Large valsartan recall, new warnings for fluoroquinolones

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

Recalls and warnings

A recall of several drug products containing valsartan due to an impurity, N-nitrosodimethylamine (NDMA), detected in products manufactured by Zhejiang Huahai Pharmaceuticals in China. NDMA is classified as a probable human carcinogen. Companies that have recalled valsartan-containing products include Major Pharmaceuticals, Teva Pharmaceuticals Industries Ltd., and Solco Healthcare. Some levels of the impurity may have been in affected products for as long as four years. Patients taking recalled medicines should continue taking their medicine until they obtain a replacement product. The FDA recommends using valsartan-containing medicines unaffected by the recall or considering other available treatment options.

Image by Thinkstock
Image by Thinkstock

Strengthened warnings added to fluoroquinolone drug labels that the antibiotics may cause significant decreases in blood glucose levels and certain mental health side effects. Most fluoroquinolone drug labels include a warning about blood glucose disturbances, and the mental health side effects described differ by individual drug. The new label changes will add that hypoglycemia can lead to coma and make the mental health side effects more prominent and more consistent across the drug class. The mental health side effects that will be added or updated include disturbances in attention, disorientation, agitation, nervousness, memory impairment, and delirium.

A recall of two lots of naloxone hydrochloride injection USP (0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject single-use cartridge syringe system) due to the potential presence of embedded and loose particulate matter on the syringe plunger. Affected lots were distributed from February 2017 to February 2018.

Warning letters sent to three marketers and distributors of kratom products for illegally selling unapproved products with unproven claims about their ability to help treat opioid addiction and withdrawal. The FDA continues to warn against using kratom (Mitragyna speciose) out of concern that the plant, which affects the same opioid receptors as morphine, may expose users to the risks of addiction.

A warning not to use drug products intended to be sterile produced and distributed by Ranier's Compounding Laboratory (also doing business as Ranier's Pharmacy and Ranier's RX Laboratory) due to lack of sterility assurance. An FDA inspection of the compounding facility found insanitary conditions, including poor sterile production practices. The company has agreed to recall all products intended to be sterile and cease sterile operations.

A warning not to use any Monsel's solution (ferric subsulfate 20%) manufactured by BioDiagnostics International because the product was made under poor conditions. During an FDA inspection, investigators found insanitary conditions and manufacturing practices that could result in contamination and decreased quality of the product. While the manufacturer has recalled all lots of the solution, drug products distributed by MedGyn Products, Inc. may remain on the market and should not be used.

A class I recall of the HeartWare Ventricular Assist System by Medtronic due to the possibility of interruption in the electrical connection between the system's power source and its controller. The recall includes 204,017 devices manufactured and distributed between March 2006 and May 2018.

A class I recall of all lots of the Cardiosave Hybrid Intra-aortic Balloon Pump by Maquet Datascope Corp. due to a design issue that allows fluid to seep into the device. Affected products were manufactured between Dec. 12, 2011, and April 25, 2018, and distributed from March 6, 2012, to April 26, 2018.

A class I recall of all lots of the HeartMate 3 Left Ventricular Assist System by Abbott due to a malfunction that may cause occlusion of the outflow graft, potentially reducing or stopping pump flow. The recall includes 4,878 devices distributed from Sept. 2, 2014, to the present.


A manufacturer decision to halt sales of the Essure permanent birth control device. The device, manufactured by Bayer, will no longer be sold or distributed after Dec. 31, 2018. In April, the FDA had issued an order restricting sale and distribution of the device due to reports of serious adverse events associated with its use. The company's decision was due to commercial reasons, as the FDA's addition of a boxed warning and patient decision checklist to the labeling was associated with about a 70% decline in U.S. sales of the device.

A notice that the FDA is evaluating the potential risk of neural tube birth defects involving the brain, spine, and spinal cord in babies born to women with HIV treated with dolutegravir (Juluca, Tivicay, Triumeq). Preliminary data suggest that women who received the drug at the time of becoming pregnant or early in the first trimester appear to have a higher risk for these defects. Clinicians should weigh the benefits and risks of dolutegravir when prescribing antiretroviral agents to women of childbearing age.


The Eversense Continuous Glucose Monitoring system, the first to include a fully implantable glucose sensor, for adults with diabetes. The sensor can be worn for up to 90 days. In clinical studies, fewer than 1% of participants experienced a serious adverse event with the implanted sensor. Potential adverse effects associated with insertion, removal, and wear of the sensor include allergic reaction to adhesives, bleeding, bruising, infection, pain or discomfort, scarring or skin discoloration, sensor fracture during removal, skin inflammation, thinning, discoloration, and redness. Other risks associated with use of the device include hypoglycemia or hyperglycemia if information provided by the device is inaccurate or alerts are missed.

Erenumab-aooe (Aimovig) for the preventive treatment of migraine in adults. The treatment, which is given once per month by self-injection, is the first in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule involved in migraine attacks. In clinical trials, patients who received the treatment had an average of one to two fewer migraine days per month than those taking placebo. The most common side effects were injection-site reactions and constipation.

Cannabidiol (Epidiolex) oral solution to treat seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients ages 2 years and older. The drug is the first FDA-approved treatment that contains a purified drug substance derived from marijuana, a Schedule I substance. It is also the first approved drug to treat Dravet syndrome. In randomized, double-blind clinical trials, the orphan drug, taken along with other medications, reduced the frequency of seizures compared to placebo. The most common side effects were sleepiness, sedation, lethargy, elevated liver enzymes, decreased appetite, diarrhea, rash, fatigue, malaise, weakness, insomnia, sleep disorder, poor quality sleep, and infections. More serious risks include suicidal ideation, feelings of agitation, new or worsening depression, aggression, and panic attacks. The drug can also cause liver injury, which is generally mild.

A new indication for tofacitinib (Xeljanz) to treat adults with moderately to severely active ulcerative colitis. The drug is the first oral medication to be approved for chronic use in this population. In placebo-controlled trials, 10 mg of tofacitinib given twice daily induced remission in 17% to 18% of patients at eight weeks. In a trial of patients who achieved a clinical response by week eight, the drug was effective in inducing remission after 52 weeks in 34% of those who received 5 mg twice daily and 41% of those who received 10 mg twice daily. Among patients who achieved remission after eight weeks of treatment, 5-mg and 10-mg doses led to sustained corticosteroid-free remission in 35% and 47%, respectively. The most common adverse events are diarrhea, elevated cholesterol levels, headache, herpes zoster, increased blood creatine phosphokinase levels, nasopharyngitis, rash, and upper respiratory tract infection. A boxed warning notes the potential for malignancy and serious infections (e.g., opportunistic infections). The drug was approved in 2012 to treat rheumatoid arthritis and in 2017 to treat psoriatic arthritis.

The Zephyr Endobronchial Valve to treat patients with breathing difficulties associated with severe emphysema. During a procedure in a hospital setting, a physician uses a flexible bronchoscope to place the valves, which are about the size of pencil erasers, into diseased areas of the lung airways. The device is designed to prevent inhaled air from entering damaged parts of the lungs and, during exhalation, allow trapped air and fluids to escape. In a multicenter study of patients with severe emphysema, 128 participants were treated with the device and guideline-concordant medical management while 62 control patients received medical management only. At one year, 47.7% of patients treated with the device had a 15% or greater improvement in pulmonary function scores, compared to 16.8% of control patients. Adverse events in the study included death, pneumothorax, pneumonia, worsening of emphysema, coughing up blood, shortness of breath, and chest pain. The device is contraindicated in patients with active lung infections, active smokers, patients unable to tolerate bronchoscopy, and those allergic to nitinol, nickel, titanium, or silicone.

Avatrombopag (Doptelet) tablets to treat adults with chronic liver disease who have thrombocytopenia and are scheduled to have a medical or dental procedure. The medication is the first to be approved by the FDA for this indication. The drug, which received priority review, was studied in two trials of 435 patients with chronic liver disease and severe thrombocytopenia who were about to have a procedure that would typically require platelet transfusion. Compared to participants who received placebo, a higher proportion of those who received oral avatrombopag for five days had increased platelet counts and did not need platelet transfusion or any rescue therapy on the day of the procedure and up to seven days later. The most common side effects of the drug were fever, abdominal pain, nausea, headache, fatigue, and edema. The drug may also increase the risk of blood clots in people with chronic liver disease or certain blood clotting conditions.

Epoetin alfa-epbx (Retacrit) to treat anemia caused by chronic kidney disease, chemotherapy, or use of zidovudine in patients with HIV infection. The drug, a biosimilar to epoetin alfa (Epogen/Procrit), is approved for use before or after surgery to reduce the potential need for red blood cell transfusions due to blood loss during surgery. Common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, medical device malfunction, blood vessel blockage, respiratory infection, and others.

Marketing of two catheter-based devices designed to create vascular access in patients with chronic kidney disease who need hemodialysis. The Ellipsys Vascular Access System and the everlinQ endoAVF System are now authorized to create arteriovenous fistulas for patients who need hemodialysis access.

The CustomFlex Artificial Iris, the first standalone prosthetic iris in the U.S. The surgically implanted device is indicated to treat people whose iris is completely missing or damaged due to a congenital condition called aniridia or other damage to the eye. It is made of thin, foldable medical-grade silicone and is custom-sized and colored for each patient. In a clinical trial, more than 70% of patients reported significant decreases in light sensitivity and glare and an improvement in health-related quality of life after the procedure, and 94% of patients were satisfied with the artificial iris' appearance. Potential complications include device movement or dislocation, strands of device fiber in the eye, increased intraocular pressure, iritis, synechiae, and the need for secondary surgery to reposition, remove, or replace the device.

Pegfilgrastim-jmdb (Fulphila) to decrease the chance of infection as suggested by febrile neutropenia in patients with nonmyeloid cancer who are receiving myelosuppressive chemotherapy that has a clinically significant incidence of febrile neutropenia. The drug is the first biosimilar to pegfilgrastim (Neulasta). Common side effects include bone pain and pain in extremities.

First-time generic approvals

Buprenorphine and naloxone sublingual film (2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg) to treat opioid dependence. (Brand name: Suboxone)

Tadalafil tablets USP (2.5 mg, 5 mg, 10 mg, and 20 mg) to treat erectile dysfunction and/or the signs and symptoms of benign prostatic hyperplasia. (Brand name: Cialis)

Budesonide extended-release tablets (9 mg) to induce remission in patients with active, mild-to-moderate ulcerative colitis. (Brand name: Uceris)

Colesevelam hydrochloride tablets (625 mg) as an adjunct to diet and exercise to reduce LDL cholesterol levels in adults with primary hyperlipidemia as monotherapy or in combination with a statin and to reduce LDL cholesterol levels in boys and postmenarchal girls, ages 10 to 17 years, with heterozygous familial hypercholesterolemia as monotherapy or in combination with a statin after no response to an adequate trial of diet therapy. (Brand name: Welchol)

Oxybutynin chloride gel (10%), a muscarinic antagonist indicated to treat overactive bladder with symptoms of urinary incontinence, urgency, and frequency. (Brand name: Gelnique)

Hydromorphone hydrochloride injection USP (2 mg/mL single-dose vials) to manage pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. (Brand name: Dilaudid)

Ertapenem for injection (1 g [base] in single-dose vials), an antibacterial indicated in adults for the prophylaxis of surgical-site infection following elective colorectal surgery and in patients ages 3 months and older to treat certain moderate to severe infections caused by susceptible bacteria. (Brand name: Invanz)

Loratadine chewable tablets USP (5 mg [OTC]) for seasonal allergic rhinitis and idiopathic urticaria. (Brand name: Children's Claritin)

Phenylephrine hydrochloride injection USP (50 mg/5 mL [10 mg/mL] and 100 mg/10 mL [10 mg/mL]; single-dose vials) to treat clinically important hypotension resulting primarily from vasodilation in septic shock or anesthesia. (Brand name: Vazculep)

Succinylcholine chloride injection USP (200 mg/10 mL [20 mg/mL]; multiple-dose vials) to serve as an adjunct to general anesthesia, to facilitate tracheal intubation, or to provide skeletal muscle relaxation during surgery or mechanical ventilation. (Brand name: Quelicin)

Phytonadione tablets USP (5 mg) to treat anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives, hypoprothrombinemia secondary to antibacterial therapy, hypoprothrombinemia secondary to administration of salicylates, and hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas in combination with bile salts. (Brand name: Mephyton)

Methylphenidate hydrochloride for extended-release oral suspension (300 mg/60 mL total volume, 600 mg/120 mL total volume, 750 mg/150 mL total volume, and 900 mg/180 mL total volume [5 mg/mL]), a central nervous system stimulant indicated to treat attention deficit hyperactivity disorder. (Brand name: Quillivant XR)

Everolimus tablets (0.25 mg, 0.5 mg, and 0.75 mg) for organ rejection prophylaxis in renal transplant patients with low to moderate immunologic risk, in combination with basiliximab induction and reduced doses of cyclosporine and corticosteroids. (Brand name: Zortress)

Miglustat capsules (100 mg), a glucosylceramide synthase inhibitor indicated as monotherapy in adults with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. (Brand name: Zavesca)

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