(5,22,32,33) A maximum of 2,600 mg should not be exceeded per day.(5 • Ibuprofen 400 mg tablets or liquid gel caps given at onset of pain and every

4 hours if repeated.(5) Liquid gel caps should be considered over tablets for patients desiring a faster onset of action.(22,34,35) A maximum of 2,400 mg should not be exceeded per day.(5) Adverse effects of NSAIDs include dizziness, drowsiness, headache, hypertension dyspepsia, nausea and vomiting and gastrointestinal bleeding.(20) Contraindications include uncontrolled hypertension, heart failure, peptic ulceration, gastrointestinal bleeding, and severe renal impairment.(20) ACETAMINOPHEN

Acetaminophen is appropriate only for migraines of mild to moderate intensity that do not require bed rest, and do not stop participation in activities.(5,22,36) The recommended dose of acetaminophen is 1000 mg at onset of pain, and repeated every 4-6 hours if necessary (maximum 4000 mg per 24 hours).(5) While acetaminophen has fewer side effects than NSAIDs, it is generally considered less effective than NSAIDs for the acute treatment of migraine.(5) Potential risks still exist for acetaminophen such as medication overuse headache and liver dysfunction with chronic use of high doses or with acute overdose.(20) COMBINATION THERAPY – TRIPTAN WITH AN NSAID

In several randomized controlled trials, the combination of a triptan with an NSAID has been shown to be more effective than using either treatment alone to treat acute migraine.(5,6,22,37) The most studied combination of triptan and NSAID is sumatriptan-naproxen sodium, which has been found to provide superior 2-hour pain free in 40% and 44% of studied patients versus 17% and 14% for placebo.(5,22) The combination of sumatriptan and naproxen sodium has also been shown to reduce the rate of migraine recurrence versus sumatriptan alone.(5) Current 2013 CHS guidelines recommend adding naproxen sodium 500 mg simultaneously to sumatriptan when migraine response to sumatriptan alone is inadequate.(5) A new ﬁxed-dose combination tablet of sumatriptan 85mg and naproxen sodium 500mg will be available in Canada later this year indicated for the acute treatment of migraine attacks with or without aura in adults.(38) This treatment provides an onset of action in as early as 30 minutes and has a pharmacokinetic proﬁle that allows for optimal drug delivery to address both early and late phases of migraine”.(7,39,40)

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In one randomized controlled trial, the sumatriptan-naproxen combination achieved a significantly higher 2-hour headache relief rate than sumatriptan monotherapy alone, naproxen monotherapy alone or placebo (65% vs. 55% vs. 44% vs. 28%, respectively), and a number needed to treat (NNT) of 2.7 with the sumatriptan-naproxen combination.(6,22) Furthermore, after taking the sumatriptan-naproxen formulation, only 22% of patients required rescue medication versus 32% on sumatriptan alone or 38% on naproxen sodium alone.(6) Early onset treatment of acute migraine with the sumatriptannaproxen combination formulation increases the therapy’s effectiveness.(39) In menstrual migraine with dysmenorrhea, after taking the sumatriptannaproxen formulation, a significantly greater percentage of participants were headache pain-free 2 hours after treatment compared with participants treated with placebo. The therapeutic gain (i.e. the difference between treatment groups) was 19% in one study and 30% in another study (Study 1, 42% compared with 23%, p<.001; Study 2, 52% compared with 22%, p<.001, and NNT of 5.3 and 3.3 respectively).(41) In another two replicate randomized controlled trials involving patients who had previously discontinued triptans due to intolerance or ineffectiveness, the fi xed dose sumatriptan-naproxen combination showed a 2- through 24-hour sustained pain-free response of 26 and 31% versus 8% for placebo (NNT of 5.6 and 4.3 respectively).(42) The combination of the sumatriptannaproxen combination may also benefit patients where medication compliance with taking both an NSAID and triptan simultaneously are a concern.(43) Adverse events for the combination of sumatriptan and naproxen was not found to be greater than monotherapy with sumatriptan alone and included dizziness, paresthesia, somnolence, dry mouth, nausea and chest discomfort.(6) Contraindications are similar to triptan and NSAID monotherapy including pre-existing cardiovascular issues and uncontrolled hypertension.(5,6) ERGOT DERIVATIVES, OPIOIDS AND BARBITURATES

Ergotamine and ergot derivatives, although approved for treatment of migraine, should not be routinely used for acute treatment of migraine due to inferior efﬁcacy compared to triptans and higher risk of side effects.(5,22) Opioids, tramadol,

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butorphanol and barbiturates should generally be avoided because they do not work well for migraine and may carry a risk of medication overuse headache, risk of dependence/abuse and withdrawal syndrome after discontinuation.(5,22) ADJUNCTIVE MEDICATIONS

Adjunctive medications can be used for individuals experiencing nausea and vomiting commonly associated with their migraine attack.(5) They also help to enhance gastric emptying in patients with gastroparesis, a commonly experienced condition during migraine attacks that may delay absorption of oral medications.(5) Adjunctive treatments include dopamine antagonists metoclopramide (10 mg) and domperidone (10 mg).(22) The best evidence exists for metoclopramide.(5) Adverse effects of metoclopramide include drowsiness and extrapyramidal effects, while domperidone should be used with caution in patients with a risk of QT prolongation.(5,22) AVOIDING MEDICATION OVERUSE

Excessive treatment of migraines with acute medications can increase the risk of more frequent headaches and result in medication overuse headache.(5) To prevent medication-overuse headache, patients should be advised to limit NSAIDs and acetaminophen use to no more than 14 days per month, and triptans, ergotamine derivatives, opioids and combination analgesics to no more than 9 days a month.(44,45)

Non-pharmacological therapy Patients may beneﬁt from resting in a dark and quiet room, applying cold

compresses to the head and sleeping to alleviate symptoms of migraine.(46) Careful management of lifestyle factors can also help, including identifying/ avoiding migraine triggers (including medications), maintaining a regular sleep and eating schedule, smoking cessation, limiting caffeine intake and reducing stress. Patients often focus on perceived food triggers (e.g., chocolate or red wine), but the evidence supporting their role as triggers is weak.(47) Interventions such as cognitive behavioural therapy, relaxation techniques and various stress management approaches have been shown to help migraine sufferers reduce stress and anxiety to better manage pain.(47)

The pharmacist’s role Pharmacists are well positioned to help patients and physicians choose the appropriate drug, dose, frequency and route of administration individualized for each patient when it comes to migraine management. For over-the-counter options, NSAIDs (ibuprofen 400 mg and naproxen sodium 220 mg), as well as ASA and acetaminophen are available for recommendation. In areas where pharmacists have prescribing authority for minor ailments, pharmacists have an additional role and responsibility to diagnose migraine, refer patients to physicians and other medical care where warranted, and prescribe an appropriate medication. Using the 3-item migraine questionnaire (Table 2) is a quick and useful tool to screen for migraine. NSAIDs and triptans remain the ﬁ rstline treatments for moderate to severe acute migraine, with the addition of a

Answer online at eCortex.ca

dopamine antagonist to reduce nausea, if necessary. For less severe migraines where NSAIDs have not been tried, it is recommended that an NSAID be prescribed ﬁ rst, and a stepwise treatment plan is considered with appropriate patient follow-up. For all medications, treatment early in the attack is more effective. It is also important to educate patients about the risk of medication overuse. Advising the patient to carefully document their migraine experience will help determine which agent meets the treatment goals, or if a combination tablet or medication switch is necessary. A detailed chronicle of each attack will also help identify triggers that can be managed or avoided. A free available electronic tool to help patients track migraines is the Canadian Migraine Tracker app.(48) A follow-up appointment should be scheduled in 30 days to review the patient’s medication/headache diary. By that time, an indication of what the migraine triggers are, and how well the patient responds to the medications, should be evident. The patient’s experience will continually shape the individualized treatment strategy going forward and it may take several visits to the pharmacy to get the patient on the road to good control. References and Table 4 for this CE lesson are available online at www.ecortex.ca. Find the questions for this CE lesson online at www.ecortex.ca. Quick Search CCCEP # 1329-2020-3030-I-P

Faculty: Exploring acute migraine treatments for adults ABOUT THE AUTHORS Victor Wong RPh, BScPhm, PharmD, completed his Bachelors of Pharmacy at the University of Toronto and his Doctor of Pharmacy at the University of Colorado. In addition to being the pharmacistowner of two Shoppers Drug Mart pharmacies, Victor is a teaching associate at the University of Toronto Faculty of Pharmacy, and Chief Examiner and Chief Administrator at the Pharmacy Examining Board of Canada. He has been awarded the University of Toronto’s Preceptor of

Answer online at eCortex.ca

the Year award and has been a four-time ﬁnalist for the Associate-Owner of the Year award for Shoppers Drug Mart. He is a contributor for the Hufﬁngton Post newspaper and featured regularly on TV and radio. Karen Au RPh, BScPhm, completed her Bachelor of Science in chemistry at the University of Western and her Bachelor of Pharmacy at the University of Toronto. She has been working as a pharmacist with Shoppers Drug Mart.

REVIEWERS All lessons are reviewed by pharmacists for accuracy, currency and relevance to current pharmacy practice. CE Project Manager: Rosalind Stefanac CE Designer: Shawn Samson

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.

This lesson is published by EnsembleIQ: 20 Eglinton Ave. West, Suite 1800 Toronto, ON M4R 1K8 Phone: 877.687.7321 Fax: 888.889.9522

·ca

5 Tips

PEARLS YOU CAN USE IN YOUR PRACTICE NOW

RECOGNIZING AND MANAGING IMMUNE CHECKPOINT INHIBITOR TOX-ICI-TIES BY PIERRE THABET, BScPharm, ACPR; JASON WENTZELL BScPharm, ACPR, BCOP, MHM

he Canadian cancer care landscape is changing, with the emergence of immunotherapy-based anticancer treatments that have demonstrated significant clinical benefit for many types of cancer. Immune checkpoint inhibitors (ICIs) have become important drug therapies for certain types of cancer including melanoma, Hodgkin lymphoma and lung, renal and bladder cancer. They are also actively being studied in many other cancer types. It is important to be aware of these contemporary anticancer agents. Pharmacists are often on the frontline of healthcare and can help identify potential side effects

Become familiar with ICIs available in Canada and their immune targets. The immune system is integral to the prevention of malignancy. For malignancy to develop and proliferate, it must successfully evade the host’s defenses. It had long been hypothesized that the immune system could be used as an effective target for anticancer therapies. It is now known that inhibition of key immune targets—cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and program cell death-1 (PD-1) receptor and ligand (PDL-1)— effectively “removes the brakes” of the immune system and that this can be exploited to target specific cancers.

from ICIs and convey appropriate recommendations regarding treatment or referral for toxicities. Many pharmacists are familiar with the classic side effects of cytotoxic chemotherapies—neutropenia, hair loss, fatigue and mucositis. ICI therapies and their resulting toxicities are fundamentally different from cytotoxic chemotherapies. Although ICIs are administered parenterally and are not dispensed from most retail pharmacies, patients may present to their frontline pharmacist with ICI-related toxicities. This article provides five tips to help pharmacists recognize and manage potential ICI toxicities, as ICIs become more prevalent therapies for patients across Canada.

ICIs available in Canada (Table 1) function to disinhibit aspects of the immune system, encouraging immune cells to flourish and fight the cancer. Depending on the indication, a single ICI may be used or two ICIs with different targets (e.g., CTLA-4 + PD-1 inhibitors) used in combination.(1,2)

adverse events. These may occur during treatment, with an onset of weeks to months after first exposure, or even weeks to months following treatment cessation. Symptoms can affect a wide variety of systems and range in severity. Grade 1 reactions are generally mild and/or only detected on bloodwork, whereas Grade 4 reactions are life-threatening. Cancer Care Ontario (CCO) has developed an excellent ICI toolkit resource for recognizing and grading ICI toxicities (www.cancercareontario.ca/ en/guidelines-advice/modality/ immunotherapy/immunetherapy-toolkit).(3) Immunerelated adverse events (Table 2) are graded in accordance with Common Terminology Criteria for Adverse Events criteria; ICI treatment is generally continued with grade 1 toxicities, held while

Recognize common ICIrelated adverse events. In contrast to traditional chemotherapy, where common adverse events typically include immune suppression and myelosuppression, ICI adverse events generally reflect an overstimulation of the immune system. As such, inflammatory complications are the hallmark of ICI-related

[Vol.7 No.5] JUNE/JULY 2020

systemic treatment (generally corticosteroids) is given for grade 2–3 toxicities, or stopped with grade 4 toxicities.(3)

Know which immunerelated adverse events can be managed without specialist referral. Grade 1 immune-related adverse events may not require immediate specialist referral. Pharmacists are well positioned to advise patients on management of certain ICI grade 1 immune-related adverse events, as nonprescription supportive therapies may be beneficial in certain cases. Rash often presents as macules/papules covering < 10% of body surface area (BSA). It may be treated 25

with topical corticosteroids (hydrocortisone 1%), emollients and oatmeal baths. Oral antihistamines may be considered for pruritis. Rashes covering > 10% BSA, or those unresponsive to one to two weeks of nonprescription treatment, should be referred for further investigation and potential systemic therapy. Mild diarrhea (< 4 stools/day more than baseline) may be conservatively managed with loperamide and adequate oral hydration, with consideration given to the use of oral electrolyte replacements.

Understand which immunerelated adverse events require prompt referral. In general, grade 2–4 ICI toxicities require prompt patient referral to their oncologist or nearest acute care (emergency) centre. Severe diarrhea, abdominal pain, blood or mucus in the stool, jaundice or worsening shortness of breath all constitute potentially severe toxicities and warrant immediate referral. Endocrinopathies from ICI treatments can affect thyroid, pituitary, adrenal or pancreatic function. Any patient presenting with hypotension, significant glucose abnormalities or with a septic appearance should immediately be referred to emergency care. This list is not exhaustive; professional judgment in combination with resources such as the CCO toolkit (see Tip #2) can be used to guide recommendations. Pharmacists should be aware that newly prescribed thyroid replacement therapy, beta-blockers or corticosteroids (especially with a long taper) may be related to management of ICI toxicities and not necessarily chronic disease management. In these cases, it is important to provide close follow-up, to ensure adequate management of the immune-related adverse event and lack of escalation of the side effect being treated. Treatment of an ICI-related toxicity involves initiating immu26

nosuppressive pharmacotherapy. Depending on the type and severity of immune-related adverse events, oral or parenteral corticosteroids are often the first line of immunosuppressive treatment. Additional immunosuppressive agents (e.g., infliximab, mycophenolate mofetil or tacrolimus) may be considered depending on the site of toxicity and initial response to corticosteroid therapy.

Consider the safety of immunizing patients receiving ICIs. Given the relationship between ICIs and the immune system, the safety of immunization in this population has been questioned. The use of live vaccines has not been studied and should be avoided.(3) Uncertainty also exists about the safety of the high-dose influenza vaccine in this population. Therefore, live attenuated (intranasal) and high-dose quadrivalent influenza vaccines are not recommended.(5,6) Recent studies support the use of inactivated influenza vaccine in those receiving PD-1 or PDL-1 inhibitors.(4-6) Guidance is available concerning influenza vaccination in patients receiving CTLA-4 inhibitors (i.e., ipilimumab), alone or in combination with PD-1/PDL-1 inhibitors. The BC Cancer Provincial Systemic Therapy Committee suggests that patients should not receive any influenza vaccinations within six to eight weeks before or after ICI exposure, while an Alberta Health Services Provincial Tumor Teams consensus recommends avoiding influenza vaccination for six months post-CTLA-4 exposure.(7,8) Although the use of influenza vaccine has been studied, little is known about the safety and efficacy of other vaccines with ICIs. In the absence of safety data and clear recommendations for their use alongside ICI therapy, vaccines commonly administered by pharmacists, except the flu vaccine, should be avoided. To JUNE/JULY 2020 [Vol.7 No.5]

TABLE 1 I mmune-checkpoint

marketed in Canada

inhibitors currently

CTLA-4

PD-1 INHIBITORS

PDL-1 INHIBITORS

Ipilimumab

Nivolumab Pembrolizumab Cemiplimab

Atezolizumab Avelumab Durvalumab

CTLA-4–cytotoxic T-lymphocyte associated antigen-4; PD-1–program cell death-1; PDL-1–program cell death-1 ligand

TABLE 2 I mmune-checkpoint

inhibitor toxicities, incidence and onset(3)

IMMUNE-RELATED ADVERSE EVENT

INCIDENCE

TYPICAL ONSET

Dermatologic (e.g., macules, papules, skin sloughing)

20%–40%

3–6 weeks

Diarrhea/colitis

< 30%

6–8 weeks

Endocrinopathies (e.g., hypo-/hyper-thyroidism, hypophysitis, adrenal insufficiency)

5%–20%

12–24 weeks

Hepatotoxicity

1%–9%

8–12 weeks

Neurotoxicity (e.g., enteric neuropathy, myopathy, optic neuritis)

< 5%

1–6 weeks

Pneumonitis

< 5%

4–26 weeks

Nephrotoxicity

< 5%

6–30 weeks

minimize the risk of infections, pharmacists should remind patients to practise good hand hygiene, avoid sick contacts and encourage close contacts to be vaccinated.

Summary

ICI therapies are emerging as first- or second-line treatments for many types of cancer. Their mechanisms of action and resulting toxicities involve up-regulation of immune system function resulting in autoimmune toxicities that are fundamentally different than traditional cytotoxic anticancer therapies. The mainstay of treatment for ICI toxicities involves immunosuppression, generally using oral or parenteral corticosteroids. Pharmacists play an important role in recognizing potential ICI toxicities and urgently referring patients experiencing moderate to severe reactions. Pierre Thabet (pierrethabet@ montfort.on.ca) is a clinical pharmacist at Hôpital Montfort in Ottawa. Jason Wentzell (jwentzell@ extendpharmacy.com) is a medical oncology pharmacist specialist at Extend Pharmacy in Ottawa. REFERENCES

1. Ledford H, Else H, Warren M. Cancer immunologists scoop medicine Nobel

prize. Nature 2018;562(7725):20–1. 2. Sweis RF, Luke JJ. Mechanistic and pharmacologic insights on immune checkpoint inhibitors. Pharmacol Res 2017;120:1–9. 3. Forbes L, Crespo A, Abella L, et al. Immune checkpoint inhibitor toxicity management - clinical practice guidelines. Cancer Care Ontario. www. cancercareontario.ca/en/file/39391/ download?token=Thzk5Jp9 (accessed November 8, 2019) 4. Gwynn ME, DeRemer DL, Saunders KM, et al. Immune-mediated adverse events following influenza vaccine in cancer patients receiving immune checkpoint inhibitors. J Oncol Pharm Pract 2019 Aug 31;1078155219868758. 5. Chong CR, Park VJ, Cohen B, et al. Safety of inactivated influenza vaccine in cancer patients receiving immune checkpoint inhibitors (ICI). Clin Infect Dis 2019 Mar 15; pii: ciz202. 6. Wijn DH, Groeneveld GH, Vollaard AM, et al. Influenza vaccination in patients with lung cancer receiving anti-programmed death receptor 1 immunotherapy does not induce immune-related adverse events. Eur J Cancer 2018;104:182-7. 7. BC Cancer. Influenza vaccine guideline. 2019. www.bccancer. bc.ca/nursing-site/Documents/BC_ Cancer_Provincial_Systemic_Therapy_ Committee-Flu_Vaccine_Guidelines. pdf (accessed November 8, 2019). 8. Alberta Health Services. Influenza immunization for adult and pediatric patients undergoing cancer treatment. 2019. www.albertahealthservices.ca/ assets/info/hp/cancer/if-hp-cancerguide-supp002-vaccination.pdf (accessed December 18, 2019).

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In Canada, most tick bites occur between April and October, with the majority of Lyme disease cases occurring during the month of July.

CLINICAL FEATURE

UNDERSTANDING LYME DISEASE Answers to 14 key questions about diagnosis and management BY VICTORIA COX, BSc(Pharm), ACPR, PharmD

yme disease is the most common tickborne infection in North America and Europe.(1) The disease emerged in the northeastern and upper midwestern United States in the 1970s and is presently spreading north to eastern and central Canada.(2) From 2016 to 2017, the number of cases of Lyme disease in Canada more than doubled and pharmacists are likely to field an increasing number of inquiries about this infection.(3) The following key questions and answers are intended to provide you with timely information regarding Lyme disease.

1. What causes Lyme disease?

In Canada, Lyme disease is caused by Borrelia burgdorferi, a spirochete bacteria transmitted to humans by the bite of infected ticks.(4,5) Different species of Borrelia cause Lyme disease in other areas of the world.(6) In central and eastern Canada, Ixodes scapularis (blacklegged [deer] ticks) are carriers of Lyme disease; in western Canada Ixodes pacificus (western blacklegged ticks) 28

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and less commonly, Ixodes angustus, are vectors.(4,7) Since I. pacificus is both less likely to be infected and to bite humans, the risk of transmission of Lyme disease is considerably lower from I. pacificus than from I. scapularis.(2)

2. How is Lyme disease transmitted?

Blacklegged ticks can be infected with Lyme disease after feeding on the blood of infected wild animals (e.g., birds, rodents).(5) These ticks are found in forests, shrubs, tall grasses and leaf piles in both rural and suburban settings.(5,8) Infected ticks move from vegetation to human or animal hosts as the host walks by.(9) When ticks bite the host, the disease can be transmitted.(9) Nymphs (immature ticks) most commonly infect humans.(10) Nymphs are tiny (< 2 mm) and feed during the late spring and summer months when people are most active outdoors.(10) Although adult ticks can also transmit Lyme disease, they are larger than nymphs (approximately the size of a sesame seed) and more likely to be discovered and removed before bacterial transmission.(10) Adult ticks are most active during the cooler months of the year.(10) In Canada, most tick bites occur between April and October, with the majority of Lyme disease cases occurring during the month of July.(4,11) Ticks bite the host and may feed for several days then drop off.(10) As a tick feeds, it becomes engorged and considerably larger in size.(1,7) Generally, ticks must be attached to the host for 36–48 hours or more before B. burgdorferi can be transmitted.(11,12) Bites may go undetected as tick saliva has anesthetic properties.(10)

3. Where can Lyme disease be contracted?

Lyme disease risk areas are regions where blacklegged and western blacklegged ticks are known to reproduce.(8) Risk areas are constantly evolving (Table 1). In the United States, a high incidence of Lyme disease (i.e., average of 10 or more confirmed cases per 100,000 persons in the previous three reporting years) is found in the northeastern states from Virginia to eastern Canada and the upper Midwest (Wisconsin and Minnesota).(13) The spread of Lyme disease into higher latitudes

TABLE 1

in North America is thought to be secondary to increases in temperature associated with climate change.(14) These changes have led to improved conditions for tick survival, increased tick population densities, widening tick geographic distribution, and prolongation of tick seasonal activity.(14) With milder temperatures, people may resume outdoor activity sooner in the spring and maintain it longer in the fall, increasing their potential exposure to ticks.(14) Expanded geographic distribution of animals that serve as reservoirs for tick reproduction (e.g., mice, birds) may also contribute to the spread of Lyme disease.(14) Presently, Lyme disease remains uncommon in most areas of Canada, but its incidence and geographic range are increasing.(4) In 2009, when Lyme disease became a national notifiable disease in Canada, a total of 144 confirmed and probable cases were reported.(3) By 2016, the number of cases had increased more than six-fold to 992, and rose to 2,025 in 2017.(3) In 2016, 88% of reported cases were in Ontario, Québec and Nova Scotia.(3) Ongoing surveillance in these three provinces demonstrates that blacklegged tick populations have been established for years; however, there have been recent increases in the number of ticks in previously identified risk areas and in the percentage of blacklegged ticks infected with B. burgdorferi.(3) In 2016, Nova Scotia reported the highest incidence of Lyme disease in Canada (34.4 cases per 100,000 population) and recently the entire province has been designated a high-risk area for Lyme disease.(3) In contrast, in western Canada the incidence of Lyme disease has remained low and stable; the BC Ministry of Health has reported a plateau in the number of infected tick populations in the past decade.(3,4) The geographical boundaries of tick populations are constantly changing and current information from Health Canada can be located online (www. canada.ca/en/public-health/services/diseases/lyme-disease/risklyme-disease.html).(8)

4. What are the symptoms of Lyme disease?

The stages of untreated Lyme disease overlap and include early localized, early disseminated and late disseminated disease.(9,15)

Risk areas for Lyme disease in Canada (January 27, 2020)(8)

Province

Area at risk

British Columbia

Vancouver Island, Southern Mainland, coast of British Columbia facing Vancouver Island and river valleys across the southern part of the province

Manitoba

Agassiz Provincial Forrest, Assiniboine River (from Winnipeg to west of Brandon), Beaudry Provincial Park, Belair area, Bellsite area, Binscarth area, Birtle area, Buffalo Point area, Crystal City area, Eriksdale area, Grand Valley Provincial Park, Grunthal area, Langford Trails, Macdonald/Delta Beach area, McCreary area, Minnedosa area, Moose Lake Provincial Park, Norris Lake Provincial Park, parts of southern Manitoba along the border with the United States from south of Brandon to Lake of the Woods, Patricia Beach Provincial Park, Pembina escarpment, Pembina Valley Provincial Park, Pinawa area, Rainbow Beach Provincial Park, Roseau River area, Sandilands Provincial Forrest, Solsgirth area, Souris area, Sprucewoods Provincial Park, Squirrel Hills Trails, St. Ambroise Provincial Park, St. Malo Provincial Park, Stuartburn area, Tolstoi area, Treherne area, Turtle Mountain Provincial Park, Vita/Arbakka area, Wasagaming (Riding Mountain National Park) area, Whitemud Watershed Wildlife Management area, Whiteshell Provincial Park (Falcon Lake, West Hawk Lake), William’s Lake Provincial Park, Winnipeg Beach area, Winnipeg (areas within and around)

Ontario

Along the north shores of Lake Erie and Lake Ontario, parts of Thousand Islands National Park, Kingston and surrounding area along the St. Lawrence Valley to the border with Quebec and northeast towards Ottawa, Northwestern Ontario in the region of Lake of the Woods, Pinery Park on the shore of Lake Huron

Quebec

Montérégie (south of Québec), Southwest of Mauricie et Centre-du-Québec, North and west of Estrie, southwest of Outaouais

New Brunswick

Areas of: Charlotte County, Saint John County, Kings County, Albert County, Westmorland County and York County

Nova Scotia

All of Nova Scotia is a risk area for Lyme disease

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If left untreated, 10%–20% of patients have neurologic symptoms, such as facial nerve palsy or meningitis.

musculoskeletal pains, continuing for months to years.(5,18,19) In the absence of alternate diagnoses, these patients may be labelled as having “chronic Lyme disease” or “post-treatment Lyme disease syndrome.”(1,5,19) The relationship of these symptoms to Lyme disease is highly controversial.(1) No human studies have demonstrated that Borrelia causes chronic infection after completion of recommended antibiotic treatment.(18) In practice, the term “chronic Lyme disease” has been applied to a heterogeneous patient population, some of whom may never have had clinical or serologic confirmation of infection, or may have tested positive using unvalidated serologic tests.(1,5,16,18) As there is no commonly accepted definition, significant controversy exists regarding the incidence and prevalence of this clinical entity.(1)

6. How is Lyme disease diagnosed? Early localized Lyme disease occurs three to 30 days after tick exposure and is characterized by a skin lesion known as erythema migrans (EM).(5,9) EM occurs in about 70%–80% of Lyme disease cases.(16,17) This circular or oval erythematous skin lesion develops at the site of the tick bite and is usually painless and nonpruritic.(1,9,15) The lesion slowly enlarges to ≥ 5 cm in diameter over days to weeks and may persist for up to eight weeks.(9,15) A “bull’s eye,” described as an erythematous centre surrounded by a zone of clearing and another ring of erythema, appears in 20%–35% of these lesions.(9,16,17) Lesions can also appear homogenously erythematous, have blue-purple hues, blister, crust or necrotic centres.(9,16) Lesions typically occur in the axilla, inguinal region, popliteal fossa or belt line.(16) Constitutional symptoms (e.g., fever, fatigue, arthralgias, myalgias, headache) may also accompany early localized Lyme disease.(5,9) Unlike EM, an erythematous skin lesion that develops while an Ixodes tick is attached or within 48 hours of detachment may indicate a tick bite hypersensitivity reaction.(1,15) Hypersensitivity lesions are typically < 5 cm in diameter, have an urticarial appearance and begin to disappear within 24–48 hours.(1,15) Early disseminated Lyme disease arises when Borrelia spreads from the primary site of infection, occurring up to three months after tick exposure.(9) Symptoms can include fatigue, general weakness and multiple EM lesions.(9) If left untreated, 10%–20% of patients have neurologic symptoms, such as facial nerve palsy or meningitis, and 4%–10% have cardiovascular complications (e.g., atrioventricular heart block and arrhythmias).(5,7,9,16) Musculoskeletal symptoms include monoarticular or oligoarticular arthritis, most commonly involving the knee and other large joints, possibly accompanied by effusions.(5,9,15) Episodes may resolve spontaneously over weeks to months.(15) Late disseminated Lyme disease occurs more than three months after tick exposure and can last months to years if untreated.(5,9) Most commonly, symptoms are musculoskeletal (e.g., arthritis, myalgias, joint effusions), but may also be neurologic (e.g., changes in memory and concentration, peripheral neuropathy).(5,9,16)

5. What is “chronic Lyme disease”?

Following appropriate treatment for Lyme disease, some patients continue to experience a constellation of nonspecific symptoms, such as fatigue, headache, memory loss and 30

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Early localized Lyme disease is a clinical diagnosis, supported by a history of travel in a Lyme endemic area and symptoms compatible with the disease.(1,20,21) A witnessed tick bite is not necessary for diagnosis as bites may go undetected.(5) Laboratory testing is appropriate for people with symptoms of noncutaneous (disseminated) Lyme disease and a history of tick exposure.(20) Both the Public Health Agency of Canada (PHAC) and the US Centers for Disease Control and Prevention (CDC) recommend using a two-tiered serological algorithm for detecting antibodies to B. burgdorferi.(2) Specifically, a highly sensitive enzyme immunoassay (EIA) is used first, and if positive or equivocal, a highly specific Western blot test is performed.(20,22) Autoimmune diseases or antibodies to other spirochetes or viruses may result in a falsely positive EIA; therefore, two-tiered testing is necessary.(21) Because detectable antibodies take days to weeks to develop, serologic testing may be falsely negative for the first few weeks after initial exposure and should not be used to diagnose early disease.(1) Prompt antibiotic treatment of acute infection may prevent the development of seropositivity.(5,16,23) Patients can be infected with Lyme disease multiple times.(20) Once a patient is known to be seropositive, one cannot distinguish between new and previously acquired infection, as antibodies to B. burgdorferi may persist for years following treatment.(21) Persistently positive tests do not indicate ineffective treatment or chronic infection, and repeat serologic testing for documentation of cure is not recommended.(16) Outside of North America, Lyme disease may be caused by non-burgdorferi species of Borrelia.(21) In patients suspected of acquiring Lyme disease abroad, laboratories should be notified as supplemental diagnostic tests may be required.(21) Canadian public laboratories are federally licensed to conduct serologic testing for Lyme disease.(9) Unlicensed private laboratories may use insufficiently validated tests that do not follow the two-tier process or the recommended standards for interpreting test results.(9) These tests have high false-positive rates, potentially misdiagnosing Lyme disease and resulting in unnecessary antibiotic treatment.(20,24) Patients should be advised to pursue Lyme disease testing only from licensed public laboratories.

7. How is Lyme disease treated?

Recommended oral antibiotics for the treatment of Lyme disease are presented in Table 2. Trials of patients with EM have found doxycycline, amoxicillin and cefuroxime axetil to have similar efficacy; all are considered first-line agents.(1,12) Azithromycin has lower efficacy compared to other agents and should only be used

TABLE 2

Recommended oral antibiotics for treatment of patients with erythema migrans(1,12,16,21) Duration of therapy (days)

Antibiotic

Adult dose

Pediatric dose

Doxycycline

100 mg po bid

4–4.4 mg/kg/day divided bid (max 100 mg per dose)

Amoxicillin

500 mg po tid

50 mg/kg/day divided tid (max 500 mg per dose)

Cefuroxime axetil

500 mg po bid

30 mg/kg/day divided bid (max 500 mg per dose)

10 mg/kg/day (max 500 mg per dose)

Alternate oral regimen* Azithromycin

500 mg po daily

* Due to concerns about lower efficacy, azithromycin is considered a second-line agent and should only be used in patients unable to take other classes of antibiotics.

if first-line antibiotics are contraindicated.(1,12,21) First-generation cephalosporins (e.g., cephalexin) are not effective in treating Lyme disease.(1,12) Intravenous antibiotics are recommended for patients with Lyme meningitis or radiculopathy, and for the initial treatment of hospitalized patients with cardiac conduction abnormalities.(1)

risk and benefit.(28) The recommended duration of therapy for Lyme disease is the same in adults and children (Table 2).

10. What counselling should be provided to patients receiving Lyme disease treatment?

Patients prescribed doxycycline for Lyme disease should be advised to take the medication with 250 mL of fluid and sit upright for 30 minutes after ingestion, to reduce the risk of esophageal irritation.(1,12,30) Doxycycline may be taken with food if gastrointestinal irritation occurs.(30) Positive cations (e.g., oral calcium, magnesium and iron) should be administered at least two hours before, or four hours after, doxycycline.(30) Doxycycline may interact with warfarin to increase INR; INRs should be closely monitored when starting and discontinuing doxycycline therapy.(30) Doxycycline may cause photosensitivity; patients should be advised to avoid the sun, wear a hat and protective clothing outdoors, and apply sunscreen liberally.(30) Amoxicillin and cefuroxime axetil may cause skin rashes and antibiotic-associated diarrhea.(1,30) One to 12 hours after antibiotic initiation to treat Lyme disease, approximately 15% of patients experience a systemic reaction.(1,6,12) This syndrome, known as a Jarisch-Herxheimer reaction, may consist of myalgias, arthralgias, headache and transient fever.(1,12) The reaction resolves within 24–48 hours without sequelae and is thought to be caused by lysis of spirochetes with subsequent release of toxins.(1,6,12) Nonsteroidal anti-inflammatory medications may be used for symptomatic relief.(1,12)

8. How should patients with persistent symptoms be managed?

Extended antibiotic therapy is not recommended for patients with chronic subjective symptoms (e.g., fatigue, headache, myalgias, arthralgias and/or memory loss for more than 6 months) after completing treatment for Lyme disease.(1,18,19) Studies have demonstrated that antibiotic treatment beyond recommended durations does not improve outcomes compared to placebo, but increases the risk of Clostridioides difficile infections, intravenous catheter site infections and allergic reactions.(18) Patients with persistent symptoms should be managed supportively and alternate diagnoses sought.(5)

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Answer online at www.eCortex.ca

Approved for

1.0 CEU

E S S O N

CCCEP #1329-2020-3030-I-P • Please consult this course online at eCortex.ca for expiry dates

Exploring acute migraine treatments for adults By Victor Wong, RPh, BScPhm, PharmD and Karen Au, RPh, BScPhm

9. Does Lyme disease treatment differ between adults and children?

Historically, doxycycline has not been recommended for use in children less than eight years of age due to concerns about cosmetic staining of permanent teeth.(25) Tooth staining and dental enamel hypoplasia in children was associated with tetracycline use in the 1960s; subsequently all antibiotics in the tetracycline class were labelled with a warning against use in children younger than eight years.(25,26) Since then, small observational studies have demonstrated no differences in dental staining between children treated with doxycycline and untreated children; however, this issue remains controversial.(26-28) Similar to the treatment of Lyme disease in adults, both the Canadian Paediatric Society and the US CDC recommend doxycycline, amoxicillin or cefuroxime as first-line options in children with Lyme disease regardless of age.(21,29) The safety of doxycycline in pregnancy and breastfeeding has not been systematically studied and treatment decisions should be made after weighing potential

Upon successful completion of this lesson, the pharmacist will be able to: 1. Explain the pathophysiology, diagnosis and symptoms of acute migraine. 2. Compare the different classes of medications available for the treatment of acute migraine. 3. Describe evidence-based strategies for the treatment of acute migraine and the avoidance of medication overuse headache. Supported by educational funding from Aralez Pharmaceuticals Canada Inc.

[Vol.7 No.5] JUNE/JULY 2020

Bathing within two hours of leaving a Lyme endemic area reduces the risk of Lyme disease and is a good opportunity to do a tick check.

11. How can Lyme disease be prevented?

Pharmacists can educate patients about preventing tick bites. If it is not possible to avoid tick habitats in areas where Lyme disease is endemic, then preventive measures should be followed.(31) Wear light-coloured clothing with long sleeves and long pants to improve visibility of ticks; tuck shirts into pants and pants into socks to minimize exposed skin.(5,31) Bathing within two hours of leaving a Lyme endemic area reduces the risk of Lyme disease and is a good opportunity to do a tick check.(32,33) Wash clothes in hot water, tumble dry, and continue to dry them at high heat for at least 10 minutes to kill ticks.(32) Insect repellents can be used to prevent tick bites.(34) Health Canada has not evaluated the safety of any repellents in infants less than six months of age; nonchemical measures should be used to protect this age group from bites.(34) Insect repellents containing up to 10% DEET (N,N-diethyl-meta-toluamide) may be applied no more than once daily to children six months to two years of age, providing protection for one to two hours.(34,35) Children two to 12 years of age should also only use products containing up to 10% DEET; however, they may be applied up to three times daily.(35) Children less than 12 years of age should not use DEET on a daily basis for longer than one month.(35) Those older than 12 years may use products with DEET concentrations up to 30%.(34,35) Products with higher DEET concentrations provide longer protection compared with lower concentrations.(34) Adverse effects to DEET are rare and may include contact dermatitis and eye irritation.(34) Icaridin (also known as picaridin) is considered the repellent of choice by PHAC’s Committee to Advise on Tropical Medicine and Travel (CATMAT) for children six months to 12 years of age.(34) Products containing up to 20% icaridin are considered safe and efficacious in preventing tick bites.(34) The efficacy of repellents containing soybean oil, citronella oil or p-menthane3,8-diol (PMD, the synthetic derivative of oil of lemon eucalyptus) against ticks is uncertain.(34) Combination sunscreen and insect repellent products are not approved in Canada.(35) If both are required, patients should apply sunscreen first, allow it to penetrate for 20 minutes, then apply insect repellent.(34) Repellents should never be applied under clothing, directly to the face, on open wounds, or to the hands (may be transferred to eyes or mouth).(34,35) Once indoors, repellent should be washed off skin with soap and water.(34,35) Clothing treated with the insecticide permethrin is available in Canada for adults, but has not been approved for use in children.(35) 32

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12. What advice should be provided to patients who discover a tick on their skin?

After visiting a Lyme disease risk area, patients should inspect their clothing and skin for ticks.(32) Ticks that have not attached to the skin may be brushed off.(5) Ticks attached to the skin should be grasped with clean tweezers or a tick removal device at the closest point of attachment to the skin and pulled steadily outwards to avoid injecting the tick’s stomach contents into the skin.(17) If tick mouth parts remain in the skin and cannot be removed with tweezers, they should be left alone as further manipulation risks infection.(5,17,33,36) Soap and water or alcohol hand sanitizer should be used to clean the bite area and the patient’s hands following tick removal.(33,36) Ticks can be killed by wrapping in tape or drowning in rubbing alcohol and disposed of in household garbage; they should never be crushed between fingers.(33,36) Smothering methods (e.g., “painting” the tick with nail polish or petroleum jelly) or using a hot match to kill and remove a tick are not advised.(17,33,36) The tick may be saved for identification in a sealed container marked with location and date, and brought to a physician or local public health unit.(33) Tick identification and testing is not done in all provinces of Canada; contact local public health authorities for details on provincial programs.(33)

13. When should antimicrobial prophylaxis for Lyme disease be recommended after a tick bite?

Antimicrobial prophylaxis for Lyme disease is only indicated for tick bites deemed high-risk.(1) High-risk bites are from an identified Ixodes tick, in an area where > 20% of ticks are infected with B. burgdorferi (check with local public health), and the tick was engorged and attached for more than 36 hours.(9) If a tick bite does not meet all three criteria, a watch-and-wait approach is recommended. If all criteria are met, a single dose of doxycycline may be given to nonpregnant adults (200 mg) and children (4.4 mg/kg, maximum 200 mg) within 72 hours of tick removal.(9) Prophylaxis after I. pacificus bites (found in western Canada) is generally not necessary because of low infection rates with B. burgdorferi in most regions in which the tick is endemic.(1) Regardless of whether prophylaxis is given, all patients should be advised to seek medical attention should the signs and symptoms of Lyme disease occur within 30 days of the tick bite.(21) There is currently no vaccine to prevent Lyme disease.(31)

14. How can pharmacists assist in the prevention and management of Lyme disease?

Pharmacists should be aware of local Lyme disease risk areas (see Question #3) and can teach patients how to prevent tick bites, remove ticks and when to seek medical attention. They can educate patients about the signs and symptoms of Lyme disease and when prophylaxis should be given following a tick bite. If diagnostic testing is indicated, pharmacists should urge patients to use licensed public labs, rather than private lab facilities. Finally, pharmacists should counsel patients on antibiotics prescribed for the treatment and prophylaxis of Lyme disease.

Summary

Lyme disease is an emerging concern, particularly in eastern Canada. Patients may increasingly seek information and advice about the signs, symptoms, prevention and treatment of Lyme disease from healthcare providers. It is important for

pharmacists to be knowledgeable about the prevention and management of this disease and prepared to optimize Lyme disease therapy for patients under their care. Victoria Cox (Victoria.Cox@interiorhealth) is a Clinical Pharmacy Specialist working with the team of Infectious Disease Specialist physicians and nurses at Kelowna General Hospital in Kelowna, BC. REFERENCES

1. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-134. 2. Ogden NH, Bouchard C, Badcock J, et al. What is the real number of Lyme disease cases in Canada? BMC Public Health 2019;19:849. 3. Government of Canada. Surveillance of Lyme disease. August 14, 2018. https:// www.canada.ca/en/public-health/services/diseases/lyme-disease/surveillance-lymedisease.html (accessed December 26, 2019). 4. Public Health Agency of Canada. Emerging infections. CCDR 2017;43(10). https:// www.canada.ca/content/dam/phac-aspc/documents/services/publications/canadacommunicable-disease-report-ccdr/monthly-issue/2017-43/ccdr-volume-43-10october-5-2017/ccdr-volume-43-10-october-5-2017-eng.pdf (accessed December 26, 2019). 5. Hu LT. In the clinic: Lyme disease. Ann Intern Med 2016;164:ITC65-80. 6. National Institute for Health and Care Excellence. Lyme disease. April 11, 2018 (last updated October 2018). www.nice.org.uk/guidance/ng95 (accessed December 7, 2019). 7. BC Centre for Disease Control. Lyme disease (Borrelia burgdorferi infection). Vancouver, BC. www.bccdc.ca/health-info/diseases-conditions/lyme-diseaseborrelia-burgdorferi-infection (accessed December 27, 2019). 8. Government of Canada. Risk of Lyme disease to Canadians. Ottawa, ON: January 17, 2020. https://www.canada.ca/en/public-health/services/diseases/lyme-disease/ risk-lyme-disease.html (accessed March 16, 2020). 9. Government of Canada. For health professionals: Lyme disease. Ottawa, ON: January 27, 2020. https://www.canada.ca/en/public-health/services/diseases/lymedisease/health-professionals-lyme-disease.html (accessed March 16, 2020). 10. Centers for Disease Control and Prevention. Lyme disease: transmission. January 29, 2020. https://www.cdc.gov/lyme/transmission/ (accessed March 16, 2020). 11. Government of Canada. Lyme disease in Canada: a federal framework. Ottawa, ON: May 2017. https://www.canada.ca/content/dam/phac-aspc/documents/ services/publications/diseases-conditions/lyme-disease-canada-federal-framework/ lyme-disease-canada-federal-framework-eng.pdf (accessed December 27, 2019). 12. Shapiro ED. Lyme disease. N Engl J Med 2014;370:1724-31. 13. Centers for Disease Control and Prevention. Lyme disease. Lyme disease maps: most recent year. November 22, 2019. https://www.cdc.gov/lyme/datasurveillance/ maps-recent.html (accessed December 26, 2019). 14. Bouchard C, Dibernardo A, Koffi J, et al. Increased risk of tick-borne diseases with climate and environmental changes. CCDR 2019;45(4):81-9. https://www. canada.ca/content/dam/phac-aspc/documents/services/reports-publications/ canada-communicable-disease-report-ccdr/monthly-issue/2019-45/issue-4april-4-2019/ccdrv45i04a02-eng.pdf (accessed October 10, 2019). 15. Government of Canada. Lyme disease 2016 case definition. Ottawa, ON: December 29, 2017. https://www.canada.ca/en/public-health/services/diseases/lyme-disease/ surveillance-lyme-disease/case-definition.html (accessed December 27, 2019). 16. Chaaya G, Jaller-Char JJ, Ali SK. Beyond the bullâ&#x20AC;&#x2122;s eye: recognizing Lyme disease. J Fam Pract 2016;65:373-9. 17. Interior Health. Medical health officers update for physicians: ticks and Lyme disease. Kelowna, BC: June 15, 2018. https://www.interiorhealth.ca/AboutUs/

Leadership/MHO/MHO%20Updates/MHO%20Update%20-%20June%2015,%20 2018.pdf (accessed December 27, 2019). 18. Association of Medical Microbiology and Infectious Disease Canada. AMMI Canada position statement on the diagnosis and treatment of people with persistent symptoms that have been attributed to Lyme disease. Ottawa, ON: 2019. https://www.ammi.ca/Content/03.17.19%20AMMI%20Canada%20Position%20 Statement%20%28EN%29.pdf (accessed December 27, 2019). 19. Centers for Disease Control and Prevention. Lyme disease. Post-treatment Lyme disease syndrome. November 8, 2019. https://www.cdc.gov/lyme/postlds/index. html (accessed December 27, 2019). 20. Lindsay LR, Bernat K, Dibernardo A. Laboratory diagnostics for Lyme disease. CCDR 2014;40(11). https://www.canada.ca/en/public-health/services/reportspublications/canada-communicable-disease-report-ccdr/monthly-issue/2014-40/ ccdr-volume-40-11-may-29-2014/ccdr-volume-40-11-may-29-2014-1.html (accessed December 27, 2019). 21. Canadian Paediatric Society. Lyme disease in Canada: focus on children. Ottawa, ON: May 16, 2019. https://www.cps.ca/en/documents/position/lymedisease-children (accessed December 26, 2019). 22. Centers for Disease Control and Prevention. Lyme disease: diagnosis and testing. November 20, 2019. https://www.cdc.gov/lyme/diagnosistesting/labtest/ twostep/index.html (accessed December 27, 2019). 23. Theel ES. The past, present, and (possible) future of serologic testing for Lyme disease. J Clin Microbiol 2016;54:1191-6. 24. Kling R, Galanis E, Morshed M, et al. Diagnostic testing for Lyme disease: beware of false positives. BC Medical Journal 2015;57:396-9. 25. Centers for Disease Control and Prevention. Rocky mountain spotted fever (RMSF). Research on doxycycline and tooth staining. February 19, 2019. https:// www.cdc.gov/rmsf/doxycycline/index.html (accessed December 27, 2019). 26. Gaillard T, Briolant S, Madamet M, et al. The end of a dogma: the safety of doxycycline use in young children for malaria treatment. Malar J 2017;16:148. 27. Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever. J Pediatr 2015;166:1246-51. 28. Wormser GP, Wormser RP, Strle F, et al. How safe is doxycycline for young children or for pregnant or breastfeeding women? Diagn Microbiol Infect Dis 2019;93:238-42. 29. Centers for Disease Control and Prevention. Lyme disease. Treatment. December 17, 2019. https://www.cdc.gov/lyme/treatment/index.html (accessed December 27, 2019). 30. Lexicomp/UpToDate. Doxycycline: drug information. Online subscription reference. (accessed December 27, 2019). 31. Ogden NH, Lindsay LR, Schofield SW. Methods to prevent tick bites and Lyme disease. Clin Lab Med 2015;35:883-99. 32. Centers for Disease Control and Prevention. Stop ticks to avoid Lyme and other tickborne diseases. Atlanta, GA: May 14, 2019. https://www.cdc.gov/Features/ StopTicks/ (accessed December 26, 2019). 33. Government of Canada. Removing and submitting ticks for testing. Ottawa, ON: September 20, 2019. https://www.canada.ca/en/public-health/services/diseases/ lyme-disease/removing-submitting-ticks-testing.html (accessed December 27, 2019). 34. Canadian Paediatric Society. Preventing mosquito and tick bites: a Canadian update. Ottawa, ON: December 12, 2019. https://www.cps.ca/en/documents/ position/preventing-mosquito-and-tick-bites (accessed December 26, 2019). 35. Government of Canada. Insect repellents. Ottawa, ON. June 6, 2019. https:// www.canada.ca/en/health-canada/services/about-pesticides/insect-repellents.html (accessed December 26, 2019). 36. Centers for Disease Control and Prevention. Tick removal: removing a tick. Atlanta, GA: September 6, 2019. https://www.cdc.gov/ticks/removing_a_tick.html (accessed December 27, 2019).

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[Vol.7 No.5] JUNE/JULY 2020

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COVER STORY

PHARMACY HEROES Pharmacists truly stepped up during COVID-19 pandemic

Getty Images

BY SONYA FELIX

The COVID-19 pandemic has presented incredible challenges for pharmacists and pharmacy staff, whether working in hospitals, community pharmacies or primary care clinics. As the crisis goes on, the focus remains on maintaining continuity of care while adopting a range of practices to keep patients and pharmacy staff safe during this unprecedented time. Every day, pharmacists and their staff face risk of infection by going to work to care for patients—and yet they continue to show up, don gowns, masks and face shields, load up on sanitizers, and perform tasks behind plexiglass barriers. Some pharmacies have taken on extra measures to help their communities, such as donating to food banks, offering free masks and compounding hand sanitizer for patients and other frontline workers. These are the faces of just a few of Canada’s pharmacy heroes. 

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LEFT (PAGE 36): (1) Sean Simpson, pharmacist/owner, Simpson’s Pharmacy, Virgil, ON. The pharmacy made its own hand sanitizer and provided it and other supplies to the local poverty support agency, Newark Neighbours. In addition, Simpson’s worked with Pure Protein and Vita Health in Winnipeg to procure 15,000 protein bars for the local United Way and the town’s long-term care workers. (2) Pharmacist at Shoppers Drug Mart, Kitchener ON. (3) Sameer Remtulla, pharmacist/owner, Pharmasave, Uxbridge, ON, with his wife Natasha Remtulla. As part of a fundraising campaign for the local food bank, Remtulla, his staff pharmacist Sherry and the mayor are shaving their beards or heads when a major goal is met. When $6,000 was raised, Remtulla shaved his beard and then his head when $9,000 was raised. At $20,000 either Sherry or the mayor will shave their heads. (4) The staff at Brant Arts Dispensary in Burlington, ON, wear their “Conquer COVID-19” t-shirts each week as part of an initiative called “Wellness Wednesdays.” The weekly initiative is designed to support employee mental health and community wellness and “to remind each other that together, we are stronger than COVID.” L-R: Petra Masirevic, Rebecca Kornel, Linda Crawford, Tim Langford, Nikki Bodnar, Jordyn Compas. (5) L-R, back: Ridwaan Safi, University of Waterloo PharmD student; Charlene Armstrong, pharmacy assistant; Cathie Lofthouse, pharmacy assistant; Melinda Copeland, pharmacy assistant; Leslie McKay, pharmacy staff; Danielle Benedict, pharmacist; Meghan Berner, pharmacy assistant; and Nick Patel, pharmacist. L-R front: Barb Avery, pharmacist/owner; and Keira Walpole, pharmacy technician at Shoppers Drug Mart, Owen Sound, ON. (6) Selena Colarossi, fourth-year pharmacy student, and Anne Le, pharmacist, Shoppers Drug Mart, King & Peter Sts., Toronto. (7) Navraj Brar, pharmacist/owner, Pharmasave, Brampton, ON. The pharmacy is providing healthcare workers—hospital, nursing home and pharmacy—with COVID-19 care packages of hand sanitizer, facial tissues, gloves and alcohol wipes. Navraj also donated compounded hand sanitizer and alcohol wipes to the Peel Regional Police Association of Brampton. (8) Holly McCorriston, pharmacist, Pharmasave, Kindersley, SK. (9) Bottom R-L: Karen Lalonde, pharmacist; Kate Polden, pharmacy assistant; Debbie Pacey, front shop assistant; Lisa Bond, front shop assistant; Jocelyne Bousquet, front shop manager (flexing both muscles); Chantal Bussieres, pharmacy assistant; Carly Dufour, pharmacy assistant; and Jennifer Mokohonuk, pharmacy technician, Espanola Remedy’sRx, Espanola, ON. The store provided home delivery and masks to seniors and, in conjunction with the Royal Canadian Legion, delivered Easter treats to seniors and group homes. (10) Kareena Ivanis, designated pharmacy manager, Raulston’s Pharmacy, Simcoe, ON. As well as providing curbside pickup and making over 500 free deliveries, Raulston’s Pharmacy set up an online shopping system with pickup or home delivery. (11) Greencrest Pharmacy, Winnipeg, L-R: pharmacy assistant Bridgette Ugalde and pharmacist Amanda Church. (12) UWaterloo students, Renal Program, Grand River Hospital Kitchener ON. (13) Shopper Drug Mart, Kitchener ON. (14) Credit Ridge RemedysRx, Brampton, ON. (15) Stewart’s Pharmacy, Mildmay, ON. (16) Matthew Bui, UWaterloo pharmacy student, Clinical teaching unit at GRH. (17) Memorial Pharmasave. (18) L-R: Edward Su, pharmacy student; Sony Poulose, pharmacy manager; and Karly Radko, pharmacy assistant, Sherman IDA Pharmacy, Hamilton, ON. A compounding pharmacy, Sherman IDA obtained a site licence and manufacturing licence from Health Canada to manufacture approved hand sanitizers with NPN numbers to ensure community access to quality hand sanitizer. Poulose also released an education video on Facebook regarding Covid-19 and diabetes. RIGHT (PAGE 37): (19) Nicole Nash, pharmacy (CONTINUED ON PAGE 38) assistant and John Paul Gloria,

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pharmacist, Memorial Pharmasave, Orillia, ON. (20) Dev Aggarawal (R) and Francis Miguel (L), pharmacist/co-owners of Westpark I.D.A. Drugs in Red Deer, AB. They started a GoFundMe campaign that raised more than $4,000 for the Red Deer Food Bank Society. (21) UWaterloo pharmacy students working at Grand River Hospital, Kitchener Waterloo, ON. L-R: Lauren Thompson (Oncology); Melissa Garellek (Emergency Department); Maria Anton (In-Patient Psychiatry) and Olivia McPherson (Intensive Care Unit). (22) Fourth-year pharmacy student Pamela at the University of Toronto. (23) Nareefa Nasrudeen, pharmacist, Lovell Drugs, Oshawa, ON. In partnership with Appletree Medical Clinic, the pharmacy refers patients to the clinic’s virtual care to book an online appointment with a doctor. (24) Colleen Hogg, pharmacist/owner of Cove Pharmacy on Quadra Island, BC, was in Israel when the pandemic hit. Although she had to go into isolation for 14 days, Hogg continued to provide patient care from home until she got the all-clear to return to work. (25) Nayan Patel, pharmacist/owner, Pharmasave, Stouffville, ON. Patel’s pharmacy team and customers donated money to the COVID-19 Relief Fund with funds directed to the Markham Stouffville Hospital Mental Health Unit or to purchase PPE. As well, the pharmacy donated N95 masks to the hospital and provides free hand sanitizer and masks for the most vulnerable individuals in their community. (26) L-R: Gurpartap Singh, pharmacy assistant; Pauline Ramirez-Hashemi, pharmacist; Jenn McGarrity, pharmacy assistant; and Kim Graham, store manager, Rainbow Pharmasave, Angus, ON. (27) Lori Shannon, Sudbury, ON. (28) Dhawni Thakkar, pharmacy student at UWaterloo and working at Rexall 8174 in Toronto. Thakkar said the pandemic highlights the importance of adapting practices in a world with limited resources, to serve each and every member of the community better. (29) Amanda Molnar, pharmacy assistant, Schomberg Village Pharmacy, Schomberg, ON. To keep patients and staff safe, pharmacist/coowners Anna Patrizio and Christina Pravado started early to source PPE and sanitizer, installed a Ring Video Doorbell to screen clients, split the pharmacy team in case someone got sick, established a rigorous dis infecting schedule, and held ‘donning and doffing’ exercises for PPE. (30) Schomberg Village Pharmacy, Schomberg, ON. (31) Pharmacists in face shields. LEFT (PAGE 38): (32) ICU, Grand River Hospital, Kitchener, ON. (33) Kathleen Leach, pharmacist/owner, Sutherland Pharmacy, Hamilton, ON. (34) Shoppers Drug Mart, Kitchener ON. (35) Youssef Labib, UWaterloo pharmacy student, working at Canadian Addiction Treatment Centre in Brampton, ON. Since patients don’t come as often as before, methadone treatment is prepared well in advance to ensure patients have up to two weeks medication at home. (36) L-R: Megan Byer, pharmacy student; Tina Dietrich, pharmacy assistant; and Erin McClure, pharmacist. As well as offering free deliver and curbside pickup, pharmacist owner Poshin Jobanputra is conducting at home INR checks for patients at high risk and going to patients’ houses to administer injections (Aranesp) that were supposed to be given in the hospital, which, due to COVID-19 access restrictions, could not accommodate them. These are being done at no charge. (37) Amy Cross, staff pharmacist, Medicine Shoppe Pharmacy, Brookside, NB. Before receiving enough PPE, the pharmacy set up a drive-thru to screen patients for COVID-19 and provide medications. Pharmacy owner Natalie Dawson asked local sewers to make masks, paying $10 per mask and selling them for $14.99 with the profit donated to a homeless shelter. (38) Raghda Al Ani, Pioneer Park Shoppers Drug Mart, Kitchener, ON. She is meeting the challenge of continuity of care to patients who require monitoring and follow-up, such as INR testing, and those who require scheduled injections. (39) George Wang, staff pharmacist, Shoppers Drug Mart, Belleville, ON.

First-year pharmacy students determined to make an impact during COVID-19 BY SONYA FELIX

When the COVID-19 pandemic hit in early March, first-year pharmacy student Mayur Tailor was frustrated that he didn’t yet have enough clinical experience to help on the frontline. So the University of Waterloo student found another way to contribute to the crisis. On March 20, he launched Pharm Against Covid-19, a student-led initiative dedicated to educating others about the role of pharmacists during the pandemic and securing donations of personal protective equipment (PPE) and other goods for pharmacies, hospitals, longterm care facilities and shelters. Three months later, Pharm Against Covid-19 has an executive team of 15 pharmacy students and 60 volunteers, with members from the University of Waterloo, the University of Toronto, McMaster University and the University of Ottawa. The group has also collaborated with other initiatives that support healthcare workers, including the Ontario Pharmacists Association’s PharmacistsOnTheFrontline and Conquer COVID-19, a national group of volunteers seeking donations to ensure frontline workers have the safety equipment they need during the pandemic. “We have the volunteers and the manpower to make

From left: Hayley Wickenheiser (six-time Olympian and owner of four Olympic gold medals), Mayur Tailor and Emil Diab of Pharm Against COVID-19 with an unidentified volunteer.

a difference,” says Tailor, adding that Pharm Against Covid-19 has so far gathered and given out 20,000 donated units. As well, when Conquer COVID-19 donated 300,000 units of PPE in Ottawa, Tailor’s volunteers did the distributing. “We also handed out ‘goodie bags’ with donations of La Roche-Posay skin care products, granola bars and other treats to pharmacists as a way to say thank you. We want them to feel appreciated.” Emil Diab, also a first-year pharmacy student at the University of Waterloo, handles social outreach for Pharm Against Covid-19. “Before we started this group, it was terrible just sitting there not having the clinical tools to work on the frontline,” he says. “But now it feels great when we are donating supplies and see how grateful people are. We are really making a difference.” The group is determined to keep going as long as there is need but, as access to PPE becomes less of a problem, Pharm Against Covid-19 is evolving into an advocacy group, with the Twitter handle @PharmCovid19. “We want to advocate for pharmacy and help educate people about what pharmacists can do for the public,” says Diab. “With a wider scope of practice, pharmacists can decrease emergency room visits, reduce wait times and provide better convenience for patients. We can also educate the public about disease states and debunk some of the misinformation that’s out there.” Meanwhile, Pharm Against Covid-19 plans to conduct more collection drives to help the homeless and other vulnerable people. “We have the volunteers and manpower,” he says. “This has definitely been a lifechanging experience.”

[Vol.7 No.5] JUNE/JULY 2020

INTRODUCING

the Science Behind F O R C A N A D I A N H E A LT H C A R E P R O F E S S I O N A L S

Your online resource for product information Specifically for Healthcare Professionals, P&G The Science Behind is a website dedicated to providing product information on your favourite P&G brands. Find clinical data, patient resources and more to help improve the lives of your patients.

SCAN THE QR CODE TO VIEW THE WEBSITE OR VISIT PGSCIENCEBEHIND.COM

INNOVATOR PROFILE

SKIP DR. GOOGLE— ASK A REAL PHARMACIST BY ROSALIND STEFANAC

Photo courtesy Phil

ASK YOUR PHARMACIST askyourpharmacist.ca Pharmacist/founder Alexandre Chagnon

Pharmacy concept:

patients got accurate answers to their healthcare questions. He launched Ask Your Pharmacist in Quebec in 2016, with subsequent upgrades to the platform in 2018 and 2020.

Background: Soon after

How does the service work? Pharmacists create an

A first of its kind, Quebecbased online service for patients’ health and drugrelated questions, manned solely by pharmacists. pharmacist Alexandre Chagnon graduated and started his job as a hospital pharmacist in 2013, he experienced first-hand the risks patients incurred every time they sought healthcare information on the internet. He also discovered that some pharmacists were using unsecure social networks, such as Facebook to provide healthcare advice. Upon doing further research on how Canadians use the internet for health information, he determined that an online service run by pharmacists was the ideal way to ensure

online profile (similar to what you would use for LinkedIn) to join the platform. When patients ask a question on the site, we ask for their postal code and we match them with any pharmacists within 15 kilometres. Each of those pharmacists get an email notice when the question comes in and when the question has been answered, a pharmacist’s picture will appear beside the question. Once their question has been answered, the patient gets an email notification along with that pharmacist’s ID and place

[Vol.7 No.5] JUNE/JULY 2020

taking a big pay cut, compared to what I was making as a hospital pharmacist. To save enough to launch this business, I worked as a relief pharmacist while I was also holding down a full-time pharmacist position.

MORE THAN 61% OF PATIENTS SAID THEY WOULDN’T HAVE THOUGHT OF CONSULTING A PHARMACIST IF HE/SHE HADN’T BEEN AVAILABLE ONLINE. of work. Alternately, patients can go to our website and use the “Find a Pharmacy” tool to look for a particular pharmacy in their area to answer their question. All questions are answered within 24 hours; most within six hours. About 33% of patients end up visiting the pharmacist who answered their question, so it’s a win for the pharmacy too.

What if no one answers within 24 hours?

A group of pharmacists (including me) are on standby to answer those questions.

How many are using the site now? We have about 300 pharmacists in Quebec. Each day, about 100-250 patient questions are posted. We’re also talking to three other provinces about replicating our platform.

Is there a fee for the service?

It’s always free for patients and for pharmacists on the regular plan. But we added some premium features in 2020, and pharmacists pay a small fee for those; much like you would for premium versions of LinkedIn, Spotify etc. The premium plan includes a library of common answers that pharmacists can provide, as well as a feature that allows pharmacists to save their replies and customize them to use for future questions that are similar. 42

What are typical questions patients ask?

Most are related to minor ailments; one in 10 are drugspecific.

What triggered the idea for a platform like this?

I was working as a relief pharmacist (in addition to my hospital work) when a new mother came in crying one day. She had read on the Internet that she couldn’t breastfeed for three days after consuming alcohol and by that point, her breast milk had dried up. We helped her by contacting her doctor and getting her on a drug to boost her milk supply. In doing research, I learned that six out of seven patients go directly to the internet at the first sign of a new symptom. Plus, right now other online/telehealth services are using nurses and doctors for questions pharmacists could be answering. Our public health phonelines are too busy. In fact, this summer we will be part of a pilot program with Quebec’s Ministry of Health and Ministry of Economy and Innovation where pharmacists from our platform will be leveraged to answer patient questions—and be paid for it.

Did you have any programming experience before developing this site? No, I had never written a single line of code so I had to connect with people who could do so. I also

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attended a telehealth course in Philadelphia in 2018 to expand my knowledge. Now I’m completing my postgraduate degree in health informatics at Sherbrooke University in Quebec.

This is unique in Canada, but did you look to similar platforms abroad? The US has one for doctors, and Australia has one for doctors and allied health professionals. We looked to both in perfecting our platform. The main thing we wanted to do in Canada was find a way to report outcome measures so that we could further prove the value of this platform. We have lots of statistics now.

Can you share some?

Our proprietary patientreported measures feature showed that there were 872 avoided consultations in connected pharmacies over the month of April alone. Almost 18% of those averted consults would have been to a family physician. More than 61% of patients said they wouldn’t have thought of consulting a pharmacist if he/she hadn’t been available online.

How does the platform make money?

Online advertising on the site, plus extra fees for premium services. We have different ads on the platform depending on whether you are a pharmacist or patient. That said, I am still

How else do pharmacists benefit from joining the platform, besides potential new patients?

During this time of COVID-19 especially, it can reduce the number of people coming into the pharmacy and putting staff at risk. Pharmacists can use our platform as a landing page on their social media, especially if they don’t have a website. But getting new patients they’ve helped online is definitely a big benefit too.

What were your challenges in launching the site? I took too much

time developing this great platform and not showing it to enough people early on. You have to show it as much as possible, as the user experience is really important in getting things just right. I also found that people didn’t understand why I was creating this website. Now that I have published research and support from government, it’s a different story. My advice to others who develop new ideas is to go out and showcase them as soon as possible.

Describe your team

Three full-time developers, one lawyer and me—the only pharmacist. Hopefully there will be more pharmacists joining me as we expand.

What are your future plans? If all goes well and we can continue to replicate this model successfully, we aim to be available coast-to-coast by 2022. I really think we will be able to get there.

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Patients with Chronic Kidney Disease

Approved by CCCEP for

1.25 CEUs CCCEP # 1329-2020-2986-I-P

This lesson has been approved for 1.25 CEUs by the Canadian Council on Continuing Education in Pharmacy. For expiry dates go to www.eCortex.ca.

CE LESSON

Managing Patients with Chronic Kidney Disease Marisa Battistella, BSc Phm, Pharm D, ACPR

LEARNING OBJECTIVES

Upon successful completion of this lesson, the pharmacist will be able to do the following: 1. Describe how pharmacists can help CKD patients reduce cardiovascular risk, manage diabetes and slow CKD progression; 2. Recognize medications that should be avoided, those that require dosage adjustment and how to adjust doses; 3. Summarize common medications used to manage CKD complications such as anemia and CKD bone disease. 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

Shutterstock

INSTRUCTIONS

Introduction

Approximately three million Canadians have chronic kidney disease (CKD), and the prevalence is increasing secondary to risk factors such as the growing elderly population and increasing rates of diabetes and hypertension.(1) CKD is associated with adverse clinical outcomes, including end stage kidney disease (ESKD), cardiovascular disease and increased mortality.(2-5) Recent guidelines suggest a risk-based approach to the evaluation and management of CKD in order to decrease adverse outcomes.(6-9) This lesson will help pharmacists understand the evaluation of patients with CKD and key issues in patient management.

CKD Definition and Staging

Chronic Kidney Disease (CKD), as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) international guidelines, is an abnormality of kidney structure or function that is present for more than three months.(6) Criteria required to make a diagnosis of CKD include having one or more of the following: (1) glomerular filtration rate (GFR) < 60 mL/min/1.73 m2; (2) albuminuria (i.e., urine albumin > 30 mg per 24 hours or urine albuminto-creatinine ratio [ACR] > 30 mg/g or 3 mg/mmol); (3) abnormalities in urine sediment, histology or imaging suggestive of kidney damage; (4) renal

JUNE/JULY 2020

CE 1

CE LESSON

PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Patients with Chronic Kidney Disease

tubular disorders; or (5) history of kidney transplantation.(6) Once a diagnosis of CKD has been made, the next step is to determine staging, which is based on GFR, albuminuria and cause of CKD (Figure 1).(6) Staging is important to help in early detection of kidney disease, risk stratify for treatment and aid in drug dosing. Although GFR can be directly measured by clearance of agents such as iohexol or iothalamate, the development of estimating equations (e.g., Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease Study [MDRD] equations) has largely replaced the need for direct measurement in clinical practice.(10,11) Clinical laboratories now routinely report

estimated GFR (eGFR) based on filtration markers (as well as age, sex and race). The most common filtration marker used is creatinine, a by-product of creatine metabolism and one for which laboratory assays have been standardized since 2003.(12) The preferred estimating equation in Canada and much of the world is the CKD-EPI creatinine equation (2009), which is more accurate than the earlier MDRD equation, particularly for eGFR values > 60 mL/min/1.73 m2 (www.kidney. org/professionals/kdoqi/gfr_calculator).(10,11) Albuminuria should then be quantified by an Albumin to Creatinine Ratio (ACR).(6) Albuminuria staging is classified as A1 (urine ACR <3 mg/mmol), A2 (3-30 mg/mmol), and A3 (>30 mg/mmol).(6) Guidelines recommend the use of urine

ACR to stage CKD rather than urine protein-to creatinine ratio because assays for ACR are more likely to be standardized and have better precision at lower values of albuminuria.(6) A case example of how to stage a patient with an eGFR of 32 ml/ min/1.73m2 and ACR of 20 mg/mmol would be to classify this patient as G3bA2 (see Figure 1).

Screening for CKD

A risk-based approach to screening for CKD is suggested by many clinical practice guidelines, with screening recommended in those older than 60 years or with a history of diabetes or hypertension.(7-9) Both hypertension and diabetes are risk factors for developing and worsening chronic kidney disease and patients

FIGURE 1

Definition and Prognosis of Chronic Kidney Diseases by GFR and Albuminuria Categories, KDIGO 2012 Persistent albuminuria categories Description and range

GFR categories (ml/min/1.73m2) Description and range

Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012

Normal or high

≥90

Mildly decreased

60-89

G3a

Mildly to moderately decreased

45-59

G3b

Moderately to severely decreased

30-44

Severely decreased

15-29

Kidney failure

<15

Normal to mildly increased

Moderately increased

Severely increased

<30 mg/g <3 mg/mmol

30-300 mg/g 3-30 mg/mmol

>300 mg/g >30 mg/mmol

Green indicates low risk (if no other markers of kidney disease and no CKD); yellow, moderately increased risk; orange: high risk; and red, very high risk. Reproduced with permission from Kidney International Supplements.(6)

GFR–glomerular filtration rate; KDIGO–Kidney Disease: Improving Global Outcomes.

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Categories are grouped by risk of progression, which includes chronic kidney disease progression, defined by a decline in GFR category (accompanied by a > 5% decrease in estimated GFR from base-line) or sustained decline in estimated GFR greater than 5 mL/ min/1.73m2 per year.

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should be screened for these risk factors. Screening should also be considered in those with clinical risk factors for CKD, including autoimmune disease, obesity, kidney stones, recurrent urinary tract infections, reduced kidney mass, exposure to certain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or lithium, and prior episodes of acute kidney injury (AKI).(13) Several sociodemographic factors can also contribute to increased risk of CKD, including nonwhite race, low education and low income.(7,13,14) Finally, genetic factors likely also contribute; for example, risk alleles in the gene encoding apolipoprotein L1 (APOL1) may increase risk of kidney disease (Table 1).(13,15) Keep in mind that no randomized clinical trials have demonstrated that screening asymptomatic patients for CKD improves outcomes; however, these risk factors should be considered in the work up of the patient.

Prognosis of CKD

Simple online tools are available to help with risk stratification. For example, the Kidney Failure Risk Equation (KFRE; www.kidneyfailurerisk.com/) predicts the two-year and five-year probabilities of requiring dialysis or transplant among individuals with an eGFR < 60 mL/min/1.73 m2.(16,17) The KFRE has been validated in more than 700,000 individuals from more than 30 countries.(17) An ongoing trial is evaluating whether a KFRE risk-based approach improves CKD management.(18)

CKD Management

The management of CKD involves the use of therapies that reduce cardiovascular risk, slow the rate of CKD progression, and minimize further kidney injury such as avoiding nephrotoxins. Reduce cardiovascular risk As a patient’s kidney function or eGFR decreases, the risk of a cardiovascular complication increases.(19) For example, the adjusted hazard ratios for cardiovascular events are 1.4, 2.0 and 2.8 for eGFR ranges

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of 45–59 mL/min per 1.73 m2, 30–44 mL/min per 1.73 m2 and 15–29 mL/min per 1.73 m2, respectively.(19) The adjusted risks for hospitalization and death follow a similar pattern.(19) These correlations therefore warrant the implementation of therapies to modify cardiovascular risk factors in patients with CKD. It is recommended that patients aged 50 years or older with CKD (but not on dialysis or with kidney transplant) be treated with a low- to moderatedose statin regardless of low-density lipoprotein cholesterol level.(20) Smoking cessation should also be encouraged.(6) Management of Hypertension The KDIGO guidelines recommend systolic and diastolic blood pressure goals of < 140 mmHg and < 90 mmHg, respectively, among adults with CKD, based on expert opinion.(6) The KDIGO guidelines further recommend that adults with a urine ACR >30 mg/g or 3mg/mmol or albumin excretion rate of at least 30 mg per 24 hours have systolic and diastolic blood pressures maintained below 130 mmHg and 80 mmHg, respectively.(6) More recently, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that among individuals with increased risk of cardiovascular disease but without diabetes, more intensive blood pressure control (goal systolic blood pressure < 120 mmHg vs. < 140 mmHg) was associated with a 25% lower (1.65% vs 2.19% per year) risk of a major cardiovascular event and a 27% lower risk of all-cause mortality compared with standard blood pressure control (goal systolic blood pressure < 140 mmHg).(21) Higher systolic BP targets (<140 mmHg) are appropriate for people with CKD who are at increased risk of adverse events, including those with a history of stroke, those with frailty, those living in long term care, elderly, those with limited life expectancy (< 3 years), or those with orthostatic hypotension (standing systolic BP < 110 mmHg); these groups were not well represented in SPRINT trial. A cautious approach

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TABLE 1

Risk Factors for Chronic Kidney Disease CLINICAL Diabetes Hypertension Autoimmune diseases Systemic infections (e.g., HIV) Nephrotoxic medications (e.g., nonsteroidal anti-inflammatory drugs, herbal remedies, lithium) Recurrent urinary tract infections Kidney stones Urinary tract obstruction Malignancy Obesity Reduced kidney mass (e.g., low birth weight) History of acute kidney injury Smoking Intravenous drug use (e.g., cocaine)

SOCIODEMOGRAPHIC Age > 60 years Nonwhite race Low income Low education

GENETIC APOL1 risk alleles Sickle cell trait and disease Polycystic kidney disease Alport syndrome Congenital anomalies Family history of kidney disease

to treatment should be taken for people who take five or more medications (polypharmacy) or whose diastolic BP is < 60 mmHg, as risks such as falls might outweigh benefits.(22,23) Use renin-angiotensin system blockade to help prevent progression to advanced CKD Achieving blood pressure control in CKD patients with hypertension, and using an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) medication (known collectively as renin-angiotensin system blockade) to manage proteinuria, can help prevent

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progression to advanced CKD.(6) For patients with CKD and diabetes who have hypertension (BP > 130/80 mmHg), as well as proteinuria (e.g., diabetic nephropathy), an ACEI or ARB should be used as first-line treatment if the urine ACR is persistently > 3 mg/mmol.(24) Renin-angiotensin system blockade has also been shown to decrease progression of CKD in normotensive patients with diabetes who have abnormal urine ACR (> 3mg/mmol).(6,7) For patients with CKD but without diabetes, whose BP levels are not at target, an ACEI or ARB should be used as first-line pharmacotherapy if the urine ACR is persistently > 30 mg/mmol.(24) In either case, if required, the dose of an ACEI or ARB should be increased over time while monitoring for unwanted side effects (e.g., orthostatic hypotension and hyperkalemia). It is important to remember to measure serum potassium and creatinine levels ( or eGFR) approximately one to two weeks after initiating or any dose titration of an ACEI or ARB, to monitor for the development of hyperkalemia or a substantial decrease in eGFR.(6,25) A substantial drop in eGFR or rise in serum creatinine level (e.g., > 30% SrCr) might suggest volume depletion, concomitant NSAID use or underlying renovascular disease that might require further evaluation. This higher-risk group should be monitored carefully and, in some cases, might need a reduction or discontinuation of the offending drug until further advice from a nephrology specialist is obtained.(25) Outpatient management strategies for hyperkalemia include restriction of dietary potassium and consideration of a thiazide or loop diuretic to increase potassium excretion.(25) Combination therapy with an ACEI plus an ARB (dual renin-angiotensin system blockade) should not be prescribed.(6,8) Trials of ACEIâ&#x20AC;&#x201C;ARB combination therapy have shown complications such as AKI and severe hyperkalemia, with no associated cardiovascular benefit or reduction in mortality.(26)

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Management of Diabetes Mellitus Optimal management of diabetes is also important. First, glycemic control may delay progression of CKD, with most guidelines recommending a glycated hemoglobin (A1C) goal of about 7.0%. Second, dose adjustments for oral hypoglycemic agents may be necessary. In general, drugs that are largely cleared by the kidneys (e.g., glyburide) should be avoided, whereas drugs metabolized by the liver and/or partially excreted by the kidneys (e.g., metformin and some dipeptidyl peptidase-4 [DPP-4] and sodium-glucose cotransporter-2 [SGLT-2] inhibitors) may require dose reduction or discontinuation, particularly when eGFR falls below 30 mL/min/1.73 m2.(26) Third, the use of specific medication classes such as SGLT-2 inhibitors should be considered in those with severely increased albuminuria. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that patients with type 2 diabetes and CKD stage G2-G3/ A3 (baseline eGFR 30 to < 90 mL/ min/1.73 m2 and urine ACR or albumin excretion rate> 300 to 5,000 mg/24 hours) taking ACEI or ARB therapy, who were randomized to canagliflozin had a 30% lower risk (43.2 vs 61.2 event rate per 1000 patient-years) of developing the primary composite renal outcome (doubling of serum creatinine, ESKD, or death from a renal or cardiovascular cause) compared with those randomized to placebo.(28) Prior trials have also suggested cardiovascular benefit with this class of medications in patients with CKD who have lower levels of albuminuria.(29,30) Avoiding Nephrotoxins To minimize further kidney injury in patients with CKD, nephrotoxins should be avoided. For example, if patients with CKD and diabetes are unable to maintain adequate fluid intake during an illness (e.g., viral gastroenteritis) and are at risk of volume depletion, potentially nephrotoxic drugs should be withheld until the patient

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has recovered.(6) These are referred to as SADMANS (sulfonylureas, ACEIs, diuretics, metformin, ARBs, NSAIDs and SGLT-2 inhibitors) by Diabetes Canada.(26) Aside from exceptional circumstances, prolonged use of NSAIDs should not be recommended to patients with CKD.(6,31) Herbal remedies are not strictly regulated by Health Canada and some, such as those containing aristolochic acid or anthraquinones, have been reported to cause kidney abnormalities, including acute tubular necrosis, acute or chronic interstitial nephritis, nephrolithiasis, rhabdomyolysis, hypokalemia, and Fanconi syndrome.(32) An excellent reference for checking the safety of herbals was developed by renal pharmacists in British Columbia (https://www.herbalckd.com/). Phosphatebased bowel preparations (both oral and enema formulations) are available over the counter and can lead to acute phosphate nephropathy; they should be avoided in patients with CKD.(33,34) Proton pump inhibitors (PPIs) are widely used and have been associated with acute interstitial nephritis and incident CKD in population-based studies.(35,36) Therefore, indications for PPI use should be addressed on a regular basis and these agents deprescribed when appropriate. Other potential nephrotoxins include lithium, aminoglycosides (gentamicin), amphotericin and cisplatin.(31) Drug Dosing Adjustments in drug dosing are frequently required in patients with CKD. Although the reporting of eGFR is calculated via the CKD-EPI equation by most labs in Canada as it less biased than MDRD particularly at high GFRs and performs equally or better compared to the MDRD equation in various age groups, it has not been validated for drug dosing. Furthermore, the automated reporting of eGFR (using either the MDRD or CKD-EPI equation) in the clinical setting has led some practitioners to consider substituting eGFR in place of estimated creatinine clearance (eCrCl

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Drug Dosing Case You are a clinical pharmacist working in a multidisciplinary team clinic. An 84-year-old female patient (MW) has been seen in clinic today due to hypoglycemia. The endocrinologist has seen the patient and made the appropriate insulin dose changes. The doctor asks for a dosing recommendation for initiating pregabalin for MW’s peripheral neuropathy. Additional information about MW includes: Serum creatinine: 139 umol/L; height: 158 cm; weight: 55 kg. Based on these values, calculated eGFRs are: 23ml/min/1.73m2(CG); 31ml/min /1.73m2(MDRD); and 30ml/min/1.73m2 (CKD-EPI).

Dosing guidelines for pregabalin from the CPS: Total pregabalin daily dose (mg/day) Recommended dose escalation

Creatinine Clearance (mL∕min)

Starting Dose

≥60

150

300

30–60

15–30

25–50

<15

Maximum Daily Dose

Dose Regimen

450

600

BID or TID

150

225

300

BID or TID

100–150

150

QD or BID

25–50

50–75

 up to

Based on this information, the dosing for pregablin falls under two categories. In this case, it would be appropriate to start low at 25-50mg (based on CrCl of 15-30ml/min) and dose to maximum of 150mg since this patient is elderly (84 years old) and at increased risk of adverse effects. Although the patient’s calculated eGFR is greater than 30ml/min based on the MDRD and CKD-EPI equations, dosing based on eGFR of 30ml/min- 60ml/min should be done with caution and only dose titrated to this higher dose (300mg) based on patient’s clinical response and after careful monitoring for adverse effects (edema, drowsiness and falls).

(i.e., Cockcroft-Gault equation [CG equation]) for renal dose adjustments. Some argue that use of the MDRD and CKD-EPI equations for drug dosing are not appropriate given that the pharmacokinetic studies were performed using eCrCl via the CG equation.(37) Therefore none of these equations for estimating GFR should be used as the sole determinant for drug dosing decision making. Potential discrepancies in kidney function estimates and corresponding drug dosing regimens necessitate careful consideration of the risk-to-benefit ratio of each approach within the context of the complete clinical picture of the patient. Pharmacists should consider all equations (if available), as well as the clinical picture of the patient in determining drug dose adjustments. Common medications that require dose reductions include some antibiotics, direct oral anticoagulants, gabapentin, pregabalin, oral hypoglycemic agents,

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insulin, chemotherapeutic agents and opiates, among others.(6,7) Many references are available that can aid pharmacists in adjusting doses in patients with CKD. For instance, the latest Canadian Diabetes Guidelines have a table on hypoglycemic agents and appropriate dosage adjustments for patients with CKD (http:// guidelines.diabetes.ca/docs/cpg/Ch13Pharmacologic-Glycemic-Managementof-Type-2-Diabetes-in-Adults.pdf).(26) In general, use of medications with low likelihood of benefit should be minimized because patients with CKD are at high risk of adverse drug events.(38-40) See above (box) for a case example on drug dosing in patients with CKD. Dietary Management The KDIGO guidelines recommend that protein intake be less than 0.8 g/kg per day (with proper education) in patients with CKD stages G4-G5.(6) Protein restriction should be balanced with malnutrition and/

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or protein wasting syndrome.(6) Low-sodium diets (generally <2 g per day) are also recommended for patients with hypertension, proteinuria, and/or fluid overload.(6)

Management of CKD Complications

Patients with moderate to severe CKD are at increased risk of developing anemia, electrolyte abnormalities, and mineral and bone disorders. Screening and frequency of assessment for laboratory abnormalities is dictated by stage of CKD and includes measurement of complete blood count, basic metabolic panel, serum albumin, phosphate, parathyroid hormone, 25-hydroxyvitamin D and lipid panel.(41) Anemia and the Role of Erythropoietin in CKD Anemia is defined as a reduction in one or more of the major red blood cell measurements: hemoglobin (Hb) concentration, hematocrit or red blood cell count. The World Health Organization defines anemia as a hemoglobin level < 130 g/L in men and postmenopausal women, and < 120 g/L in premenopausal women.(42) The overall prevalence of CKD-associated anemia is approximately 50%. Although anemia may be diagnosed in patients at any stage of CKD, there is a strong correlation between the prevalence of anemia and the severity of CKD.(42,43) While anemia in CKD can result from multiple mechanisms (iron, folate or vitamin B12 deficiency, gastrointestinal bleeding, severe hyperparathyroidism, systemic inflammation, and shortened red blood cell survival), decreased erythropoietin synthesis in the kidney is the most important and specific cause of CKD-associated anemia as the kidneys produce 90% of erythropoietin.(42) Anemia of CKD is treated with erythropoietin-stimulating agents (ESAs), such as darbepoetin and erythropoietin. This intervention has replaced transfusions as the mainstay of treatment and has improved the quality of life and survival of anemic CKD patients.(42,43) The target

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level of Hb in patients with CKD has recently changed as more studies have reported survival outcomes. The Canadian Society of Nephrology now recommends the initiation of ESA treatment when the Hb level is 90–100 g/L, and states that an acceptable range for Hb level is 95–115 g/L, with a target of 100–110 g/L.(42,43) The studies showed that patients targeting a higher hemoglobin (> 130g/L) had increased risk of mortality.(43) Therefore, most clinicians now target a Hb between 100-110 g/L for patients with CKD. Treatment with ESAs can cause hypertension and an increased risk of thrombotic events, so patients should be monitored for these adverse events.(42) Management of hypertension may include the discontinuation of the ESA and/or the addition of antihypertensives. In patients with CKD-associated anemia, iron supplementation may also be administered to ensure adequate iron stores for erythropoiesis, to correct iron deficiency and, in patients receiving ESA treatment, to prevent iron deficiency from developing. The two most widely available tests for assessing iron status are the transferrin saturation (TSAT) and serum ferritin level. The KDIGO working group suggests that for adults on dialysis and ESA therapy, a trial of intravenous (IV) iron is warranted. In CKD non-dialysis patients, a one- to three-month trial of oral iron therapy is suggested if an increase in Hb concentration or a decrease in ESA dose is desired and TSAT is ≤ 30% and ferritin is ≤ 500 ng/mL (≤ 500 μg/L).(42) Oral iron is typically prescribed to provide approximately 200 mg of elemental iron daily (e.g., ferrous fumarate 300 mg twice daily; each pill provides 100 mg elemental iron). Smaller daily doses may be useful and better tolerated in some patients. Although ferrous fumarate is commonly available and inexpensive, other oral iron preparations such as ferrous gluconate, ferrous sulfate, heme iron polypeptide or iron polysaccharide may also be used; however, there is no significant evidence to suggest that these oral iron formulations are more effective

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or associated with fewer adverse side effects than ferrous fumarate. Oral iron supplementation can cause constipation as well as nausea and vomiting. If the goals of iron supplementation are not met with a one- to three-month course of oral iron, it may be appropriate to consider IV iron supplementation.(42,43)

Electrolyte, Mineral, and Bone Abnormalities in CKD

Electrolyte abnormalities are present in 3%–11% of patients with CKD.(41) Initial treatment strategies usually involve dietary restrictions and prescription of supplements. For example, patients with hyperkalemia should follow a lowpotassium diet.(44,45) For patients with a serum bicarbonate level persistently below 22 mmol/L, oral bicarbonate supplementation should be considered, as studies have suggested that chronic metabolic acidosis is associated with faster CKD progression.(46-49) Mineral and bone disorders are also common. CKD-associated mineral bone disorders significantly increase mortality in CKD patients. In fact, hyperphosphatemia is one of the most important risk factors associated with cardiovascular disease in CKD patients.(44) The exact mechanism underlying this association remains unclear. It is believed to be related to hyperparathyroidism and vascular calcification, which results from high phosphorus levels.(44,45) Use of calcium-based binders and excessive vitamin D therapy may also contribute to vascular calcification. The principle goal of the treatment of CKD-associated bone and mineral disorders is phosphorus level reduction to normal levels.(33,44) Initial treatment restricts dietary phosphorus intake when phosphate or parathyroid hormone (PTH) levels begin to rise. Different classes of phosphate binders can be used to accomplish this goal. Calcium-based formulations for management of CKDassociated hyperphosphatemia (e.g., Calcium Carbonate) are the most widely used class of phosphate binders. However, calcium-based phosphate binders can

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induce hypercalcemia, which increases the tissue calcium deposition, especially in the presence of hyperphosphatemia. They also can cause gastrointestinal disturbances such as constipation. Calcium-free agents such as sevelamer hydrochloride and lanthanum carbonate are also used. More recently a new agent marketed in Canada, sucroferric oxyhydroxide may have potential for use as a phosphate binder. These non calcium based binders are very expensive and can also cause gastrointestinal (GI) side effects such as nausea and vomiting.(44,45) Furthermore, it is important to note some interactions with these agents including fluroquinolones and should be dosed separately. In addition to phosphate binders, several other classes of drugs have been developed to manage CKD-associated mineral disorders, specifically elevated PTH levels. Given the reduced 1-hydroxylation of vitamin D by the failing kidney, activated vitamin D (i.e., calcitriol) may be needed to raise the serum calcium concentration sufficiently to suppress PTH secretion. Patients can also be given a calcimimetic (i.e., cinacalcet), which increases the calcium sensitivity of the calcium-sensing receptor expressed by the parathyroid gland, down-regulating PTH secretion and reducing hyperplasia of the parathyroid gland. These agents are costly and can also cause GI disturbances (nausea and vomiting) and in some cases, severe hypocalcemia.(44,45)

Conclusion

Chronic kidney disease affects up to 16% of the population worldwide and is a leading cause of death.(50) Optimal management of CKD includes cardiovascular risk reduction, treatment of albuminuria, avoidance of potential nephrotoxins and adjustments to drug dosing. Patients also require monitoring for complications of CKD, such as hyperkalemia, metabolic acidosis, anemia and other metabolic abnormalities. Diagnosis, staging and appropriate therapies to slow disease progression in patients with CKD are important to reduce the burden of CKD worldwide.

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QUESTIONS

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Answer online at www.eCortex.ca, Quick Search CCCEP #1329-2020-2986-I-P

1. At a routine checkup, a 42-year-old male with diabetes is found to have an eGFR of 32 mL/min/1.73 m2. When repeated 3 months later, it is 35 mL/ min/1.73 m2. His albumin:creatinine ratio (ACR) is 35 mg/mmol (310 mg/g). Macroalbuminuria is defined as ACR > 30 mg/mmol (> 300 mg/g). What stage of CKD does he have?

a) Stage G4A2 b) Stage G2A1

7. Guidelines recommend the following calculator(s) be used to estimate GFR for CKD staging:

a) CKD-EPI b) MDRD

glomerular filtration rate, calculated using the CKD-EPI equation, is 33 mL/min/1.73 m2. Therapy with an erythropoiesis-stimulating agent is initiated. Which of the following is the target hemoglobin level for this patient?

a) 78 g/L

c) Cockcroft-Gault

b) 95–115 g/L

d) All of the above

c) 130–140 g/L d) 150–160 g/L

a) Gentamicin

8. A 55-year-old Caucasian-American man has a history of type 2 diabetes (15 years), hypertension (3 years), dyslipidemia (5 years) and cardiovascular disease (myocardial infarction 3 years ago). He was recently diagnosed with CKD. His most recent labs reveal an eGFR of 45 mL/min/1.73m2 and an ACR of 8mg/mmol. Which of the following should be avoided

b) NSAIDs

a) ACEI and ARB in combination

c) Metoprolol

b) Beta Blockers (i.e. metoprolol)

13. A 65-year-old male patient has a glomerular filtration rate of 45 mL/min and ACR of 8mg/mmol. The patient has a history of uncontrolled hypertension and coronary artery disease. You’re assessing the new medication orders received for this patient. Which medication ordered by the physician will help treat the patient’s hypertension along with providing a protective mechanism to the kidneys?

d) Lithium

c) NSAIDs

a) Perindopril

d) Statins

b) Metoprolol

e) A and C

c) Amlodipine

c) Stage G4A3 d) Stage G3aA3 e) Stage G3bA3 2. Which of the following is not nephrotoxic?

3. Almost 90% of the erythropoietin in the body is produced by the:

a) liver b) bone marrow

9. The most important nutrition goal(s) for patients with CKD include:

c) kidneys

a) Limit sodium, decrease blood pressure

d) thyroid and parathyroid

b) Reduce protein

4. The main contributing factor to anemia in CKD is:

a) iron deficiency

d) All of the above 10. Which kidney disease is known to be inherited?

c) chronic inflammation

a) End-stage kidney disease

d) low levels of erythropoietin

b) albuminuria

a) Decrease calcium b) Start a calcimimetic c) Start calcitriol d) Decrease phosphorus levels 6. Risk factors for CKD include:

a) Diabetes b) Hypertension c) History of acute kidney injury d) Frequent NSAID use e) All of the above

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14. A patient with stage 4 chronic kidney disease asks what type of diet they should follow. You explain the patient should follow a:

a) low sodium, low potassium, low phosphate diet

c) Glycemic control

b) folate deficiency

5. In managing CKD bone disease, the first step in treatment is

d) Verapamil

b) low sodium, low potassium, high phosphate diet c) high sodium, high potassium, high phosphate diet d) high sodium, low potassium, high phosphate diet

c) Hypertension

15. With regard to blood pressure control in people with diabetes and albuminuria, which of the following is true?

d) Polycystic kidney disease 11. The leading cause(s) of kidney failure is/are:

a) Diabetes b) Infection

a) ACE inhibitors and angiotensin receptor blockers (ARBs) are equally effective in reducing albuminuria. b) The combination of an ACE inhibitor and an ARB confers renal protection over and above the use of each agent alone.

c) Hypertension d) A and C 12. A 36-year-old woman with diabetic nephropathy comes to the physician’s office for follow-up. During the interview, the patient says she has had fatigue for the past month. Physical examination shows pallor and mild pitting edema of the lower extremities. Laboratory studies show hemoglobin level of 89 g/L and estimated

c) The general blood pressure target for people with diabetic CKD and proteinuria is < 120/90 d) Any agent such as beta blockers, ACE inhibitors or calcium channel blockers can be used to decrease blood pressure and albuminuria.

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PHARMACY PRACTICE + BUSINESS NATIONAL CONTINUING EDUCATION PROGRAM Managing Patients with Chronic Kidney Disease

REFERENCES 1. Levin A, Hemmelgarn B, Culleton B, et al. Guidelines for the management of chronic kidney disease. CMAJ 2008;179:1154-62. 2. Matsushita K, Coresh J, Sang Y, et al; CKD Prognosis Consortium. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol 2015;3:514-25. 3. Astor BC, Matsushita K, Gansevoort RT, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease: a collaborative meta-analysis of kidney disease population cohorts. Kidney Int 2011;79:1331-40. 4. Gansevoort RT, Matsushita K, van der Velde M, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes: a collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011;80:93-104. 5. van der Velde M, Matsushita K, Coresh J, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality: a collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011;79:1341-52. 6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3(1):1150. 7. Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014;63:713-35. doi:10. 1053/j.ajkd.2014. 8. Bilo H, Coentrao L, Couchoud C, et al; Guideline Development Group. Clinical practice guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR <45 mL/min). Nephrol Dial Transplant 2015;30(suppl 2):ii1-ii142. 9. Farrington K, Covic A, Aucella F, et al; ERBP Guideline Development Group. Clinical practice guideline on management of older patients with chronic kidney disease stage 3b or higher (eGFR <45 mL/ min/1.73m2). Nephrol Dial Transplant 2016;31(suppl 2):ii1-ii66. 10. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12. 11. Levey AS, Bosch JP, Lewis JB, et al; Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-70. 12. Myers GL, Miller WG, Coresh J, et al; National Kidney Disease Education Program Laboratory Working Group. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem 2006;52(1): 5-18. 13. Kazancioğlu R. Risk factors for chronic kidney disease: an update.

Kidney Int Suppl (2011) 2013;3 (4):368-71. 14. Banerjee T, Crews DC, Wesson DE, et al; CDC CKD Surveillance Team. Food insecurity, CKD, and subsequent ESRD in US adults. Am J Kidney Dis 2017;70(1):38-47. 15. Peralta CA, Bibbins-Domingo K, Vittinghoff E, et al. APOL1 genotype and race differences in incident albuminuria and renal function decline. J Am Soc Nephrol 2016;27:887-93. 16. Tangri N, Grams ME, Levey AS, et al; CKD Prognosis Consortium. Multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis. JAMA 2016;315:164-74. 17. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronickidney disease to kidney failure. JAMA 2011;305:1553-9. 18. Harasemiw O, Drummond N, Singer A, et al. Integrating risk-based care for patients with chronic kidney disease in the community: study protocol for a cluster randomized trial. Can J Kidney Health Dis 2019;6:2054358119841611. 19. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305. 20. Tonelli M, Wanner C; Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Intern Med 2014;160:182. 21. Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16. 22. Zia A, Kamaruzzaman SB, Tan MP. Polypharmacy and falls in older people: balancing evidence-based medicine against falls risk. Postgrad Med 2015;127:330-7. 23. Ruzicka M, Edwards C, McCormick B, et al. Thus far and no further: should diastolic hypotension limit intensive blood pressure lowering? Curr Treat Options Cardiovasc Med 2017;19(10):80. 24. Akbari A, Clase C, Acott P, Battistella M, Bello A, Feltmate P, et al. Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management. Am J Kidney Dis 2015;65(2):177-205. 25. Vassalotti JA, Centor R, Turner BJ, et al. Practical approach to detection and management of chronic kidney disease for the primary care clinician. Am J Med 2016;129:153-62.e7. 26. 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/docs/CPG2018-full-EN.pdf (accessed December 12, 2019). 27. Shurraw S, Hemmelgarn B, Lin M, et al; Alberta Kidney Disease Network. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study. Arch Intern Med 2011;171:1920-7.

THIS MONTH MANAGING PATIENTS WITH CHRONIC KIDNEY DISEASE AUTHOR By Marisa Battistella, BSc Phm, Pharm D, ACPR Marisa graduated from the Faculty of Pharmacy at the University of Toronto in 1998, and completed her pharmacy residency at Sunnybrook and Women’s Health Sciences Centre in 1999. She has worked at the University Health Network (UHN) since 1999 in various positions, including cardiology and internal medicine. She has worked as a clinical pharmacist specialist in the hemodialysis unit at UHN since 2002. As an Associate Professor at the Leslie Dan Faculty of Pharmacy and Clinician Scientist in Pharmacy at UHN, Marisa has focused her research in the area of pharmaco-nephrology. CE PROJECT MANAGER Rosalind Stefanac CE CLINICAL EDITOR Lu-Ann Murdoch, RPh, BScPhm, ACPR CE DESIGNER Nancy Peterman, Toronto, Ont. CE MANAGING EDITOR Vicki Wood, Toronto, Ont. vwood@ensembleiq.com 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.

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JUNE/JULY 2020 • 1.25 CEUs • 1329-2020-2986-I-P Managing Patients with Chronic Kidney Disease For expiry dates go to www.eCortex.ca.

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