Zolpidem dose for women lowered, diabetes drug approved

This regulatory update covers warnings to lower zolpidem doses in women and approvals for a new drug to improve blood glucose control in adults with type 2 diabetes.

Recalls, warnings and label changes

A reduction in the recommended dose of zolpidem (Ambien, Ambien CR, Edluar, Zolpimist) for women from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products because of data showing blood levels the morning after use can be high enough to impair activities.


A safety communication and updated recommendations on metal-on-metal hip implants, describing how metal release from the implants may damage bone and/or soft tissue surrounding the implant and/or cause symptoms or illnesses elsewhere in the body. Symptoms of systemic problems from metal release, for which physicians should be alert, include general hypersensitivity reaction, cardiomyopathy, neurological changes, psychological status change, renal function impairment and thyroid dysfunction.

A warning on tolvaptan (Samsca) about risk of liver injury. In a trial of about 1,400 patients, three developed significant increases in serum alanine aminotransferase and serum total bilirubin. Clinicians should perform liver tests promptly in patients taking the drug who report symptoms of liver injury. If hepatic injury is suspected, the drug should be promptly discontinued, appropriate treatment instituted, and investigations performed to determine the cause of symptoms.

A recall of two lots of mitomycin kits (Mitosol), 0.2 mg/vial, because the affected lots may be non-sterile.

A recall of one lot of Hospira Inc.'s Lactated Ringers and 5% Dextrose injection, USP, 1,000 mL, due to one confirmed customer report that a spore-like structured particulate, consistent with mold, was noted in the solution. No adverse events have been reported, but if contaminated solution is used on a patient, this may cause thrombosis, phlebitis, bacteremia, sepsis, septic shock and/or endocarditis, or result in a fatal infection.

A class I recall of Vycor Viewsite Brain Access System because an unidentified black fiber was found on the device. This product may cause serious adverse health consequences, including death.


Alogliptin (Nesina) and two new combination drugs (alogliptin and metformin hydrochloride [Kazano] and alogliptin and pioglitazone [Oseni]) to improve blood sugar control in adults with type 2 diabetes, along with diet and exercise. Alogliptin was demonstrated safe and effective in clinical trials of about 8,500 patients in which it reduced hemoglobin A1c (HbA1c) by 0.4% to 0.6% compared with placebo after 26 weeks of use. The combination of alogliptin/metformin reduced HbA1c 1.1% more than alogliptin alone and 0.5% more than metformin alone after 26 weeks. The alogliptin/pioglitazone combination reduced HbA1c 0.4% to 0.9% more than alogliptin monotherapy and 0.4% to 0.6% more than pioglitazone monotherapy. The FDA is requiring five postmarketing studies: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for liver abnormalities, serious cases of pancreatitis and severe hypersensitivity reactions; and three pediatric studies. The most common side effects are stuffy or runny nose, headache, and upper respiratory tract infection.

A new indication for apixaban (Eliquis), to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation that is not caused by a heart valve problem. Safety and efficacy in patients with atrial fibrillation not caused by cardiac valve disease were studied in a clinical trial of more than 18,000 patients in which patients taking apixaban had fewer strokes than those who took warfarin. Bleeding, including life-threatening and fatal bleeding, is the most serious risk. There is no agent that can reverse the anticoagulant effect and the drug is not approved for patients with prosthetic heart valves.

A new indication for onabotulinumtoxinA (Botox) to treat adults with overactive bladder who cannot use or do not adequately respond to anticholinergics. Safety and effectiveness were established in trials in which patients received bladder muscle injections of 100 units (20 injections of 5 units each) or placebo. Treated patients experienced urinary incontinence 1.6 to 1.9 times less per day than patients on placebo and needed to urinate 1.0 to 1.7 times less per day. Treatment can be repeated when the benefits from the previous treatment have decreased, but there should be at least 12 weeks between treatments. Common side effects included urinary tract infections, painful urination and urinary retention. Treated patients should not have a urinary tract infection and should take antibiotics before, during and for a few days after injections to lower the chance of developing an infection.

Over-the-counter approval of oxybutynin (Oxytrol for Women) to treat overactive bladder in women ages 18 years and older. The drug, a patch that is applied to the skin every four days, will remain available for men with overactive bladder by prescription only.

Flublok, the first trivalent influenza vaccine made using an insect virus (baculovirus) expression system and recombinant DNA technology. The vaccine does not use the influenza virus or eggs and is approved for the prevention of seasonal influenza in people ages 18 through 49. In a trial of 2,300 patients, the vaccine was about 44.6% percent effective against all circulating influenza strains, not just the strains included in the vaccine. The most commonly reported adverse events included pain at injection site, headache, fatigue and muscle aches. The vaccine has a shelf life of 16 weeks.

xTAG Gastrointestinal Pathogen Panel, the first test that can simultaneously identify 11 causes of infectious gastroenteritis from a single sample. The accuracy of the test was assessed by comparing the panel's results to individual tests known to separately and reliably detect the 11 viruses, bacteria or parasites in 1,400 patients. Results were comparable. Due to the risk of false positives, all positive results from the new panel need to be confirmed by additional testing.

Octaplas, a pooled plasma blood product for the replacement of coagulation factors in certain medical conditions where patients have insufficient levels. It is a sterile, frozen solution of pooled human plasma from several donors that has been treated with a solvent detergent process, an alternative to single-donor fresh frozen plasma. It should be matched to the recipient's blood group and has been used extensively in Europe. Approval was primarily based on studies in patients with liver disease, liver transplant, heart surgery and thrombotic thrombocytopenic purpura.

A new indication for deferasirox (Exjade) to treat patients ages 10 years and older who have chronic iron overload resulting from non-transfusion-dependent thalassemia (NTDT). The drug was previously approved for treatment of chronic iron overload due to blood transfusions. It should be used in patients with NTDT who have a liver iron concentration (LIC) of at least 5 mg of iron per gram of dry liver tissue weight. In clinical trials of 5 mg/kg and 10 mg/kg doses, 15% and 27% of patients achieved target LIC, respectively, compared with 4% of placebo-treated patients. The FDA is also authorizing marketing of FerriScan as an imaging companion diagnostic for the drug.

Mipomersen sodium (Kynamro) injection as an addition to lipid-lowering medications and diet to treat homozygous familial hypercholesterolemia. In a clinical trial of 51 patients, levels of low-density lipoprotein cholesterol fell by about 25% during the first 26 weeks of treatment. The drug carries a boxed warning on the risk of liver toxicity and was approved with a Risk Evaluation and Mitigation Strategy, including a required prescription authorization form for each new prescription. The most common adverse reactions included injection site reactions, flu-like symptoms, nausea, headache and elevations in serum aminotransferase levels. The FDA is requiring four postmarketing studies.

Glycerol phenylbutyrate (Ravicti) for the chronic management of some urea cycle disorders (UCDs). The drug, a liquid taken three times a day with meals, is intended for patients whose UCD cannot be managed by a protein-restricted diet or amino acid supplements alone. It must be used with a protein-restricted diet and, in some cases, supplements. In a trial of 44 adults, effectiveness was comparable to another drug approved to control UCDs. The most common side effects include diarrhea, flatulence and headache.

A generic version of doxorubicin hydrochloride liposome (Doxil), under a priority review system to expedite the review of generic applications to help alleviate shortages.

Pomalidomide (Pomalyst) to treat patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease is relapsed and refractory. In a clinical trial, 7.4% of patients had their cancer completely or partially disappear after treatment with the drug. The median duration of response has not yet been reached in these patients. In patients treated with the drug plus low-dose dexamethasone, 29.2% achieved that result with a 7.4-month median duration of response. The drug carries a boxed warning that it should not be used in pregnant women because it can cause severe life-threatening birth defects, and that it can cause blood clots.

A new indication for imatinib (Gleevec) to treat children newly diagnosed with Philadelphia chromosome- positive acute lymphoblastic leukemia. In a trial, patient deaths decreased with increasing duration of imatinib treatment in combination with chemotherapy. The most common side effects included decreased levels of neutrophils, decreased levels of blood platelets, liver toxicity and infection.