Safety Alerts

Safety advisory on oral ketoconazole

29 August 2014

Audiences

Healthcare professional

Industry member

Product-type

Therapeutic Products

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Additional measures to mitigate the risk of hepatotoxicity

HSA would like to update healthcare professionals on the outcomes of its benefit-risk assessment on oral ketoconazole. Warnings and recommendations for liver function monitoring will be strengthened in the local package inserts (PIs) to mitigate the risk of hepatoxicity with this drug. This decision was made in consultation with HSA’s Medicines Advisory Committee (MAC) and clinical experts, following concerns raised internationally on liver toxicity associated with oral ketoconazole.

Ketoconazole is an azole antifungal indicated for the treatment of superficial infections of the skin, hair and mucosa, as well as systemic fungal infections, in patients whom the potential benefits for the use of the drug are considered to outweigh the potential risks, after taking into consideration the availability of other antifungal therapies. Janssen, a division of Johnson & Johnson Pte Ltd, has cancelled the Singapore product licence for Nizoral^_® (ketoconazole) 200mg tablets in October 2013, citing availability of alternative treatments. Currently, there are 10 generic oral ketoconazole-containing products registered in Singapore.

Background

The French National Agency for the Safety of Medicine and Health Products (ANSM) suspended the use of oral ketoconazole in 2011 and the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended its suspension throughout the European Union in July 2013.¹ These regulatory decisions were made following independent benefit-risk assessments by both agencies which concluded that the benefits of oral ketoconazole for treating fungal infections did not outweigh its risks due to the concerns on liver toxicity compared to other alternative treatments. In Australia, the product licence of the only oral ketoconazole-containing product, Nizoral®, was voluntarily withdrawn by the sponsor.²

Ketoconazole continues to be available in the US and Canada although the US Food and Drug Administration (FDA) and Health Canada (HC) had in 2013 restricted the indications of oral ketoconazole to serious systemic fungal infections when alternative antifungal therapies were not available or tolerated, and for treatment of severe, recalcitrant dermatophytoses unresponsive to other forms of therapies, respectively. In addition to updating safety information in the PIs for assessing and monitoring patients for liver toxicity, the US FDA added a new contraindication for patients with acute or chronic liver disease,³while HC advised mandatory liver function testing.⁴

HSA’s benefit-risk assessment

HSA’s review took into consideration expert opinions from infectious disease physicians, dermatologists, O&G specialists and family physicians, local ADR reports, scientific literature related to ketoconazole-associated hepatotoxicity, and actions taken by other regulatory agencies. It also took into account the availability of other alternative therapies.

Hepatotoxicity is a known adverse effect of ketoconazole although its incidence was reported as uncommon in the Singapore PI. It was noted that while safety data from a cohort study showed that the risk of acute liver injury is highest with ketoconazole,⁵ there may be imbalances in the study design due to sample sizes and person-months duration of use. There was also uncertainty in quantifying precise estimates of risk, due to other methodological limitations such as lack of assessment of confounders and retrospective nature of the study.

HSA has received four local adverse reaction reports of hepatotoxicity (one case each of hepatitis and hepatitis cholestasis, and two cases of jaundice) over the past five years. The causality for all cases was assessed as possible, although the hepatitis case was confounded by concomitant administration of phentermine.

Based on the local physicians’ input, there remains a place in therapy for oral ketoconazole for the treatment of fungal infections in Singapore. HSA, in consultation with its MAC, has concluded that the benefit-risk profile of oral ketoconazole for treatment of fungal infections remains favourable if additional measures were taken to mitigate the risk of hepatotoxicity. These include reinforcing that oral ketoconazole should only be used as last-line therapy for patients who have failed or who are intolerant to other therapies, and strengthening the warnings and recommendations for liver function monitoring in the local PIs.

HSA’s advisory

Healthcare professionals are advised to take note of the following to minimise the risk of ketoconazole-associated hepatotoxicity:

Ketoconazole should only be used in patients who have failed or who are intolerant to other therapies for superficial fungal infections of the skin, hair and mucosa, and systemic fungal infection.
Serious hepatotoxicity was reported by patients receiving high doses for short treatment durations and those receiving low doses for long durations.
Patients should be advised against alcohol consumption while on ketoconazole treatment. If possible, concomitant use with other potentially hepatotoxic drugs should be avoided.
During the course of treatment, serum alanine aminotransferase (ALT) should be monitored weekly. If ALT values increase above the upper limit or 30% above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained

HSA will be working with the companies to update the local PIs of oral ketoconazole-containing products to reflect the above recommendations. A Dear Healthcare Professional Letter was issued on 1 August 2014 to advise healthcare professionals on these new recommendations.⁶

Safety advisory on oral ketoconazole

Additional measures to mitigate the risk of hepatotoxicity

Background

HSA’s benefit-risk assessment

HSA’s advisory

References

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