Rwanda Recalls Ketoconazole Oral Tablets Over Safety Concerns

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The National Agency for Food and Drug Administration and Control is notifying the Public that Rwanda FDA governing pharmacovigilance for pharmaceutical products and medical devices, has conducted a deep analysis and concluded that “Ketoconazole Oral tablets have higher risks of liver injury than benefits when treating fungal infections”. Hence the authority withdrew all the brands of Ketoconazole oral tablets from the Rwandan market and called for alternative drugs for the treatment of fungal infections.

On July 26, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) announced their negative risk-benefit assessment for oral ketoconazole-containing medicines used to treat infections caused by dermatophytes and yeasts and recommended suspensions of these medicines throughout the European Union (EU)

In addition, U.S. Food and Drug Administration (FDA) has taken several actions related to Nizoral (ketoconazole) oral tablets, including limiting the drug’s use, warning that it can cause severe liver injuries and adrenal gland problems and advising that it can lead to harmful drug interactions with other medications. FDA has approved label changes after conducting a comprehensive benefit-risk assessment of the safety an efficacy of Nizoral (ketoconazole) tablets and added a new Medication Guide to address these safety issues. As a result, Nizoral oral tablets should not be a first-line treatment for any fungal infection.  Ketoconazole should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated. 

Possible Risk

Liver Injury (Hepatotoxicity):

oral ketoconazole-containing medicines can cause liver injury, which may potentially result in liver transplantation or death.  FDA has revised the Boxed Warning, added a strong recommendation against its use (contraindication) in patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxic. Serious liver damage has occurred in patients receiving high doses of ketoconazole for short periods of time as well as those receiving low doses for long periods. Some of these patients had no obvious risk factors for liver disease.  The liver injury is sometimes reversible upon stopping the drug, but not always possible.

Adrenal Gland Problems (Adrenal Insufficiency)

oral ketoconazole-containing medicines may cause adrenal insufficiency by decreasing the body’s production of hormones called corticosteroids. Corticosteroids are produced by the adrenal glands, which are small glands located on top of each kidney.  Corticosteroids affect the body’s balance of water and salts and minerals (electrolytes). 

In summary, FDA has approved the drug label to include the following information:

• Limitation of the usage of oral ketoconazole-containing medicines by removing indications in which the risk outweighs the benefits.  The use of ketoconazole tablets in Candidaand dermatophyte infections is no longer indicated. ketoconazole tablets should be used only when other antifungal drugs are not available or tolerated by the patient. (Boxed Warning, Warnings, Precautions, and Indications and Usage sections)
• ketoconazole tablets are not indicated for the treatment of fungal infections of the skin or nails.
• Updated information on the risk of liver injury, or hepatotoxicity, with new assessment and monitoring recommendations (Boxed Warning, Warnings, andPrecautions sections).
• Updated information on drug interactions (Precautionssection).
• A warning regarding adrenal insufficiency with recommendations for monitoring populations at risk (Warningssection).

Additional Information for Patients

• Patient should contact their health care professional right away if you take oral ketoconazole-containing medicines ketoconazole (Nizoral) tablets and experience any of these signs and symptoms of liver problems:
  • Loss of appetite, nausea, vomiting, or abdominal discomfort
  • Fever, feeling unwell, or unusual tiredness
  • Yellowing of the skin or the whites of the eyes (jaundice)
  • Unusual darkening of the urine or lightening of the stools
  • Pain or discomfort in the right upper abdomen, where the liver is located
  • Patient should contact their health care professional if they are taking ketoconazole tablets for any non-life-threatening infection or if you are unsure, or if you have liver or adrenal problems.
• Patient should not drink alcohol or use drugs or medications (e.g., acetaminophen) that can cause liver problems while taking ketoconazole  
• Should Carefully read the patient Medication Guide that comes with your ketoconazole prescription.

Recommendation for Health Care Professionals

• Oral ketoconazole-containing medicines should be used only for the treatment of certain life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or tolerated.
• Do not use oral ketoconazole-containing medicines in patients with underlying liver disease.
• Prompt recognition of liver injury is essential.  
  • Assess the liver status of the patient before starting oral ketoconazole, with baseline laboratory
  • While the patient is taking oral ketoconazole, serum ALT should be monitored weekly for the duration of treatment Liver tests should be repeated to ensure normalization of values.
• Other hepatotoxic drugs and alcohol should be avoided while taking ketoconazole
• Review all concomitant medications for the potential for drug interactions with ketoconazole
• Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.)

Healthcare providers and patients are encouraged to report adverse events or quality issues experienced with the use of this product to the nearest NAFDAC office, via pharmacovigilance@nafdac.gov.ng, E-reporting platforms available on the NAFDAC website or via the Med- safety application for download on android and IOS stores.

References

1. https://rwandafda.gov.rw/authority-recalls-ketoconazole-oral-tablets/
2. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems | FDA
3. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146613.pd
4. https://www-hsa-gov-sg.cwp.sg/announcements/Dear-Healthcare-Professional-Letters
5. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Ketoconazole-containing_medicines/human_referral_000348.jsp&mid=WC0b01ac05805c516f
6. http://www.fda.gov/drugs/drugsafety/ucm362415.htm

NAFDAC……..Customer-focused, Agency-minded!!!

Signed Management