Recalls and warnings
Recalls of several forms of over-the-counter (OTC) ranitidine due to potential contamination with N-nitrosodimethylamine (NDMA), a probable human carcinogen. An FDA investigation found that the levels of NDMA detected in ranitidine are low; however, the agency has asked manufacturers to recall ranitidine if product lots contain NDMA levels above the acceptable limits. It has also asked companies to recall nizatidine, a chemically similar histamine H2 receptor antagonist, if NDMA is detected above the acceptable level. Manufacturers that have recalled ranitidine tablets (150 mg and 300 mg) and oral solution (15 mg/mL) include Novitium Pharma LLC, Aurobindo Pharma USA, Inc., Amneal Pharmaceuticals, LLC, American Health Packaging, and Lannett Company, Inc. The FDA recommended that patients taking OTC ranitidine or nizatidine can consider using other OTC products approved for their condition. So far, FDA and industry testing of H2 blockers and proton-pump inhibitors has only identified NDMA in ranitidine and nizatidine. Alternative medicines, such as famotidine, cimetidine, esomeprazole, lansoprazole, and omeprazole, have not tested positive for NDMA impurities. Patients taking prescription ranitidine who wish to stop should speak to their clinicians about other treatment options, the FDA said.
A class I recall of the Forte Gamma Camera System by Philips Medical Systems due to the potential for the gamma camera detector (660 pounds) to drop in an uncontrolled manner to the end of its range of motion without a command from the clinician. While the manufacturer received one customer complaint, no serious injuries or deaths were reported. A total of 852 recalled devices were distributed from Jan. 1, 1998, to Dec. 31, 2008.
A recall of 22 lots of blood administration sets by B. Braun Medical due to potential for leakage at the joint between the blood filters and tubing of the administration sets. A total of 43,026 units of the recalled sets were distributed between June 11 and Sept. 27, 2019.
A recall of one lot of alprazolam tablets USP (0.5 mg) by Mylan Pharmaceuticals due to the potential presence of a foreign substance. The batch was distributed between July and August 2019.
A warning letter to Greenbrier International, Inc. (doing business as Dollar Tree), for receiving potentially unsafe drugs. The warning letter details Dollar Tree's receipt of adulterated OTC drugs from manufacturers that received FDA warning letters in 2018. The warning letters sent to the contract manufacturers show a pattern of serious violations of federal law, such as not testing raw materials or finished drugs for pathogens and quality. The FDA has requested that Dollar Tree implement a system to ensure that it does not import adulterated drugs.
A new report on the root causes of and potential solutions to recent drug shortages. At the request of Congress in 2018, the FDA formed a Drug Shortages Task Force of economists and scientists to study the problem. The task force analyzed 163 drugs that went into shortage from 2013 to 2017 and compared them to similar medicines that did not go into shortage. Shortage drugs were more likely to be relatively low-price, financially unattractive to manufacturers, and sterile injectables. Shortages often occurred as a result of disruption in supply. Prices rarely rose after shortages began, and during shortages, production typically did not increase enough to restore supply to pre-shortage levels. The task force's three recommendations to address the root causes of drug shortages are: 1) increasing understanding of the impacts of drug shortages and companies' contracting practices that may contribute to them, 2) developing a system to measure and rate a facility's quality management maturity, and 3) considering new contracting approaches that help ensure a reliable supply of drugs. The full report is online.
A safety communication about the FDA's evaluation of the risk of type III endoleaks when AFX endovascular grafts by Endologix are used for the treatment of abdominal aortic aneurysm. There are three approved versions of the device: AFX with Strata, AFX with Duraply, and AFX2. In June 2018, the FDA reported on the greater risk of type III endoleaks occurring with the AFX with Strata endovascular graft. The new safety communication presented real-world data suggesting that there may also be a high risk of type III endoleaks occurring with the use of the two other types of AFX endovascular grafts. Because endoleaks can occur after repair with any endovascular graft and typically do not result in symptoms, the FDA strongly recommends that physicians monitor for type III endoleaks through lifelong follow-up visits at least yearly in all patients who have any of the three AFX endovascular grafts.
An update on the postmarket safety of the Essure device. While the manufacturer, Bayer, stopped selling and distributing the permanent birth control device in the U.S. on Dec. 31, 2018, the FDA has continued to monitor the safety of the device for women who have it implanted. Health care professionals could implant the device up to one year from the date it was purchased. The FDA will soon report interim results from the manufacturer's postmarket surveillance study comparing complications in patients who chose the device and those who chose laparoscopic tubal ligation.
A safety communication reminding clinicians that biotin, or vitamin B7, can significantly interfere with certain lab tests. High levels of the water-soluble vitamin are often found in multivitamins, prenatal vitamins, and dietary supplements marketed for hair, skin, and nail growth. Since first communicating about this issue in 2017, the FDA has continued to receive adverse event reports related to biotin interference, including with troponin tests. The agency recommends that patients and clinicians discuss all supplement use.
An update on the FDA's evaluation of device failures associated with Getinge's Maquet/Datascope intra-aortic balloon pump devices, the Cardiosave (Hybrid and Rescue) CS300 and CS100/CS100i. In a letter to clinicians on Nov. 1, 2018, the agency reported that there had been incidences of the devices shutting down while running on battery power, leading to pump stop and loss of hemodynamic support. Since then, the FDA has received more than 60 additional medical device reports related to the issue, including two patient deaths and one serious patient injury (which cannot be definitively attributed to the device shutting down). The FDA recommends that those who use the devices review the urgent medical device correction notice from June 2019, use the newly developed quick reference guides, and schedule a training visit as soon as possible. The agency is working with the manufacturer to examine and address the root cause of the problem, and the manufacturer is developing a battery maintenance software upgrade.
Efforts to reduce reliance on ethylene oxide in medical device sterilization techniques due to environmental and public health concerns. Through two innovation challenges, the FDA has selected 11 applications from companies to identify new, alternative sterilization methods as well as strategies or technologies that can reduce the amount of ethylene oxide used to sterilize devices. The agency is working directly with the applicants to accelerate the development and review of these technologies.
Voxelotor (Oxbryta) to treat sickle cell disease in patients ages 12 years and older. In a trial of 274 patients, those who received 1,500 mg/d had a 51.1% increase in hemoglobin response rate at 24 weeks, compared to 6.5% in the placebo group. Common side effects of the orphan drug were headache, diarrhea, abdominal pain, nausea, fatigue, rash, and fever.
Crizanlizumab-tmca (Adakveo) to reduce the frequency of vaso-occlusive crisis in patients ages 16 years and older. In a trial of 198 patients with sickle cell disease and a history of vaso-occlusive crisis, patients who received the drug had fewer health care visits for vaso-occlusive crisis (median annual rate of 1.63 visits) than patients who received placebo (median annual rate of 2.98 visits). In addition, 36% of patients who received the orphan drug did not experience vaso-occlusive crisis during the study, and treatment delayed the time that patients first experienced vaso-occlusive crisis after starting treatment from 1.4 months to 4.1 months. Common side effects were back pain, nausea, fever, and arthralgia. Clinicians should monitor patients for infusion-related reactions and discontinue the drug in the case of severe reactions. Patients who receive the drug should also be monitored for interference with automated platelet counts or platelet clumping. Clinicians are advised to run blood tests as soon as possible after samples are collected or to use tubes containing citrate.
Marketing of a test to detect HIV-1 drug resistance mutations using next-generation sequencing technology. The Sentosa SQ HIV Genotyping Assay is the first HIV drug-resistance assay using this technology to be authorized for marketing in the U.S. In performance studies, the assay demonstrated a greater than 95% sensitivity and specificity in detecting 342 HIV drug-resistant mutations. It is indicated for use only in patients with HIV-1 who are about to start or are already taking antiviral therapy and is not intended for diagnosing HIV infection. Test results are intended to be used in conjunction with clinical observations, patient history, and other laboratory evidence to make patient management decisions.
Cenobamate tablets (XCOPRI) to treat partial-onset seizures in adults. In two trials of 655 patients, doses of 100 mg, 200 mg, and 400 mg daily reduced the percent of seizures per 28 days compared with the placebo group. The recommended maintenance dose, following a titration period, is 200 mg daily; however, some patients may need additional titration to 400 mg/d, the maximum recommended dose. The most common side effects were somnolence, dizziness, fatigue, diplopia, and headaches. Some patients experienced drug reaction with eosinophilia and systemic symptoms, and one patient died, when the drug was titrated rapidly (weekly or faster titration). In addition, a higher percentage of patients who received the drug had a shortening of the QT interval of greater than 20 ms compared to those who received placebo.
Luspatercept–aamt (Reblozyl) to treat anemia in adults with beta-thalassemia who require regular red blood cell transfusions. In a trial of 336 patients, 21% of patients who received the drug had at least a 33% reduction in transfusions compared to 4.5% of the patients who received placebo. Common side effects were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the orphan drug should be monitored for hypertension and thrombosis.
Cefiderocol (Fetroja) to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible gram-negative microorganisms. The antibacterial drug is indicated for patients who have limited or no alternative treatment options. In a study of 448 patients with complicated urinary tract infections, 72.6% of those who received the drug had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% of patients who received an alternative antibiotic. Clinical response rates were similar between the two groups. The drug's labeling includes a warning with regard to the higher all-cause mortality rate observed in critically ill patients with multidrug-resistant gram-negative bacterial infections who received the drug compared to those treated with other antibiotics. While the cause of the increase in mortality has not been established, the higher all-cause mortality rate was observed in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. Common adverse reactions included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion site reactions, candidiasis, cough, headache, and low potassium levels. The drug should not be used in individuals with a known history of severe hypersensitivity to beta-lactams.
Marketing of the first duodenoscope with a sterile, disposable elevator component. While the FDA has previously cleared duodenoscopes with removable endcap components, the Pentax Medical Video ED34-i10T2 model duodenoscope is the first device with a disposable elevator component, a part that has been traditionally difficult to clean and reprocess. The disposable elevator component will reduce the number of device parts that need to be cleaned and disinfected between uses. The device is intended to be used with endoscopic devices, and its risks include burns, electric shock, perforation, infection, and bleeding.
Supplemental approval of acalabrutinib (Calquence) to treat adults with chronic lymphocytic leukemia or small lymphocytic lymphoma. In two trials, patients receiving the drug had a longer progression-free survival than those receiving other standard treatments. The most common side effects were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. Patients may experience atrial fibrillation and flutter and should be monitored for symptoms of arrhythmias. They should also be monitored for serious infections, bleeding, and low blood counts.
Zanubrutinib (Brukinsa) capsules to treat adults with mantle cell lymphoma who have received at least one prior therapy. In a single-arm trial of 86 patients, 84% had tumor shrinkage, with a median duration of response of 19.5 months. In another single-arm trial of 32 patients, 84% had tumor shrinkage with a median duration of response of 18.5 months. Common side effects were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin levels, rash, bruising, diarrhea, and cough. During treatment with the orphan drug, patients should be monitored for bleeding, signs and symptoms of infection, cytopenias, and cardiac arrhythmias.
Givosiran (Givlaari) to treat adults with acute hepatic porphyria. The rare genetic disorder results in the buildup of toxic porphyrin molecules, which are formed during the production of heme. In a trial of 94 patients, those who received the drug had 70% fewer porphyria attacks than patients in the placebo group. Common side effects of the orphan drug were nausea and injection site reactions. Clinicians are advised to monitor patients for anaphylactic reaction and renal function, and patients should have their liver function tested before and periodically during treatment.
Adalimumab–afzb (Abrilada), a biosimilar to Humira. The approval is one of nine new biosimilar products the FDA has taken action on in 2019, bringing the overall total of biosimilar approvals to 25.
First-time generic approvals
Digoxin oral solution USP (0.05 mg/mL) for the treatment of atrial fibrillation in adults and heart failure in adult and pediatric patients. (No brand name provided.)
Vilazodone hydrochloride tablets (10 mg, 20 mg, and 40 mg) for the treatment of major depressive disorder. (Brand name: Viibryd)
Ivermectin cream (1%) for the treatment of inflammatory lesions of rosacea. (Brand name: Soolantra)
Fosaprepitant for injection (115 mg) for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin, and of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. (Brand name: Emend)
Carfilzomib for injection (60-mg single-dose vial) for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. (Brand name: Kyprolis)
Note: The FDA states that drugs are not always commercially available immediately after approval.