Making therapeutic decisions with ongoing drug shortages Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic Family Health.

Making therapeutic decisions with ongoing drug shortages

Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Pharmacist, Bruyere Academic Family Health TeamAssistant Professor, Department of Family Medicine, University of Ottawa

[email protected]

November, 2013

Faculty/Presenter DisclosureFaculty/Presenter Disclosure

• Faculty: Dr. Roland Halil

• Program: 51st Annual Scientific Assembly

• Relationships with commercial interests:– Not Applicable

Disclosure of Commercial Disclosure of Commercial SupportSupport

• This program has received No Commercial Support

Mitigating Potential BiasMitigating Potential Bias

• Not Applicable

Objectives• Understand contributory factors to drug

shortages in North America • Promote a logical process for selecting

alternative drug therapy.– Promote a process for applying population level

evidence to individual patients.– List the 4 steps in rationalizing drug therapy choices

using EBM.• List resources in determining most recent drug

shortages in Canada.

Drug Shortages

• Multifactorial– FDA driven crack-down on manufacturing quality

• Globalization of manufacturing– Raw material shortages– Small number of suppliers / shrinking profit

margins– Increasing demand– “Just-in-time” inventory management

1) Drug Shortages. A Guide for Assessment and Patient Management. CPhA 20102) Darrell Issa (CA-49), Chairman U.S. House of Representatives Committee on Oversight and Government Reform. FDA’s Contribution to the Drug Shortage Crisis. U.S. HOUSE OF REPRESENTATIVES, 112TH CONGRESS, COMMITTEE ON OVERSIGHT AND GOVERNMENT REFORM, JUNE 15TH, 2012

Don’t Panic!The (Relatively) Good News

• Most shorted drugs are: – Injectables

• Less commonly used in primary care– Can be obtained within a reasonable delay

• Most patients can ‘make do’– Competing manufacturers can handle part of the

demand to increase supply– Therapeutic alternatives exist

• Four Steps of Rational Prescribing • A logical process for finding alternatives

Options

• First, lay out therapy options: – Drug A– Drug B– Drug C– Non-drug options D, E, & F– No treatment

• (Always an option!)

Rational Prescribing Needs a Process to Provide Structure

1. Efficacy2. Toxicity3. Cost 4. Convenience

1. What’s it going to do for me?

2. What’s the catch?3. How much is this

going to run me?4. How much work is

this going to be?

1. Efficacy – Ask About…1. Hard outcomes:

a) Reduction in mortality?b) Reduction in morbidity?

2. Surrogate outcomes:• Clinically relevant?

3. Then, “What is the quality of this evidence?” • Meta-analysis?• Randomized Controlled Trial?• …• Case series?• Anecdotal evidence?

1. Efficacy

• If there is no efficacy, why waste your time on the potential toxicity, cost and inconvenience of a drug?

• If there is proven efficacy at the population level, then balance this against the potential toxicity to the individual.

2. Toxicity – Ask About…

Bothersome Severe

Common Not legal

Rare Who cares

2. Toxicity

• N.B. RCTs are usually powered to show differences in efficacy, not always toxicity. – Efficacy endpoint: ~ 1 in 5000 – Toxicity endpoint: ~ 1 in 20,000

• So, might need > 4 RCTs to see statistical signals of toxicity after a drug reaches market.

• Age is important: • Newer agents = Less Safety Data• Older agents = More Safety Data

3. Cost – Ask About…

• Patient cost vs Societal cost

• Covered by provincial drug plan? – By private plans?

4. Convenience – Ask About…

• What is the likelihood of compliance?1. Frequency of administration?

– Daily vs QID?

2. Special restrictions? – PO vs IV? – Home vs Office vs Hospital therapy?

3. Many interactions?4. Special monitoring requirements?5. Constraints in supply?

A simple example:

Metformin

VS

Januvia®

Efficacy1. HARD Outcomes

– Mortality benefit – MetforminMetformin – reduction in CV events (UKPDS-34 trial)– Januvia - none

– Morbidity benefit– MetforminMetformin – reduction in microvascular complications– Januvia - none

Efficacy

2. SURROGATE Outcomesa) Hgb-A1c reduction

• MetforminMetformin ~ 1% - 2%• Januvia® ~ 0.5% - 0.8%

b) Insulin Sparing Effects• MetforminMetformin - yes - yes• Januvia® - none

c) Weight neutral• MetforminMetformin – yes• Januvia - yes

Toxicity• Metformin

– ?Rare cause of lactic acidosis?• 0.03 cases / 1000 pt-yrs

– ~ 50% fatal• Never clearly implicated

– GI upset / diarrhea • Start low, go slow!

– B12 / folate deficiency / anemia (6 - 8/100)

• Reduced absorption – easy to supplement

– Anorexia • usually transient

• Januvia® – ?Unknown

• ?Pancreatitis– Too few patients examined

– GI upset– edema– ?elevated risk of infection?

Cost & Convenience

• Metformin– ~ $33 / 100 days(^)

– $ 0.0587 / tab(*) – Covered by ODB

– QD to TID po

• Januvia®– ~ $315 / 100 days(^)

– $ 2.8948 / tab(*)

– Covered by ODB

– Once daily po

(*) – Ontario Drug Benefit e-Formulary. Accessed Oct 26/12(^) – Rxfiles.ca Hypoglycemic Comparison Charts. Aug 2012

A simple example:

Metformin

VS

• Life saving• Well tolerated• Dirt-cheap• A classic!

Januvia®

• Young and sexy

What if Metformin 500mg tablets were in short supply?

1. Do nothing and wait

2. Rx 850mg tabs of metformin– No ODB coverage

3. Rx Janumet 850/50mg tabs– (Januvia + metformin) – ODB covered

4. Rx sitagliptin (Januvia®) instead

5. Rx other therapies instead– Eg. glyburide, gliclazide, acarbose, etc.

Clinical scenario 1• 60 y.o. female patient • PMHx

– Diabetes type 2 (1998)– NSTEMI (2009)

• Meds– Bisoprolol 5mg qhs– ASA 81mg daily– Simvastatin 20mg qhs

• BP: 148/98; HR 60 bpm• eGFR 80mL/min, urACR = 10• K+ = 4.0; LDL = 1.5

• This patient is missing an:– ACE inhibitor!

Choosing ACEinh• Enalapril (Vasotec) • Ramipril (Altace) • Quinapril (Accupril) • Perindopril (Coversyl) • Lisinopril (Prinivil/Zestril) • Benazepril (Lotensin) • Trandolapril (Mavik) • Fosinopril (Monopril)

• Efficacy– All equivalent

• Cardio- and Nephro-protection

• BP reduction

• Toxicity– All equivalent

• Hyperkalemia, ARF, angioedema

• Convenience– All QD-BID

Cost• Any except PERINDOPRIL (Coversyl®)

– Not yet generic, although covered under ODB

– Perindopril $0.63- $1.10 per tab– Enalapril $0.20 - $0.35 per tab– Fosinopril $0.23- $0.27 per tab– Ramipril $0.17 – $0.25 per cap– Lisinopril $0.13 - $0.19 per tab

• N.B. In cases of shortage or high costs, higher strength tabs could be cut in ½ or ¼.

Drug Shortage Resources

• www.vendredipm.ca/ • www.fridaypm.ca/

– By SigmaSanté • A non-profit organization

that negotiates goods & services for healthcare organizations in Montreal & Laval regions

• www.drugshortages.ca/ – Government of Canada

& Province of Alberta• Multi-Stakeholder

Steering Committee on Drug Shortages to advance collaborative work on drug shortages.

• www.ashp.org/menu/DrugShortages• American Society of Health-System Pharmacists database

Summary• Drug shortages are likely here to stay.

– Step 1: assess indication– Step 2: assess options– Step 3: choose best option using a logical process

• Applying EBM requires a process– It distills out high quality information

• (Efficacy)– It protects patients from unnecessary harm (and you from

medico-legal harm!) • (Toxicity)

– It saves time • (Cost and Convenience)

Suggested Readings: On Shortages

• University of Saskatchewan – MedSask - Primer on drug shortages– http://medsask.usask.ca/

• CPhA (Canadian Pharmacists Association) - Drug Shortages - A Guide for Assessment and Patient Management

– http://www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/DrugShortagesGuide.pdf

• CSHP (Canadian Society of Hospital Pharmacists) - CSHP Speaks Up on Drug Shortages

– http://www.cshp.ca/advocacy/CSHPspeaks/drugShortages_e.asp– http://www.cshp.ca/advocacy/CSHPspeaks/docs/CMA_CPhA_CSHPnewsrelease_jan2013.pdf – http://www.cshp.ca/advocacy/CSHPspeaks/docs/survey_backgrounder_Jan2013.pdf– http://www.cshp.ca/dms/dmsView/1_Drug-shortages---OVRDIS-Update-Mar%2712.pdf– http://www.cshp.ca/dms/dmsView/1_Standing-Com-on-Health-Mar%2712---CSHP-Speaking-Notes-

FINAL.pdf

• U.S. House of Representatives Committee on Oversight and Government Reform - FDA’s Contribution to the Drug Shortage Crisis (June 2012)

– http://oversight.house.gov/wp-content/uploads/2012/06/6-15-2012-Report-FDAs-Contribution-to-the-Drug-Shortage-Crisis.pdf

QUESTIONS?