New warnings for gabapentinoids; other drugs approved

This column reviews details on recent recalls, warnings, and approvals.

Recalls, warnings, and alerts

A warning that serious breathing problems may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors. Risk factors include the use of opioids and other central nervous system depressants and conditions that reduce lung function, such as chronic obstructive pulmonary disease. Elderly patients are also at higher risk. The FDA is requiring that new warnings about the risk of respiratory depression be added to the drugs' prescribing information. The agency is also requiring the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing and may increase the risk of respiratory depression.

A class I recall of the SynchroMed II implantable drug infusion pump by Medtronic due to the potential presence of foreign particles inside the pump motor assembly. The manufacturer received five reports of early permanent motor stall due to this issue, but no deaths have been reported. The recall includes 7,317 devices distributed from May 11, 2018, to Sept. 5, 2019.

A class I recall of the Medfusion 4000 Syringe Pump with Firmware Version 1.7.0 by Smiths Medical due to the potential for low-battery alarms to stop working. The manufacturer has received 74 complaints related to the software update; no injuries or deaths have been reported. A total of 627 recalled pumps were distributed from Sept. 27 to Oct. 31, 2019.

A class I recall of certain CrossCath Support Catheters by Cook Medical due to a manufacturing error. The error may cause the radiopaque marker bands to be too loose on certain models and too tight on others. The recall includes 117 devices distributed from Sept. 3 to 19, 2019.

A warning letter to Alkermes Inc. for misbranding the extended-release injection formulation of naltrexone (Vivitrol). The company omitted warnings about the most serious risks associated with the drug from promotional materials, the FDA said. The drug is approved for the prevention of relapse to opioid dependence, in combination with psychosocial support. The warning letter was issued in response to a print advertisement for the drug, which communicated its benefits but failed to adequately communicate important warnings and precautions listed in the product labeling, including the potentially fatal risk of vulnerability to opioid overdose. The FDA has asked the company to immediately cease advertising practices that misbrand the drug and to disseminate truthful, nonmisleading, and complete corrective messages to the audiences that received the promotional materials.

A recall of all unexpired lots of ranitidine tablets (150 mg and 300 mg) by Glenmark Pharmaceuticals Inc. due to the possible presence of N-nitrosodimethylamine (NDMA), a probable carcinogen. The 928 recalled lots were manufactured in India.

A recall of two lots of levetiracetam oral solution (100 mg/mL) by Lannett Company Inc. due to contamination with Bacillus subtilis. The B. subtilis was identified during an evaluation of a raw material used to manufacture the product.

A public safety alert regarding multiple reports of serious adverse events experienced by patients in Nebraska who were treated with unapproved products marketed as containing exosomes. Certain clinics across the country, including some that manufacture or market illegal “stem cell” products, are now also offering exosome products to patients. Patients should be aware that there are currently no FDA-approved exosome products.


A notice of proposed rulemaking that, if finalized, would allow certain prescription drugs to be imported from Canada. The proposed rule is the first step in implementing a provision of federal law that would allow importation of certain prescription drugs from Canada under specific conditions that ensure the importation poses no additional risk to public health and safety while reducing the cost of covered products for Americans. It also includes draft guidance for industry.

An investigation into whether metformin in the U.S. market contains NDMA. Over the past year and a half, some drugs, such as certain angiotensin-receptor blockers and ranitidine, have been recalled due to small amounts of the impurity. Metformin in other countries was reported to have low levels of NDMA, although levels were within the range that naturally occurs in some foods and in water. The agency is testing for the impurity in samples of metformin sold in the U.S. but noted that there are no domestic metformin recalls at this time.

Global launch of the CURE ID app for clinicians. Through the app, clinicians can share their experiences treating difficult-to-treat infectious diseases with novel uses of existing FDA-approved drugs through a website, a smartphone, or other mobile device. The platform enables the crowdsourcing of medical information from clinicians to guide potentially lifesaving interventions and facilitate the development of new drugs for neglected diseases. The internet-based repository is a collaboration between the FDA and the National Center for Advancing Translational Sciences, which is part of the National Institutes of Health. The app is available from the App or Play Store and online.

Authorized marketing of two new tobacco products with reduced nicotine content. The two new combusted, filtered cigarette products, Moonlight and Moonlight Menthol, are manufactured by 22nd Century Group Inc. and contain a reduced amount of nicotine compared to typical commercial cigarettes.


Icosapent ethyl (Vascepa) as an adjunctive therapy to reduce the risk of cardiovascular events among adults with elevated triglyceride levels of 150 mg/dL or higher. Used as an add-on to maximum-tolerated statin therapy, the drug is indicated for patients who also have either established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease. Taken orally, its active ingredient is the omega-3 fatty acid eicosapentaenoic acid, which is derived from fish oil. The drug was initially approved in 2012 for adults with severe hypertriglyceridemia. In a study of nearly 8,200 patients, those who received the drug were significantly less likely to experience a cardiovascular event than those who did not. Risks of the drug include bleeding events and atrial fibrillation or atrial flutter requiring hospitalization. The most common side effects are musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia. Patients are advised to continue physical activity and maintain a healthy diet during treatment.

Marketing of the cobas vivoDx MRSA diagnostic test to detect methicillin-resistant Staphylococcus aureus (MRSA) bacterial colonization. The test uses a new bacteriophage technology based on bioluminescence to detect MRSA from nasal swab samples in as little as five hours, compared to 24 to 48 hours for conventional culture. In performance studies, it correctly identified MRSA in about 90% of samples where MRSA was present and correctly identified no MRSA in 98.6% of samples that did not have MRSA present.

Marketing of the Tandem Diabetes Care Control-IQ Technology, the first interoperable, automated glycemic controller. The device automatically adjusts insulin delivery to a person with diabetes by connecting to an alternate controller-enabled insulin pump and integrated continuous glucose monitor. Together, the three components create a complete automated insulin dosing system. In one study of 168 participants with type 1 diabetes, the controller determined and commanded safe and effective insulin delivery from a compatible alternate controller-enabled pump based on integrated continuous glucose monitor readings, with limited user intervention outside of mealtimes. Risks associated with the interoperable controller include delay of insulin delivery and incorrect insulin delivery as a result of loss of communication between connected devices or from exploitation of cybersecurity vulnerabilities.

Enfortumab vedotin-ejfv (Padcev) to treat certain adult patients with locally advanced or metastatic urothelial cancer. The drug is indicated for patients who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy. In a trial of 125 patients, the overall response rate to the drug was 44%, with 12% of patients having a complete response and 32% having a partial response. The median duration of response was 7.6 months. The most common side effects are fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, altered taste, diarrhea, dry eye, pruritus, and dry skin. As patients may experience hyperglycemia regardless of diabetes status, clinicians should closely monitor blood glucose levels in patients receiving the drug.

Marketing of the EXALT Model D single-use duodenoscope to provide visualization and access to the upper gastrointestinal tract. The device is the first fully disposable duodenoscope cleared for marketing in the U.S. It is intended for use on a single patient, removing the infection risks associated with ineffective reprocessing. Risks of using the fully disposable duodenoscope include the potential for injuries, including burns, electric shock, perforation, infection, and bleeding.

First-time generic approvals

Apixaban tablets (2.5 mg, 5 mg) to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the prophylaxis of deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; to treat DVT and PE; and to reduce the risk of recurrent DVT and PE following initial therapy. (Brand name: Eliquis)

Mesalamine extended-release capsules USP (0.375 g) for the maintenance of remission of ulcerative colitis in adult patients. (Brand name: Apriso)

Fingolimod capsules for the treatment of relapsing forms of multiple sclerosis in adults. (Brand name: Gilenya)

Etonogestrel and ethinyl estradiol vaginal ring (0.120 mg/0.015 mg per day) for use by women to prevent pregnancy. (Brand name: Nuvaring)

Deferasirox tablets (90 mg, 180 mg, 360 mg) for the treatment of chronic iron overload due to blood transfusions in patients ages 2 years and older. (Brand name: Jadenu)

Everolimus tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg) for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women; advanced renal cell carcinoma; renal angiomyolipoma and tuberous sclerosis complex; progressive neuroendocrine tumors of pancreatic origin; and progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable. (Brand name: Afinitor)

Gadoterate meglumine injection (5 mmol/10 mL [0.5 mmol/mL], 7.5 mmol/15 mL [0.5 mmol/mL], 10 mmol/20 mL [0.5 mmol/mL] single-dose vials) for IV use with magnetic resonance imaging in brain, spine, and associated tissues in adult and pediatric patients to detect and visualize areas with disruption of the blood-brain barrier and/or with abnormal vascularity. (Brand name: Clariscan)

Note: The FDA states that drugs are not always commercially available immediately after approval.