Ketoconazole discontinued

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Practice points | Ketoconazole deregistered from 1 December 2013 | Harm outweighs benefit | Oral ketoconazole indications already limited | When to start oral antifungals for superficial infections | Information for patients | References


Oral ketoconazole will be deregistered and discontinued in Australia from 1 December 2013, because of the risk of severe liver toxicity.1

This follows the European Medicines Agency (EMA) recommendation in July 2013 to suspend ketoconazole in Europe.2 The EMA decision was made on the basis that the associated harm outweighed the treatment benefit, and because of the availability of safer alternative antifungals.2 A number of risk-minimisation measures have been in place for several years but these have not reduced the hepatotoxicity risk to an acceptable level.2

Oral antifungal treatments are only recommended for superficial fungal infections when there is no response to topical therapy, or for fungal infections of the scalp (tinea capitis)  where topical agents are generally ineffective.3,4 For these cases consider oral terbinafine, itraconazole, fluconazole and griseofulvin.3

Practice points

  • Avoid oral antifungals because of potential severe and life-threatening adverse effects1,5
  • Trial topical antifungals where indicated and confirm the diagnosis with fungal microscopy and culture before treatment, particularly when using oral antifungals.3

  • Consider switching patients currently being treated with oral ketoconazole to a safer alternative antifungal1
  • While several cases of liver injury have been reported in association with griseofulvin, itraconazole, terbinafine and fluconazole, ketoconazole has been shown to have the highest incidence of liver injury when compared with other systemic antifungals.6

  • Avoid initiating treatment with oral ketoconazole in patients who are not already treated with this medicine1
  • If continuing patients on oral ketoconazole until its discontinuation, restrict treatment duration to a maximum of four weeks, with a maximum daily dose of less than or equal to 400 mg1
  • The cumulative dose of the treatment is a risk factor for serious hepatotoxicity7

  • There are no obvious risk factors for drug-induced liver injury and the clinical signs and symptoms are non-specific8
  • Advise all patients treated with oral ketoconazole to promptly seek medical attention if they experience signs of liver injury, such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine.1 Monitoring of liver function is also strongly advised.1 If these tests indicate liver injury, stop treatment immediately.1

Ketoconazole deregistered from 1 December 2013

Janssen-Cilag (Australia), in consultation with the TGA, will deregister and discontinue supply of oral ketoconazole (Nizoral) 200 mg tablets from 1 December 2013.1 Severe liver toxicity is a known risk associated with oral ketoconazole treatment and, for this reason, risk minimisation measures have been in place for several years.1,7

Topical ketoconazole (Nizoral cream and shampoo) is not affected by the deregistration and will continue to be available, as the amount of ketoconazole absorbed systemically is very low with these formulations.1,2

This decision follows the EMA recommendation in July 2013 to suspend ketoconazole in Europe,2 and FDA revisions to the product’s indications and safety warnings about liver and adrenal gland problems, and harmful drug interactions.9 The FDA has maintained the registration and supply of ketoconazole when alternative antifungal therapies are not available or not tolerated, but removed indications for dermatophyte and Candida infections, thereby limiting its use.9

The EU-wide review of oral ketoconazole was triggered by the suspension of the medicine in France. The French National Agency for the Safety of Medicine and Health Products concluded that the risk of severe liver injury associated with ketoconazole outweighed the benefit, in view of the currently available safer alternative antifungals.2

Harm outweighs benefit

The potential harm of liver injury following use of ketoconazole outweighs the possible treatment benefit. Although liver injury is a known side effect of antifungal medicines, the incidence and severity of liver injury with oral ketoconazole were higher than with other antifungals.6

Risk-minimisation measures not enough

As drug-induced liver injury is unpredictable, may be fatal and may have a rapid onset (within a week of starting treatment),7,8 risk-minimisation measures have not been enough to reduce the risk of hepatotoxicity to an acceptable level.2

Severe liver damage has occurred in patients receiving oral ketoconazole at high doses in short courses as well as those receiving low doses for long periods of time,9 but other contributing factors and the pathogenesis of drug-induced liver injury are poorly understood.8 Most cases from a single medicine lack a dose-relationship and are believed to result from an immunoallergic reaction or an atypical metabolism of the medicine.8 The pattern of injury is mostly hepatocellular but there have also been cases of mixed cholestatic-hepatocellular or cholestatic injury reported.6

Oral ketoconazole indications already limited

Ketoconazole tablets were only approved for patients who failed topical and other conventional treatments or where other treatments were contraindicated for:

  • Systemic and deep mycoses (due to susceptible fungi)7
    These infections are generally treated with newer antifungal agents such as voriconazole, lipid formulations of amphotericin B, posaconazole or itraconazole under the supervision of microbiologists or infectious disease specialists.4
  • Recalcitrant cases of superficial mycoses (due to susceptible fungi)7
    Unless there is no alternative, Australian guidelines emphasise avoiding oral ketoconazole for superficial fungal infections, such as onychomycosis (fungal nail infections), tinea pedis (athlete’s foot), tinea captis and pityriasis versicolor (infective skin discolouration).4

When to start oral antifungals for superficial infections

Use oral terbinafine for adults and griseofulvin for children, for tinea capitis

Topical therapy is ineffective in treating tinea capitis (for example ketoconazole or selenium sulfide shampoos), but they may be used as an adjunct to oral antifungals to help limit the spread of infection.3 Australian guidelines recommend griseofulvin as first-line treatment for children, while oral terbinafine is recommended for adults.3 Only griseofulvin and terbinafine are PBS approved for treating children with tinea capitis. Before starting treatment confirm the fungal infection by culture of scrapings.3,10

When superficial fungal infections fail to respond to topical treatments use ...

Oral terbinafine for onychomycosis

In 2008 ADRAC warned against oral terbinafine (which may put patients at risk of rare but life-threatening adverse effects) without a trial of topical therapy. This prompted the TGA to recommend oral terbinafine for the shortest possible time and with regular monitoring and only after topical treatment has failed.5

In clinical trials, compared with other oral antifungal agents terbinafine consistently improved mycological and clinical cure rates and lowered relapse rates for dermatophyte nail infections.11,12 A meta-analysis of 36 studies found higher cure rates with terbinafine (76%) than for pulsed itraconazole (63%), continuous itraconazole (59%), griseofulvin (60%) or fluconazole (48%).12

Many other disorders can mimic fungal nail infections, so it is important to establish the diagnosis microbiologically before starting treatment.3 Oral terbinafine is PBS listed (authority required) for proximal or extensive onychomycosis (> 80% nail involvement) caused by dermatophyte infection (proven by microscopy or culture) when topical treatment has failed.10

Consider oral itraconazole or fluconazole for people unable to tolerate oral terbinafine.3 UK guidelines recommend itraconazole for people with candidal or non-dermatophyte nail infections.13,14 One small non-blinded trial of pulse therapy with itraconazole found mycological cure rates of 90% for toenail infections (3 courses) and 100% for fingernail infections (2 courses).15 Oral terbinafine is recommended for fungal nail infections in children as there is limited published data on the use of itraconazole or fluconazole.3

Oral terbinafine for athlete’s foot (tinea pedis)

Topical antifungal agents are the preferred choice for localised tinea pedis.3 Oral therapy is recommended for tinea pedis unresponsive to topical therapy and for tinea in heavily keratinised areas such as diffuse scaling of the soles.3 Always confirm diagnosis with a fungal culture before starting treatment.3

A Cochrane review found that oral terbinafine was more effective than griseofulvin in treating tinea pedis.16 Small trials found no significant differences in efficacy between the different azoles, terbinafine and itraconazole, or ketoconazole and griseofulvin.16 Oral terbinafine is PBS listed (authority required) for the treatment of dermatophyte infection in an Aboriginal or Torres Strait Islander person where topical treatment has failed or in patients aged up to 18 years when topical treatment and griseofulvin have failed.10

Oral itraconazole or fluconazole for pityriasis versicolor

Pityriasis versicolor is a common condition seen in young adults (particularly between 20 and 30 years of age) caused by Malassezia yeasts.3 Patches of hyper- or hypo-pigmentation may lead a patient to seek treatment for cosmetic reasons and topical agents are always first-line treatment.3 For unresponsive cases itraconazole or fluconazole are the preferred oral antifungal agents.17

Information for patients

  1. Australian Government Department of Health Therapeutic Goods Administration. Oral ketoconazole (Nizoral) 200 mg tablets Product deregistration. 10 October 2013. [Online] (accessed 10 October 2013).
  2. European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. 26 July 2013. [Online] (accessed 10 October 2013).
  3. eTG complete [Internet]. Therapeutic Guidelines: Dermatology, version 3. Melbourne: 2009.
  4. Australian Medicines Handbook. Adelaide: 2013. [Online]  (accessed  10 September 2013).
  5. Australian Government Department of Health Therapeutic Goods Administration. Australian Adverse Drug Reactions Bulletin Vol 27 No 1. 2008. [Online] (accessed 14 October 2013).
  6. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999;48:847–52. [PubMed
  7. JANSSEN-CILAG Pty Ltd. Nizoral tablets Product Information. 2011. [Online] (accessed 10 October 2013).
  8. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924-34, 34 e1–4. [PubMed
  9. U.S. Food and Drug Administration. 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. 26 July 2013. [Online]  (accessed 11 October 2013).
  10. Australian Government Department of Health and Ageing. Pharmaceutical Benefits Schedule. 2013. [Online] (accessed 11 October 2013).
  11. Crawford F, Young P, Godfrey C, et al. Oral treatments for toenail onychomycosis: a systematic review. Arch Dermatol 2002;138:811–6. [PubMed]
  12. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol 2004;150:537–44. [PubMed]
  13. Health Protection Agency. Fungal skin & nail infections: diagnosis & laboratory investigation: quick reference guide for primary care. 2009. [Online] (accessed 15 October 2013).
  14. National Institute for Health and Care Excellence. Clinical Knowledge Summaries: Fungal Nail infection. Treating Candida nail infection. May 2009. [Online] (accessed 15 October 2013).
  15. Gupta AK, De Doncker P, Haneke E. Itraconazole pulse therapy for the treatment of Candida onychomycosis. J Eur Acad Dermatol Venereol 2001;15:112–5. [PubMed]
  16. Bell-Syer SE, Hart R, Crawford F, et al. Oral treatments for fungal infections of the skin of the foot. Cochrane Database Syst Rev 2002:CD003584. [PubMed]
  17. National Institute for Health and Care Excellence. Clinical Knowledge Summaries: Pityriasis versicolor. Systemic treatment. November 2010. [Online] (accessed 15 October 2013).