New FDA Watch List: Possible ED Drug–Melanoma Link and More

July 01, 2016

The US Food and Drug Administration (FDA) yesterday said it will study a potential link between melanoma and erectile dysfunction (ED) drugs such as sildenafil (Viagra, Pfizer) and tadalafil (Cialis, Lilly), a trail other researchers have gone down only to turn up less-than-conclusive results.

The announcement appeared in the agency's latest watch list of drugs with possible safety issues collected by the FDA Adverse Event Reporting System (FAERS) in the first 3 months of 2016. In all, the watch list contains 17 drugs or drug classes, including treatments for cancer, circulatory problems, psychiatric conditions, and diabetes. Regarding that last disease, the agency said it was checking out patients experiencing hepatitis after taking drugs that contain metformin.

A drug's appearance on a quarterly FAERS watch list does not mean the FDA has determined there is a cause-and-effect relationship between the drug and the cited adverse event. Instead, the agency evaluates the need for regulatory action. If its investigation uncovers a causal link, the agency could gather more information to better describe the threat, revise the drug's label, require a Risk Evaluation and Mitigation Strategy, or in extreme cases, pull the drug from the market.

As sometimes happens, the FDA has already addressed some of the potential signals of serious risk reported to FAERS in the first quarter of 2016. For example, the FDA identified impulse control disorders (think of a gambling, shopping, eating, and sex binge in Las Vegas) as a potential problem with psychiatric drugs containing aripiprazole (the agency previously had pointed out the possibility of pathological gambling). After confirming this pattern, the FDA revised the labels of these drugs in May to warn about the rare, but real, risk for major league impulsiveness.

For most of the drugs on the watch list for the first 3 months of 2016, however, the FDA said it is still studying the matter.

The agency will be on the heels of other researchers when it comes to the class of ED drugs called phosphodiesterase (PDE)-5 inhibitors. A study published in JAMA Internal Medicine in April 2014 found an association between sildenafil and an increased risk for melanoma. However, the authors said their epidemiological evidence was not strong enough to change clinical recommendations for treating ED.

Likewise, a study published in JAMA in June 2015 did not nail down a cancer risk for these drugs. Mining a massive health database of Swedish patients, the authors reported that among 4000 men diagnosed with malignant melanoma, use of a PDE-5 inhibitor was linked to a 20% increase in the relative risk for the cancer.

However, one telltale finding weakened this link: The melanoma risk was highest for men who filled only a single prescription for a PDE-5 inhibitor, not for men who filled multiple prescriptions. That counterintuitive fact made the authors suspect that the higher risk had to do with lifestyle or demographic factors. After all, the melanoma risk also was higher for men with more education and income, as well as men with basal cell carcinoma, which was not biochemically implicated with ED drugs. The conclusion? Men taking ED drugs who had melanoma probably were the sort with enough leisure time on their hands to get too much sun exposure.

What the FDA discovers about ED drugs and melanoma remains to be seen.

Potential Signals of Serious Risks/New Safety Information Identified by FAERS, January to March, 2016

Product Name: Active Ingredient (Trade) or Product Class Potential Signal of a Serious Risk/New Safety Information Additional Information (as of June 30, 2016)
Aripiprazole-containing drug products:
  • Abilify (aripiprazole; Otsuka America Pharmaceutical Inc): orally disintegrating tablet, tablet, oral solution, and injection for intramuscular (IM) use

  • Abilify Maintena (aripiprazole; Otsuka America Pharmaceutical Inc): extended-release injectable suspension for IM use

  • Aristada (aripiprazole lauroxil; Alkermes Inc): extended-release injectable suspension for IM use

Impulse control disorders FDA is evaluating the need for regulatory action
Aripiprazole Drug Safety Communication (May 3, 2016)
http://www.fda.gov/Drugs/DrugSafety/ucm498662.htm
Belviq (lorcaserin hydrochloride; Eisai Inc): tablets Hypersensitivity FDA is evaluating the need for regulatory action
Brilinta (ticagrelor; AstraZeneca): tablets Atrioventricular block FDA is evaluating the need for regulatory action
Cometriq (cabozantinib; Exelixis Inc): capsules Drug interaction between cabozantinib and warfarin FDA decided that no action is necessary at this time, based on available information
  • Cysto-Conray II (iothalamate meglumine; Mallinckrodt Inc): injection

  • Gastrografin (diatrizoate meglumine and diatrizoate sodium; Bracco Diagnostics Inc): solution

  • MD-Gastroview (diatrizoate meglumine and diatrizoate sodium; Guerbet): solution

Medication error reports associated with wrong route of administration FDA is evaluating the need for regulatory action
Diflucan (fluconazole; Pfizer): tablets Adverse pregnancy outcomes FDA is evaluating the need for regulatory action
Diflucan Drug Safety Communication (April 26, 2016)
http://www.fda.gov/Drugs/DrugSafety/ucm497482.htm
Exparel (bupivacaine liposome; Pacira Pharmaceuticals): injection Local anesthetic systemic toxicity FDA is evaluating the need for regulatory action
First- and second-generation antipsychotics Falls that may result in injury FDA is evaluating the need for regulatory action
Kynamro (mipomersen sodium; Kastle Therapeutics): injection for subcutaneous use Ineffectiveness of the Risk Evaluation and Mitigation Strategies The Boxed Warning, "Warnings and Precautions," "Patient Counseling Information," "Indications and Usage," "Dosage and Administration," and sections of the product labeling, as well as the patient medication guide, were updated to include information pertaining to appropriate patient selection and monitoring of patients for hepatotoxicity
Kynamro Labeling
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203568s008lbl.pdf
FDA is evaluating the need for further regulatory action
Loperamide hydrochloride capsules, oral solution Abuse, misuse, and serious cardiac adverse events, including Torsades de Points FDA is evaluating the need for regulatory action
Metformin-containing drug products Hepatitis FDA is evaluating the need for regulatory action
Noxafil (posaconazole; Merck): injection, extended-release tablets, and oral suspension Drug interaction between posaconazole and vincristine potentially causing neurotoxicity FDA is evaluating the need for regulatory action
Paregoric oral solution Labeling error with the potential to cause medication errors The container label and package insert were revised to clarify the product name, strength, and alcohol content
PDE-5 inhibitors:
  • Adcirca (tadalafil; Eli Lilly and Company): tablets

  • Cialis (tadalafil): tablets

  • Levitra (vardenafil hydrochloride; GlaxoSmithKline): orally disintegrating tablets

  • Revatio (sildenafil citrate; Pfizer): tablets, oral suspension, and injection

  • Staxyn (vardenafil hydrochloride; GlaxoSmithKline): orally disintegrating tablets

  • Stendra (avanafil; Vivus and Auxilium Pharmaceuticals): tablets

  • Viagra (sildenafil citrate): tablets

Skin melanomas FDA is evaluating the need for regulatory action
Ranexa (ranolazine; Gilead Sciences Inc): extended-release tablets Seizure FDA is evaluating the need for regulatory action
Vascepa (icosapent ethyl; Amarin Pharma Inc): capsules Liver injury FDA decided that no action is necessary at this time, based on available information
Velcade (bortezomib; Millennium Pharmaceuticals Inc): injection for subcutaneous and IV use Stevens-Johnson syndrome and toxic epidermal necrolysis FDA is evaluating the need for regulatory action

Source: US Food and Drug Administration

More information on FAERS and its quarterly watch lists is available on the FDA website.

Follow Robert Lowes on Twitter @LowesRobert

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