FDA Puts 16 Drugs on Watch List

April 17, 2012

April 17, 2012 — The US Food and Drug Administration (FDA) today issued its latest quarterly list of drugs to monitor after having identified potential signs of serious risks or new safety information in the agency's Adverse Event Reporting System (AERS) database during the last 3 months of 2011.

The 16 drugs on the list include milnacipran (Savella, Forest Pharmaceuticals), a drug for managing fibromyalgia, with a potential safety issue of homicidal ideation as identified through AERS. A similar concern put milnacipran in the news in 2010 when the consumer watchdog group Public Citizen asked the FDA — to no avail — to ban the drug on account of adverse events such as suicidal ideation.

The appearance of any drug on the AERS watch list, however, does not mean that the FDA has concluded that the drug actually poses the health risk reported through AERS, the FDA cautioned. It means only that the agency will study these drugs to determine whether there is a causal link. If the FDA establishes this link, it then would consider a regulatory response, such as gathering more information to better characterize the risk, revising the drug's label, or requiring a risk evaluation and mitigation strategy.

Likewise, the FDA said that it is not suggesting that clinicians should stop prescribing any drugs on the watch list, or that patients should stop taking them. It advises patients with questions about watch-list drugs to discuss them with their clinician.

Potential Signals of Serious Risks/New Safety Information Identified by AERS, October to December 2011

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Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (as of February 15, 2012)*
Bortezomib (Velcade, Takeda) Death from intrathecal administration (medication error) The Dosage and Administration and Contraindications sections of the labeling for bortezomib were updated January 2012 to include fatal events with intrathecal administration.
Brentuximab vedotin (Adcetris, Seattle Genetics) Progressive multifocal leukoencephalopathy (PML) The Boxed Warning and Warnings and Precautions sections of the labeling for brentuximab were updated January 2012 to include PML.
Fluoroquinolone products Peripheral sensorimotor neuropathy FDA is continuing to evaluate this issue to determine whether the current labeling, which contains information about peripheral sensorimotor neuropathy, is adequate.
Gabapentin HCl (Neurontin, Pfizer) Increase in blood creatine phosphokinase levels and rhabdomyolysis  
Gadolinium-based contrast agents products Acute kidney injury FDA is continuing to evaluate this issue to determine whether the current labeling, which contains information about kidney injury, is adequate.
Iloprost inhalation solution (Ventavis, Actelion Pharmaceuticals) Hemoptysis  
Loperamide HCl–containing products (Imodium, McNeal Consumer Healthcare) Pancreatitis  
Magnesium sulfate for injection Fetal skeletal demineralization, hypermagnesemia, and other bone abnormalities with continuous long-term use in pregnant women 
Milnacipran HCl (Savella, Forest Pharmaceuticals) Homicidal ideation  
Pegloticase (Krystexxa, Savient Pharmaceuticals) Anaphylaxis and infusion reactions  
Phenytoin (Dilantin, Pfizer) and nondepolarizing neuromuscular blocking agents Drug interactions resulting in decreased effectiveness of the nondepolarizing neuromuscular blocking agent  
Polyethylene glycol 3350 over-the-counter oral laxative (Miralax, MSD Consumer Care) Neuropsychiatric events FDA decided that no action is necessary at this time on the basis of available information.
Proton-pump inhibitor over-the-counter (OTC) products Clostridium difficile-associated diarrhea  
Rubidium Rb82 generator (CardioGen-82, Bracco Diagnostics) Unintended radiation exposure to strontium isotopes after myocardial imaging Rubidium Rb82 generator was voluntarily recalled by the manufacturer in July 2011; a return to the US market is planned. The Boxed Warning, Dosage and Administration, and Warnings and Precautions sections of the labeling for rubidium Rb82 generator were updated February 2012 to include information about unintended radiation exposure.
Sorafenib tosylate (Nexavar, Onyx Pharmaceuticals) Osteonecrosis of the jaw  
Telaprevir (Incivek, Vertex Pharmaceuticals) Serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS)  

*Unless otherwise noted, the FDA is continuing to evaluate these issues to determine the need for any regulatory action.

Of 8 Drugs on Third-Quarter 2011 List, 5 Underwent Label Changes

The FDA's watch list covering July through September 2011 was shorter than the list for the last quarter of that year, containing only 8 drugs or drug classes. Since September 2011, 5 of those 8 drugs have undergone label changes involving the safety issues that surfaced in AERS.

For example, the FDA revised the label of dabigatran etexilate (Pradaxa, Boehringer Ingelheim), an anticoagulant, to recommend that clinicians assess renal function before and during therapy — and adjust the dose accordingly — because the drug's anticoagulant activity and half-life increase in patients with renal impairment. The label change followed postmarketing reports of fatal bleeding events.

Potential Signals of Serious Risks/New Safety Information Identified by AERS, July to September 2011

Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (as of February 15, 2012)*

Adalimumab (Humira, Abbot Laboratories)

Golimumab (Simponi, Janssen Biotech)

Optic neuritis The Warnings and Precautions section of the labeling for adalimumab and golimumab was updated December 2011 to include optic neuritis.
Clevidipine butyrate intravenous emulsion (Cleviprex, The Medicines Company) Hypoxemia (decreased oxygen saturation) The Adverse Reactions section of the labeling for clevidipine butyrate intravenous emulsion was updated December 2011 to include decreased oxygen saturation.
Dabigatran etexilate mesylate (Pradaxa, Boehringer Ingelheim) Bleeding events, including hemorrhage with fatal outcome

The Dosage and Administration section of the labeling for dabigatran was updated January 2012 to include information about monitoring renal function in patients taking dabigatran and adjusting dose if necessary because dabigatran's anticoagulant activity and half-life are increased in patients with renal impairment.

FDA is continuing to evaluate this issue to determine the need for any further regulatory action.

Diazepam injection (Valium) Propylene glycol toxicity  
Infliximab (Remicade, Janssen Biotech) Sarcoidosis The Adverse Reactions section of the labeling for infliximab was updated October 2011 to include sarcoidosis.
Topical analgesic nonprescription monograph products containing menthol, methyl salicylate, and capsaicin Application site burns FDA is continuing to evaluate this issue to determine whether the current labeling for the monograph products is adequate.
Orlistat (Alli, GlaxoSmithKline) Kidney stones

FDA is continuing to evaluate this issue to determine whether the current labeling for orlistat, which includes kidney stones, is adequate to address other kidney-related adverse events.

The Warnings and Precautions and Adverse Reactions sections of the labeling for Xenica (the prescription orlistat product) were updated January 2012 to include increases in urinary oxalate.

The European Medicines Agency is also evaluating orlistat for this potential risk.

Valproate products: valproic acid, divalproex sodium, valproate sodium Liver failure and injury (involving hereditary mitochondrial disorders, such as Alpers-Huttenlocher syndrome and other conditions)  

*Unless otherwise noted, the FDA is continuing to evaluate these issues to determine the need for any regulatory action.

More information on these watch-list drugs from the second half of 2011 and their potential safety issues is available on the FDA's Web site.

Also available are the AERS-generated watch lists covering earlier time periods.

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