New warnings added on multiple diabetes drugs

This update also covers a risk evaluation and mitigation strategy for liraglutide and approval of a new PCSK9 inhibitor.

Recalls and warnings

A recall of all nonexpired drug products produced for sterile use by Medistat RX because of possible contamination. Recalled products were distributed between Nov. 1, 2014, and Sept. 3, 2015. There have been reports of several adverse events that may be associated with these drug products, and, after inspections raised concerns about the facility's ability to assure sterility, it voluntarily ceased sterile compounding operations on Sept. 1.

Image by iStock
Image by iStock

An expanded warning on compounded or repackaged drugs stored in Becton-Dickinson (BD) general-use syringes. Syringes of 1 mL, 10 mL, 20 mL, and 30 mL as well as oral syringes were added to the 3-mL and 5-mL varieties based on reports that an interaction with the rubber stopper can cause some drugs stored therein to lose potency if filled and not used immediately. The manufacturer reports that the following drugs can be affected by the stoppers, although the FDA does not know whether other drugs may be affected: fentanyl, rocuronium, neostigmine, morphine, midazolam, methadone, atropine, hydromorphone, cisatracurium, and remifentanil.

A recall of certain lots of the OmniPod Insulin Management System by Insulet Corporation because of the possibility that some pods may have a failure rate higher than current manufacturing standards. The cannulas in affected pods may either completely retract or fail to fully deploy, which may cause the patient not to receive the expected insulin dose, or the pod may trigger an audible alarm indicating it will no longer deliver insulin and must be replaced. The recall is of 40,846 boxes, distributed from December 2013 to March 2015.

A warning that dipeptidyl peptidase-4 (DPP-4) inhibitors may cause joint pain that can be severe and disabling. The FDA has added new warning and precaution labels about this risk for all medicines in this drug class, including sitagliptin, saxagliptin, linagliptin, and alogliptin and recommends that clinicians should consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue the drug if appropriate.

A strengthened warning on canagliflozin (Invokana, Invokamet) about increased risk of bone fractures and decreased bone mineral density. Clinicians should consider factors that contribute to fracture risk prior to starting patients on canagliflozin, which has also been linked to decreases in bone mineral density at the hip and lower spine. The FDA continues to evaluate the risk of bone fractures with other sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, to determine if additional label changes or studies are needed.

A risk evaluation and mitigation strategy (REMS) launched for liraglutide (Victoza) about risk of acute pancreatitis and medullary thyroid carcinoma (MTC). Physicians should educate patients regarding the risk of MTC and symptoms of thyroid tumors. Patients found incidentally to have thyroid nodules or elevated serum calcitonin should be referred to an endocrinologist. Physicians should observe patients carefully for signs and symptoms of pancreatitis after initiating or increasing the dose of the drug and discontinue the drug if pancreatitis is suspected.

Revised prescribing information and creation of a REMS program regarding clozapine's risk of severe neutropenia. Under the new program, neutropenia will be monitored by the absolute neutrophil count (ANC) only, and the requirements for ANC are being modified so that patients will be able to continue treatment with a lower ANC. Patients with benign ethnic neutropenia may also now be eligible for treatment.


Evolocumab (Repatha) injection for patients with high cholesterol who are unable to get their LDL cholesterol under control with current treatment options. The second drug approved in a new class of drugs called PCSK9 inhibitors, it is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. In clinical trials, participants taking evolocumab had an average reduction in LDL cholesterol of about 60% compared to placebo. The most common side effects include nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising where the injection is given.

Rolapitant (Varubi) to prevent delayed-phase chemotherapy-induced emesis. The tablet form is approved in adults in combination with other antiemetic drugs that prevent nausea and vomiting associated with initial and repeat courses of chemotherapy. In 3 trials, patients taking rolapitant in combination with granisetron and dexamethasone had a greater reduction in vomiting and use of rescue medication for nausea and vomiting compared to those receiving placebo, granisetron, and dexamethasone. It is contraindicated with the use of thioridazine, and the most common side effects include neutropenia, hiccups, decreased appetite, and dizziness.

Cariprazine (Vraylar) capsules to treat schizophrenia and bipolar disorder in adults. In 3 clinical trials, it reduced the symptoms of schizophrenia compared to placebo, and the most common side effects were extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements. In 3 other trials, the drug reduced symptoms of bipolar disorder in participants, and the most common side effects were extrapyramidal symptoms, the urge to move, indigestion, vomiting, drowsiness, and restlessness. Cariprazine and all other FDA-approved drugs used to treat schizophrenia and bipolar disorder have a boxed warning about the increased risk of death associated with their use in older people with dementia-related psychosis. No drugs in this class are approved to treat such patients.