More recalls, information on impurity found in ARBs

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

Recalls, warnings, and alerts

Several recalls of antihypertensive drugs due to the presence of an impurity, N-nitrosodiethylamine (NDEA), a probable human carcinogen:

  • all lots of amlodipine/valsartan combination tablets and amlodipine/valsartan/hydrochlorothiazide combination tablets by Teva Pharmaceuticals;
  • seven lots of valsartan tablets USP (40 mg, 80 mg, 160 mg, and 320 mg), six lots of amlodipine and valsartan tablets USP (5 mg/160 mg, 10 mg/160 mg, and 10 mg/320 mg), and two lots of valsartan and hydrochlorothiazide tablets USP (320 mg/25 mg) by Mylan Pharmaceuticals;
  • one lot of losartan potassium hydrochlorothiazide tablets USP (100 mg/25 mg) by Sandoz Inc.; and
  • 22 batches of irbesartan by Aurobindo Pharma Limited.

A new FDA webpage also provides answers about impurities found in certain generic angiotensin II receptor blockers (ARBs). The agency explained that in June 2018, it found that some generic versions of valsartan contained probable human carcinogens. N-nitrosodimethylamine (NDMA) was the first impurity to be discovered in some valsartan products, and then a second impurity, NDEA, was found upon testing that now includes other ARBs. All products found to contain these impurities have been recalled, and the FDA's investigation and testing activities are ongoing. More information is available online.

A warning that when the multiple sclerosis (MS) drug fingolimod (Gilenya) is stopped, the disease can become much worse than before the medicine was started or while it was being taken. While the worsening of MS is rare, it can result in permanent disability. Clinicians should inform patients about this risk before starting treatment and carefully observe them for evidence of MS exacerbation when the drug is stopped. If an increase in disability occurs, clinicians should test patients for new or enhancing lesions using MRI and begin appropriate treatment as needed.

A recall of more than 1.1 million packages of CoaguChek XS PT test strips by Roche Diagnostics due to inaccurate results. Recalled products were manufactured and distributed from Jan. 12 through Oct. 29, 2018. The test strips, which are used with Roche INR test meters to monitor patient response to warfarin, were recalibrated in January 2018 to correspond to a newly released INR international standard. Since then, patients have reported experiencing abnormally high or inaccurate INR test results. Patients and clinicians should switch to new batches of test strips that are calibrated to the previous international standard, which the manufacturer has provided to customers.

An alert that some EpiPen (0.3 mg) and EpiPen Jr (0.15 mg) auto-injectors, as well as authorized generic versions, may not readily slide out of the carrier tube, potentially preventing easy access to the product. In a letter to clinicians, the manufacturer explained that the label sticker may have been improperly applied to the auto-injector unit, causing resistance during removal from the carrier tube. The device and the epinephrine it delivers are not affected by this issue and can be used as prescribed. However, patients and caregivers should inspect their auto-injectors to ensure they can quickly access the product when needed.

A recall of one lot of norethindrone/ethinyl estradiol tablets (ORTHO-NOVUM 1/35) and two lots of norethindrone/ethinyl estradiol tablets (ORTHO-NOVUM 7/7/7) by Janssen Pharmaceuticals, Inc., due to omission of patient information. Recalled packages do not include appropriate instructions for the product dispenser, which could affect the patient's ability to take the contraceptive correctly.

An alert about the risk of serious complications when using off-label medications with implanted pumps for pain management. Implantable intrathecal pump failure is more common with the use of medicines not approved for use with the pump, and dosage errors may also occur. Yet the FDA has found that patients are sometimes being treated with medications that are not approved for this use (e.g., compounded medicines, hydromorphone, bupivacaine, fentanyl, and clonidine). The agency recommended that clinicians review the implanted pump labeling to identify the medicines and medicine concentrations approved for use with the specific pump.

A class I recall of FC500 Series Flow Cytometers and EPICS XL Series Flow Cytometers by Beckman Coulter Life Sciences due to potentially inaccurate results caused by an electrical circuit error. The recall includes 535 FC500 devices distributed from June 2002 through February 2018 and 460 EPICS XL devices distributed from July 1992 through April 2012.

A recall of 163 lots of sodium chloride injection USP (0.9%, 10 mL fill in 10-mL vials) and sodium chloride injection USP (0.9%, 20 mL fill in 20-mL vials) by Fresenius Kabi USA due to labeling that inaccurately states the products do not contain latex. Stoppers for both recalled products contain natural rubber latex.

An alert not to use drug products intended to be sterile that are produced and distributed by Pharm D Solutions LLC due to lack of sterility assurance. In December 2016, the FDA issued a warning letter to the company following an inspection, and a follow-up inspection of its compounding facility in August 2018 found insanitary conditions. The company recalled all unexpired drug products intended to be sterile on Sept. 10, 2018, and agreed to cease sterile operations until the problems were addressed. However, on Oct. 8, 2018, it resumed sterile operations and distributed purportedly sterile products without making adequate corrections at the facility. While the company agreed to cease sterile operations again on Nov. 9, 2018, it has not agreed to follow the FDA's recommendation to recall all unexpired drug products intended to be sterile.

A class I recall of Millennium Nuclear Medicine Systems by GE Healthcare due to an incident in which the top detector detached and fell onto the detector below it. The incident was deemed to be caused by an improperly functioning primary motion stopper and a missing mechanical stopper. No patient injuries were reported. The recall includes 996 imaging devices manufactured from Jan. 1, 1997, to July 1, 2012, and distributed from Jan. 1, 1997, to Sept. 1, 2018.

An expanded recall of TB Unshrouded Bipolar Pacing Leads by Oscor Inc. The recall was expanded to ensure proper disposition of expired units distributed between Dec. 21, 2011, and May 17, 2018.

A warning that rare but serious cases of stroke and tears in the lining of arteries in the head and neck have occurred in patients with multiple sclerosis shortly after they received alemtuzumab (Lemtrada). The FDA has received 13 reports of stroke or cervicocephalic arterial dissection that occurred shortly after the patient received the drug. In response, the FDA has added a new warning about these risks to the drug label and patient medication guide and has also added the risk of stroke to the existing boxed warning. The drug is also approved under the brand name Campath to treat B-cell chronic lymphocytic leukemia, and that drug's label will also be updated to include these risks. Clinicians should advise patients at every infusion of the drug to seek immediate emergency medical attention if they experience symptoms of ischemic or hemorrhagic stroke or cervicocephalic arterial dissection. Because early symptoms such as headache and neck pain are not specific, clinicians should promptly evaluate patients who report symptoms consistent with these conditions.

An alert not to use drug products intended to be sterile that were produced and distributed by Promise Pharmacy due to lack of sterility assurance. During an FDA inspection of the company's facility, investigators observed insanitary conditions, including poor sterile production practices and inadequate design of one of its processing rooms. The FDA has recommended that the company recall all unexpired drug products intended to be sterile and cease sterile operations until adequate corrections are made. While the company agreed to cease sterile operations in the inadequately designed processing room, it did not recall drug products it compounded in that room.

A warning that signs and symptoms of differentiation syndrome are not being recognized in patients with acute myeloid leukemia who are receiving enasidenib (Idhifa). While the drug's prescribing information and patient medication guide already contain a warning about the syndrome, the FDA is aware of cases that were not recognized and patients who did not receive the necessary treatment. Clinicians should describe the symptoms of differentiation syndrome to patients when starting the drug and at follow-up visits. The syndrome has occurred as early as 10 days and up to five months after starting the medicine. Consider a diagnosis of differentiation syndrome if patients experience unexplained respiratory distress or other symptoms, and treat promptly with oral or intravenous corticosteroids.


Rifamycin (Aemcolo) to treat adults with travelers' diarrhea. The oral antibacterial is indicated to treat cases of travelers' diarrhea caused by noninvasive strains of Escherichia coli that are not complicated by fever or blood in the stool. It is contraindicated in patients with a known hypersensitivity to the medication, its components, or any of the other antimicrobial agents in the class, such as rifaximin.

Compared to placebo, the drug significantly reduced symptoms in a randomized controlled trial of 264 adults with travelers' diarrhea in Guatemala and Mexico. Safety of the drug, taken orally for three to four days, was evaluated in two trials of 619 adults, and the most common side effects were headache and constipation.

Marketing of the PicoAMH Elisa diagnostic test to aid in the determination of a patient's menopausal status. The test, which measures the amount of anti-Müllerian hormone (AMH) in the blood, is meant to be used only in conjunction with other clinical assessments and laboratory findings. The FDA reviewed data from 690 women ages 42 to 62 years who participated in a multicenter, longitudinal study that showed the test performed reasonably well at determining AMH levels, identifying women who had their last menstrual period, and identifying women who were more than five years away from their last menstrual period.

Clinicians should carefully evaluate results from the test in the context of a full workup to ensure that contraceptives are not discontinued in women who have not yet reached menopause and that uterine bleeding due to endometrial cancer is not dismissed as a diagnosis. The test should not be used to assess fertility status or response to fertility treatments.

Primatene Mist to provide temporary relief for symptoms of mild, intermittent asthma. The drug, the only over-the-counter metered-dose inhaler, is approved only for patients who have been diagnosed with asthma by a clinician. The product is being reintroduced after it was taken off the market in 2011 because it contained chlorofluorocarbon propellants, which are known to deplete the ozone layer. The new version contains hydrofluoroalkane propellants, which are permitted under current international and U.S. law and are also used in prescription inhalers.

An oral formulation of sufentanil (Dsuvia). The drug, a more potent form of fentanyl, has been approved for intravenous and epidural use since 1984. The new sublingual formulation is delivered through a disposable, prefilled single-dose applicator and is restricted to use in certified medically supervised health care settings (e.g., hospitals, surgical centers, emergency departments) for administration by a health care professional. It cannot be dispensed to patients for home use and should not be used for more than 72 hours. The drug is intended for use in patients who do not tolerate or are not expected to tolerate alternative pain treatment options, or where existing treatments have not provided or are not expected to provide adequate analgesia. A Risk Evaluation and Mitigation Strategy accompanies the drug and will tightly control its distribution and use. Boxed warnings and common side effects are the same as with other opioids.

Glasdegib tablets (Daurismo) to treat newly diagnosed acute myeloid leukemia in adults ages 75 years and older who have comorbidities that may preclude the use of intensive chemotherapy. The drug is approved to be used in combination with low-dose cytarabine.

In a randomized clinical trial of 111 adults, the median overall survival was 8.3 months for patients treated with both therapies compared with 4.3 months for patients treated with low-dose cytarabine alone. Common side effects include anemia, fatigue, hemorrhage, febrile neutropenia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

Larotrectinib (Vitrakvi) to treat adult and pediatric patients who have solid tumors that have a neurotrophic receptor tyrosine kinase gene fusion without a known acquired resistance mutation, who have metastatic disease, or in whom surgical resection is likely to result in severe morbidity. In three clinical trials of 55 patients, the orphan drug demonstrated a 75% overall response rate across different types of solid tumors, with 73% of responses lasting at least six months and 39% lasting a year or more. Examples of tumor types that responded to the drug include soft-tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer, and lung cancer. Side effects include fatigue, nausea, cough, constipation, diarrhea, dizziness, vomiting, and increased aminotransferase levels.

The DPP Ebola Antigen System to detect Ebola virus. While the test is the second Ebola rapid-antigen fingerstick test made available under emergency use authorization, it is the first to use a portable battery-operated reader to help provide clear diagnostic results outside of laboratories and in areas where patients are likely to be treated.

Brentuximab vedotin injection (Adcetris) in combination with chemotherapy for adults with certain types of peripheral T-cell lymphoma. The monoclonal antibody is approved to treat previously untreated systemic anaplastic large-cell lymphoma and other CD30-expressing peripheral T-cell lymphomas in combination with chemotherapy. The expanded approval was based on a trial of 452 patients, in which overall survival, progression-free survival, and overall response rates were significantly better in patients who received the drug plus chemotherapy compared to those who received standard chemotherapy. Side effects include peripheral neuropathy, nausea and vomiting, diarrhea, low white blood cell counts, fatigue, mouth sores, constipation, hair loss, fever, and anemia.

Marketing (with special controls) of the 23andMe Personal Genome Service Pharmacogenetic Reports test for providing information about genetic variants that may be associated with a patient's ability to metabolize some medicines. The direct-to-consumer test is authorized to detect 33 variants for multiple genes and is indicated to help inform discussions with a clinician. After DNA from a self-collected saliva sample are analyzed, the test generates a report describing what the results might mean, what the test does not do, and how to interpret results. The FDA determined that the company showed that the test is accurate and can provide reproducible results. Clinicians should not use test results to make treatment decisions; rather, results should be confirmed with independent pharmacogentic testing before making any medical decisions. The test labeling clarifies that the test is not intended to provide information on a patient's ability to respond to any specific medication and that it should not be used to make any treatment decisions without additional testing.

Marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy and parathyroidectomy. The Fluobeam 800 Clinic Imaging Device and the Parathyroid Detection PTeye System are intended to assist, not replace, experienced visual assessment in identifying the parathyroid tissue along with a biopsy to confirm thyroid tissue. They are only to be used to assist the surgeon in locating potential parathyroid tissue or glands, not in confirming the absence of parathyroid tissue or glands.

Emapalumab-lzsg (Gamifant) to treat pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy. The drug is the first specifically approved for HLH. In a study of 27 pediatric patients, 63% responded to the treatment and 70% were able to proceed to stem cell transplant. Side effects include infections, hypertension, infusion-related reactions, low potassium, and fever.

A mobile medical application to help increase retention in an outpatient treatment program for individuals with opioid use disorder. The reSET-O app, a prescription cognitive behavioral therapy, is intended to be used in addition to outpatient treatment under the care of a health care professional in conjunction with treatment that includes buprenorphine and contingency management. It may be downloaded directly to a patient's mobile device after he or she receives a prescription to do so from a doctor.

In a 12-week clinical trial of 170 patients treated with buprenorphine and a behavior therapy program, with or without a desktop version of the app, those who used the app had a significant increase in retention in their treatment program compared to those who did not. However, the app was not shown to decrease illicit drug use or improve abstinence. It is not intended to be used as a standalone therapy, as a substitute for medication, or for patients whose primary language is not English. The app was not associated with side effects.

First-time generic approvals

Adapalene and benzoyl peroxide gel (0.3%/2.5%) for the topical treatment of acne vulgaris. (Brand name: Epiduo Forte)

Naproxen sodium and diphenhydramine hydrochloride tablets (220 mg/25 mg, over-the-counter) to relieve occasional sleeplessness when associated with minor aches and pains. (Brand name: Aleve PM)

Abiraterone acetate tablets (250 mg) to treat patients with metastatic castration-resistant prostate cancer. (Brand name: Zytiga)

Clobazam tablets (10 mg, 20 mg) and oral suspension (2.5 mg/mL) for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients ages 2 and older. (Brand name: Onfi)

Vardenafil hydrochloride orally disintegrating tablets (10 mg) to treat erectile dysfunction. (Brand name: Staxyn)

Azelaic acid gel (15%) for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. (Brand name: Finacea)

Docosanol cream (10%, over-the-counter) to treat cold sores/fever blisters on the face or lips, shortening healing time and duration of symptoms. (Brand name: Abreva)

Dyclonine hydrochloride topical solution (0.5%, 1%) for anesthetizing accessible mucous membranes (e.g., the mouth, pharynx, larynx, trachea, esophagus, and urethra) prior to various endoscopic procedures. (Brand name: Dyclone)

Buprenorphine transdermal system (5 mcg/hour, 10 mcg/hour, 15 mcg/hour, 20 mcg/hour) to manage pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (Brand name: Butrans)

Oxycodone hydrochloride and acetaminophen oral solution (10 mg/300 mg per 5 mL) to manage pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (Brand name: Roxicet)

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