Stronger warning for montelukast; COVID-19 actions

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

Recalls, warnings, and alerts

An alert that EpiPen (0.3-mg) and EpiPen Jr (0.15-mg) auto-injectors and their generic versions may malfunction. The devices may have delayed injection or be prevented from properly injecting due to factors including spontaneous premature activation and difficulty removing the device from the carrier tube, manufacturer Pfizer said in a letter to clinicians. Patients and caregivers should inspect their devices prior to needing them to ensure that the blue safety release is not raised and that the device can be easily removed from the carrier tube, the FDA said.

An alert about the use of fecal microbiota for transplantation (FMT). Several infections caused by enteropathogenic Escherichia coli and Shiga toxin-producing E. coli have occurred in patients following investigational use of FMT to treat Clostridioides difficile infection not responsive to standard therapies. The FDA suspects that these infections are due to transmission of these pathogenic organisms from FMT product supplied by a U.S.-based stool bank company that manufactures it from prescreened donors and provides it to clinicians and researchers.

In addition, with recent evidence demonstrating that individuals infected with SARS-CoV-2 may have the virus in their stool, it is possible that SARS-CoV-2 may be transmitted by FMT, although the risk of such transmission is unknown, the FDA said. Due to this risk, the FDA has established additional protections for any investigational use of FMT, including testing donors and/or donor stool for SARS-CoV-2.

A strengthened boxed warning for montelukast (Singulair and generics). The FDA is strengthening existing warnings about serious behavior and mood-related changes with the asthma and allergy drug based on its re-evaluation of the drug's benefits and risks. While the prescribing information had previously included warnings about mental health side effects, including suicidal thoughts or actions, many clinicians, patients, and caregivers were not aware of this risk, the FDA said.

A class I recall of Alaris System Infusion Pumps by Becton Dickinson/CareFusion 303 due to multiple system errors, software errors, and use-related errors. These errors can lead to delay in infusion, interruption of infusion, under-infusion, and over-infusion. There have been 55 reported injuries and one death. The recall includes 774,000 devices distributed at various points from July 2004 to Jan. 23, 2020.

A class I recall of the Pipeline Flex Embolization Device by Medtronic due to risk of device fracture during placement of the stent inside the patient. If the device has already been implanted successfully, there is no increased risk to patients due to this issue. The FDA has received 50 medical device reports, with 10 injuries and one death. The recall includes 822 devices distributed from Nov. 6, 2019, to Feb. 7, 2020.

A class I recall of BodyGuard Infusion Pump Systems by CME America due to risks of over- and under-infusion. The reason for the infusion errors is not known. There have been 158 related complaints and no reported injuries or deaths. The recall includes 28,448 devices distributed from March 6, 2009, to Nov. 29, 2019.

A class I recall of BodyGuard Microset Infusion Sets by CME America due to risk of under-infusion. Specific infusion sets have an extended section of tubing longer than standard lengths, which prohibitively restrict medication flow to the pumping chamber and may result in under-infusion of therapy. There have been three complaints of under-infusion, but no reported injuries or deaths. The recall includes 91,500 devices distributed from Oct. 6, 2017, to July 15, 2019.

A recall of four lots of phytonadione injectable emulsion, USP (10 mg/mL in single-dose ampules) by Dr. Reddy's Laboratories Ltd. and its subsidiaries due to ampules breaking and shattering upon opening. The company has received reports of this issue causing lacerations in health care professionals. Affected batches were distributed nationwide between June 21, 2019, and Feb. 26, 2020, to wholesalers, distributors, hospitals, and pharmacies.

An expanded recall of eight lots of ketorolac tromethamine injection USP (30 mg/mL, 1 mL fill/2 mL vials) by Hikma Pharmaceuticals USA Inc. due to the presence of particulate matter. Particles in some of the recalled lots are of a gelatinous/oily nature and appear black. Recalled lots were manufactured between March 22, 2018, and Feb. 21, 2019.

An alert about the SweynTooth family of cybersecurity vulnerabilities. Security researchers have identified 12 vulnerabilities associated with Bluetooth Low Energy wireless communication technology. An unauthorized user can wirelessly exploit these vulnerabilities to crash the device, deadlock the device, or bypass security to access device functions. The following manufacturers are affected by these vulnerabilities: Texas Instruments, NXP, Cypress, Dialog Semiconductors, Microchip, STMicroelectronics, Telink Semiconductor. Manufacturers are assessing which devices are affected by SweynTooth, evaluating the risk, and developing remediation actions.

A recall of 11 lots of ranitidine tablets, USP (150 mg) by American Health Packaging due to the potential to contain excess amounts of N-nitrosodimethylamine (NDMA), a probable carcinogen. The recall was initiated in response to a separate recall by the manufacturer (Amneal Pharmaceuticals, LLC), which included affected lots that were repackaged by American Health Packaging. Recalled products were distributed nationwide to wholesalers for use in hospital settings.

Coronavirus disease 2019 (COVID-19) updates

A new program to expedite the development of potentially safe and effective treatments for patients with COVID-19. The Coronavirus Treatment Acceleration Program aims to bring treatments to market as quickly as possible while supporting research to further evaluate whether they are safe and effective for treating patients with COVID-19. A variety of treatments are being evaluated, including antiviral drugs like remdesivir that may treat the specific virus, as well as host targets, such as interleukin-6 receptor inhibitors that may help reduce lung inflammation and improve lung function in patients with COVID-19.

Emergency use authorization to allow hydroxychloroquine sulfate and chloroquine phosphate products donated to the Strategic National Stockpile (SNS) to be distributed and used for certain hospitalized patients with COVID-19. The drugs will be distributed from the SNS to states for doctors to prescribe to adolescent and adult patients hospitalized with COVID-19, as appropriate, when a clinical trial is not available or feasible. The authorization requires that fact sheets about using the drugs to treat COVID-19, including the known risks and drug interactions, be made available to clinicians and patients.

Emergency use authorizations for 34 tests, including point-of-care diagnostics, that detect SARS-CoV-2, the virus that causes COVID-19. As of April 13, more than 300 test developers have submitted or have said they will be submitting applications to make such tests. In addition, more than 180 laboratories have begun testing. While the agency has not authorized any test that is available for individuals to purchase to test themselves at home, it warned that unauthorized fraudulent test kits are being marketed to test for COVID-19 in the home.

Mitigation strategies to address the shortage of personal protective equipment (PPE). The FDA recommended conservation strategies for PPE, including surgical masks, gowns, and gloves, in a letter to clinicians. The agency has also taken steps to help import PPE into the U.S. from overseas using emergency use authorizations.

A new policy allowing manufacturers of certain vital sign–measuring devices to expand their use so that clinicians can use them to monitor patients remotely. The policy applies to certain modifications to the indications, claims, functionality, or hardware/software of FDA-cleared, noninvasive remote monitoring devices used to support monitoring of patients' body temperature, respiratory rate, heart rate, and blood pressure. The policy is limited to the duration of the COVID-19 emergency.

Emergency use authorizations for ventilators (including anesthesia gas machines and positive-pressure breathing devices that have been modified for use as ventilators), ventilator tubing connectors, and ventilator accessories. Amid shortages of respirators, such devices meeting FDA criteria for safety, performance, and labeling may be approved for emergency use in health care settings to treat patients during the COVID-19 pandemic.

An amended emergency use authorization for the Battelle Decontamination System for use in decontaminating compatible N95 respirators for reuse by health care personnel during the COVID-19 pandemic. The authorization aims to help reduce shortages in N95 respirators.

An emergency use authorization for STERRAD Sterilization Cycles (STERRAD 100S Cycle, STERRAD NX Standard Cycle, or STERRAD 100NX Express Cycle), which use vaporized hydrogen peroxide gas plasma sterilization. About 6,300 hospitals across the country use the sterilization systems, and their authorization has the potential to decontaminate about 4 million N95 or N95-equivalent respirators per day for reuse by clinicians in U.S. hospital settings, the FDA said.

New guidance for clinicians regarding certain Risk Evaluation and Mitigation Strategy (REMS)-required testing during the COVID-19 pandemic. The FDA acknowledged that undergoing testing or imaging studies in order to obtain a drug that is subject to a REMS can put patients and others at risk for transmission of the coronavirus. Clinicians should use their best medical judgment to weigh the risks and benefits of continuing treatment in the absence of lab testing and imaging studies, the FDA said. The agency's guidance will be in effect for the duration of the public health emergency.

Facilitated access to convalescent plasma taken from blood donated by people who have recovered from COVID-19. The antibody-rich blood products could shorten the length of or lessen the severity of the illness. The FDA has also issued guidance providing recommendations on pathways for use of investigational COVID-19 convalescent plasma, patient eligibility, and plasma collection, including donor eligibility and qualifications.

Warning letters to several companies for selling fraudulent COVID-19 products, including nasal sprays, herbal products, teas, essential oils, tinctures, and colloidal silver. There are no FDA-approved products to prevent or treat COVID-19, and products for veterinary use or for research use only may have adverse effects, the FDA noted.

A letter reminding consumers not to use chloroquine phosphate intended for fish as treatment for COVID-19 in humans. Some consumers may mistake chloroquine phosphate used to treat disease in aquarium fish for FDA-approved drugs (used to treat malaria and certain other conditions in humans) that are being studied as a COVID-19 treatment for humans, the FDA said. At least one person in the U.S. has died after reportedly taking the fish drug in an attempt to prevent COVID-19.

Guidance outlining an enforcement policy to help expand the availability and capability of sterilizers, disinfectant devices, and air purifiers. The devices include those intended to make devices sterile, kill pathogens or other microorganisms, and kill pathogens or microorganisms in the air.

Guidance to help expand the availability of surgical apparel for health care professionals. The guidance applies to gowns, hoods, and surgeon and patient examination gloves during the public health emergency.


A new regulatory pathway for insulin and certain other biologic drugs. The regulatory transition, mandated by Congress and implemented by the FDA, will for the first time open a pathway for products that are proposed as biosimilar to or interchangeable with the transitioned products. The FDA expects the availability of biosimilars and interchangeable versions to increase patient access to these drugs, which are used for many conditions, including diabetes, respiratory distress syndrome, fertility conditions, Cushing's syndrome, deep venous thrombosis, and Gaucher disease.

A final rule banning electrical stimulation devices used for self-injurious or aggressive behavior. The FDA took the rare step to ban these devices for this behavior because they present an unreasonable and substantial risk of illness or injury that cannot be corrected or eliminated through new or updated device labeling.

A safety communication about devices claiming to clean, disinfect, or sanitize continuous positive airway pressure (CPAP) devices or accessories using ozone gas or ultraviolet light. These products are not legally marketed for this use by the FDA, and their safety and effectiveness for use with CPAP devices and accessories are unknown.

A final rule requiring new health warnings on cigarette packages and in cigarette advertisements. The 11 warnings feature statements with photo-realistic color images depicting some of the lesser-known but serious health risks of cigarette smoking, including impact on fetal growth, cardiac disease, and diabetes. They will go into effect on June 18, 2021.


Osilodrostat (Isturisa) to treat adults with Cushing's disease. The orphan drug is indicated for patients who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. It is the first FDA-approved drug to directly address the cortisol overproduction caused by the disease by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis. In a clinical trial, more patients receiving the drug maintained cortisol levels within normal limits than those receiving placebo. The most common side effects were adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema. Low cortisol levels, QT prolongation, and elevations in adrenal hormone precursors and androgens may also occur.

Isatuximab-irfc (Sarclisa), in combination with pomalidomide and dexamethasone, to treat adults with multiple myeloma. The orphan drug, administered through IV infusion, is a CD38-directed cytolytic antibody. It is indicated to treat patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. In a clinical trial, patients who received the drug in combination with pomalidomide and low-dose dexamethasone showed improvement in progression-free survival, with a 40% reduction in the risk of disease progression or death compared to those who received only pomalidomide and dexamethasone. Common side effects include neutropenia, infusion-related reactions, pneumonia, upper respiratory tract infection, diarrhea, anemia, lymphopenia, and thrombocytopenia. Serious side effects include infusion-related reactions and neutropenia, and the drug may also interfere with laboratory tests.

Nintedanib (Ofev) to treat patients with chronic fibrosing interstitial lung diseases with a progressive phenotype. The drug is the first FDA-approved treatment for this group of fibrosing lung diseases that worsen over time. In a clinical trial, patients who received the oral capsules had less lung function decline than those who received placebo. The most common side effects were diarrhea, nausea, stomach pain, vomiting, liver problems, decreased appetite, headache, and weight loss. The drug is not recommended for patients with moderate or severe hepatic impairment. It may cause elevated liver enzymes and drug-induced liver injury and gastrointestinal disorders.

First-time generic approvals

Dabigatran etexilate capsules (75 mg and 150 mg) to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, to treat deep venous thrombosis (DVT) and pulmonary embolism (PE), and to provide prophylaxis against DVT and PE in certain patients. (Brand name: Pradaxa)

Naproxen and esomeprazole magnesium delayed-release tablets (375 mg/20 mg and 500 mg/20 mg) for the symptomatic relief of arthritis to decrease the risk of developing naproxen-associated gastric ulcers. (Brand name: Vimovo)

Pyrimethamine tablets (25 mg) to treat toxoplasmosis when used conjointly with a sulfonamide. (Brand name: Daraprim)

Dihydroergotamine mesylate nasal spray (4 mg/mL [1-mL vial]) for the acute treatment of migraine headaches with or without aura. (Brand name: Migranal)

Sodium iodide I-131 solution and capsules USP (1,000 mCi/mL) to treat hyperthyroidism and selected cases of carcinoma of the thyroid. (Brand name: Hicon)

Olopatadine hydrochloride ophthalmic solution USP (0.7%) to treat ocular itching associated with allergic conjunctivitis. (Brand name: Pazeo)

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