Metformin Extended-Release Formulation Recall

CLINICAL UPDATE

• What You Need to Know

• How CVS Health Supports Patient Safety

The metformin recall is part of the FDA’s commitment to keeping the U.S. drug supply safe.

If drugs contain levels of nitrosamines above acceptable daily intake limits, the FDA recommends they be recalled.

Recently, on the recommendation of the U.S. Food and Drug Administration (FDA), five manufacturers issued recalls for certain extended-release (ER) metformin formulations. Metformin is prescribed to manage blood glucose levels for many people who have type 2 diabetes. This recall — and others — are part of the agency’s commitment to keeping the U.S. drug supply safe.

As part of that commitment, the FDA has been investigating the presence of nitrosamine impurities —

such as N-nitrosodimethylamine (NDMA) — above acceptable intake limits in medications. The agency

has tested and systematically requested manufacturers to remove impacted formulations from the

market. This includes medications used to treat a variety of conditions such as hypertension, heart failure

(angiotensin receptor blockers), and heartburn (ranitidine, nizatidine), and most recently, ER formulations

of metformin.

According to the FDA, nitrosamine impurities are common in water and foods, including cured and grilled

meats, dairy products and vegetables.1 The agency, in collaboration with regulatory counterparts around

the world, has set internationally recognized acceptable daily intake limits for nitrosamine impurities such

as NDMA. If drugs contain levels of nitrosamines above the set limits, the FDA recommends they be

recalled by the manufacturer as appropriate.

The recall affected certain metformin ER formulations from multiple manufacturers. There are other

companies that manufacture metformin ER, whose formulations were not recalled. The recalls have not

included immediate-release (IR) version of metformin, the most commonly prescribed type.2 While such

large, wide-ranging drug recalls are infrequent, they do occur.

CVS Health: Metformin Extended-Release Formulation Recall | 2

Why Are Recalls Issued?

What Are the Different Types of Recall?

The FDA regulates manufacturing facilities of pharmaceutical manufacturers, both inside and outside the United

States. When the FDA finds drug products containing impurities beyond acceptable levels, it may take action including

recommending that a manufacturer conduct a recall and/or publishing alerts for providers, pharmacies, patients and

others regarding drugs in the U.S. market that may have quality or safety issues.

A recall is a voluntary action taken by a company to remove a defective drug product from the market. Drug recalls may be conducted on a company’s own initiative or by FDA request. The FDA defines its role in a recall as being “to oversee a company’s strategy, assess the adequacy of the recall, and classify the recall.”

Recalls can be classified as Class I, II, or III to indicate the relative degree of health hazard presented by the product

being recalled.3 A Class I recall is one in which there is a reasonable probability that the use of or exposure to the

product will cause serious adverse health consequences or death.4 A Class II recall is one where the product “may

cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health

consequences is remote.” The FDA issues a Class III recall when use of or exposure to the product “is not likely to cause

adverse health consequences.”

In cooperation with the FDA, the manufacturer determines the “depth” of the recall — the level in the distribution chain to which a recall is to extend — as part of its recall strategy, in cooperation with the FDA.5

The recall of metformin ER formulations is a voluntary consumer-level recall initiated by the manufacturers based on guidance from the FDA.

Wholesale

The manufacturer removes the product from

a warehouse or distribution center where the

product is not under their direct control

Retail

The product is removed from retail stores

Consumer

The product has been sold to consumers

and, in addition to removal of the product

from warehouse and retail sale, there may be

a possible public notification to consumers

CVS Health: Metformin Extended-Release Formulation Recall | 3

What Steps Does the FDA Take to Regulate Drugs Sourced from Overseas?

What Role Does CVS Health Play in Supporting the Safety of the Drug Supply Chain?

The FDA is responsible for protecting the public health by ensuring the safety, efficacy and security of drugs and

medical devices in the United States.6 An estimated 40 percent of finished drugs are imported and 80 percent of active

pharmaceutical ingredient manufacturers are located outside the U.S.7, 8 The FDA also works to make sure imported

drugs are safe, often in cooperation with foreign counterpart regulatory authorities.

As part of the process of reviewing new and generic drug product applications, the FDA conducts inspections of facilities

involved in the manufacturing process for prescription drugs, including entities located outside the United States.9,10 The

FDA also performs routine surveillance inspections of foreign manufacturing facilities throughout a product’s lifetime on

the market and tests finished drugs sampled from retail locations, distribution warehouses and manufacturing sites.9,10

In recent years, the FDA has made significant investments in the inspection of drugs sourced from overseas, and has

increased the frequency of inspections. Part of the increase in recall notices reflects this greater level of scrutiny.11

We have policies and procedures in place to help ensure the medications we dispense to patients are safe, reliable

and of high quality. Our suppliers must warrant that their products comply with FDA and all other applicable regulatory

requirements, and are manufactured in accordance with current good manufacturing practices. We carefully monitor

FDA notices and recalls so that we can move quickly to remove any impacted products from our distribution centers and

pharmacies across the country.

CVS Health has policies and procedures in place to help ensure the medications we dispense to patients are safe, reliable and of high quality.

In managing recalls and possible related decreases in product supply, we work to minimize disruption of therapy and support continuity of care for patients.

In the event of a consumer level recall, we notify patients to whom we dispensed the recalled product and work with them

and/or their prescribers to replace the products or obtain new prescriptions.

CVS Health: Metformin Extended-Release Formulation Recall | 4

What Should Those Affected by the Metformin Recalls Do?

Those taking recalled metformin should consult their prescriber about their options. Depending on the patient’s individual circumstances, these could include:

• Switching to the same medication from a different manufacturer

• Switching to a different formulation — such as IR instead of ER

• Switching to a different clinically equivalent medication

The health and safety of patients is our highest priority. We have policies and procedures in place to help ensure the medications we dispense to patients are safe, reliable and of high quality. We also work to promptly respond to any product recalls for affected drugs in our supply chain, including, where applicable, products that have been dispensed to patients. And we work to minimize disruption of therapy, and support continuity of care for patients.

1. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications.

2. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin.

3. https://www.fda.gov/safety/industry-guidance-recalls/recalls-background-and-definitions.

4. https://www.fda.gov/safety/industry-guidance-recalls/recalls-background-and-definitions#:~:text=Recalls%20may%20be%20conducted%20on,adverse%20health%20consequences%20or%20death.

5. https://www.fmi.org/docs/default-source/food-safety/guidance-for-food-retail-product-recall.pdf?sfvrsn=2.

6. https://www.fda.gov/about-fda/what-we-do.

7. US Food and Drug Administration (2012) Global Engagement Report; https://wayback.archive-it.org/7993/20170722112636/https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM298578.pdf.

8. https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance.

9. https://www.fda.gov/drugs/information-healthcare-professionals-drugs/transcript-fdas-role-foreign-drug-manufacturing-november-2017.

10. FDA, Compliance Program 7346.832, New Drug Evaluation, Implementation Date: 09/16/2019, https://www.fda.gov/media/121512/download.

11. https://www.fda.gov/news-events/congressional-testimony/generic-drug-user-fee-act-reauthorization-gdufa-ii-biosimilar-user-fee-act-reauthorization-bsufa-ii.

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Sree Chaguturu, M.D.Senior Vice President, CVS Health and Chief Medical Officer, CVS Caremark

Arpana Mathur, M.D.Medical Director, CVS Health