Data Sheet
NIZORAL™
Ketoconazole 200mg tablets
NAME of medicine
NIZORAL™ ketoconazole 200 mg tablet
Presentation
White, scored, tablet marked with 'K/200' and 'Janssen' on reverse.
Uses
Actions
Ketoconazole is a synthetic imidazole dioxolane derivative with a fungicidal or fungistatic activity against dermatophytes, yeasts (Candida, Pityrosporum, Torulopsis, Cryptococcus), dimorphic fungi and eumycetes. Ketoconazole is less sensitive to Aspergillus spp., Sporothrix schenckii, some Dematiaceae, Mucor spp. and other phycomycetes, except Entomophthorales.
Ketoconazole inhibits the biosynthesis of ergosterol in fungi and changes the composition of other lipid components in the membrane.
Pharmacokinetics
Mean peak plasma levels of approximately 3.5 micrograms/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the gastrointestinal tract, ketoconazole is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged. The major route of excretion is through the bile into the intestinal tract. In vitro, the plasma protein binding is about 99%, mainly to the albumin fraction. Only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid. Ketoconazole is a weak dibasic agent and therefore, it requires adequate acidity for dissolution and absorption.
Indications
Because of the risk for serious hepatotoxicity, NIZORAL tablets should be used only when the potential benefits are considered to outweigh the potential risks, taking into consideration the availability of other effective antifungal therapy.
NIZORAL tablets are indicated for the treatment of:
- Systemic and deep mycoses (attributable to susceptible fungi) where other available antifungal therapies have failed or are contraindicated. Ketoconazole does not penetrate well in the CNS. Therefore, fungal meningitis should not be treated with oral ketoconazole.
- Recalcitrant cases of superficial mycoses (attributable to susceptible fungi) which fail to respond to topical therapy and other conventional treatments.
- Chronic recurrent vaginal candidosis.
Dosage and Administration
Adults
Skin, gastrointestinal and systemic infections: one tablet (200 mg) once daily with a meal. If the response is not adequate, the dosage may be increased to two tablets (400 mg) once daily with a meal.
Vaginal candidosis: two tablets (400 mg) once daily with a meal.
The usual duration of treatment is:
Vaginal candidosis: 5 consecutive days
Skin mycoses induced by dermatophytes: approximately 4 weeks
Pityriasis versicolor: 10 days
Oral and skin mycosis caused by Candida spp: 2-3 weeks
Hair infections: 1 to 2 months
Paracoccidioidomycosis, histoplasmosis, coccidioidomycosis: the usual duration of therapy is 6 months.
For all indications, treatment should be continued without interruption until clinical parameters or laboratory tests indicate that the fungal infection has resolved. An inadequate treatment period may lead to recurrence of the active infection. However, treatment should be stopped immediately and liver function testing should be conducted when signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine occur (see WARNINGS AND PRECAUTIONS)
Contraindications
Patients with a known hypersensitivity to ketoconazole or any components of NIZORAL tablets. NIZORAL tablets are also contraindicated in pregnant women and patients with acute or chronic liver disease (see WARNINGS AND PRECAUTIONS).
Co-administration of the CYP3A4 substratres terfenadine, astemizole, bepridil, mizolastine, cisapride, disopyramide, dofetilide, halofantrine, levacetylmethadol (levomethadyl), quinidine, sertindole or pimozide with NIZORAL tablets is contraindicated since the increased plasma concentrations of these drugs caused by the interaction can lead to QTc prolongation and rare occurrences of torsades de pointes. The concomitant use of oral midazolam or oral triazolam with oral ketoconazole is also contraindicated.
Co-administration of domperidone is contraindicated since the combination can lead to QTc prolongation.
Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin or lovastatin with NIZORAL tablets is contraindicated.
Co-administration of Ergot Alkaloids (ergometrine, methylergometrin, ergotamine or dihydroergotamine) with NIZORAL tablets is contraindicated because of the increased risk for ergotism and other serious vasospastic disorders.
Co-administration of nisoldipine
Co-administration of eplerenone
Co-administration of irinotecan
Co-administration of everolimus
Warnings and Precautions
WARNING: because of the risk for serious hepatotoxicity,
NIZORAL tablets should be used only when the potential benefits are considered
to outweigh the potential risks, taking into consideration the availability of
other effective antifungal therapy.
Assess liver function, prior to treatment to rule out acute or chronic liver
diseases, and monitor at frequent and regular intervals during treatment, and
at the first signs or symptoms of possible hepatotoxicity.
NIZORAL has a potential for clinically important interactions (see INTERACTIONS).
Decreased gastric acidity: Absorption is impaired when the gastric acidity is decreased. In patients who are also receiving acid neutralising medicine (e.g. aluminium hydroxide), these should be administered at least 2 hours after the intake of NIZORAL. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists, proton pump inhibitors), it is advisable to administer NIZORAL with a cola beverage.
Hepatotoxicity
Very rare cases of serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, have occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Cases have been reported that occurred within the first month of treatment, including some within the first week.
The cumulative dose of the treatment is a risk factor for serious hepatotoxicity. Factors which may increase the risk of hepatitis are: prolonged treatment with NIZORAL tablets, females over 50 years of age, previous treatment with griseofulvin, a history of liver disease, known drug intolerance and concurrent use of medication which comprises liver function. A period of one month should be allowed between cessation of griseofulvin treatment and commencement treatment with NIZORAL tablets because of an apparent association between recent griseofulvin therapy and hepatic reactions to NIZORAL tablets.
Monitor liver function in all patients receiving treatment with NIZORAL tablets (see Monitoring of Hepatic Function).
Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine. In these patients, treatment should be stopped immediately and liver function testing should be conducted.
Monitoring of Hepatic Function
Monitor liver function in all patients receiving treatment with NIZORAL tablets. Monitor liver function prior to treatment to rule out acute or chronic liver disease (see CONTRAINDICATIONS) and at frequent and regular intervals during treatment, and at the first signs or symptoms of possible hepatic toxicity. When the liver function tests indicate liver injury, the treatment should be stopped immediately.
In patients with elevated liver enzymes, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In such cases close monitoring of the liver enzymes is necessary.
Monitoring of Adrenal Function
In volunteers on daily doses of 400 mg and more, NIZORAL tablet has been shown to reduce the cortisol response to ACTH stimulation. Therefore, adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress, such as major surgery, intensive care, etc, and in patients on prolonged therapy presenting signs and symptoms suggestive of adrenal insufficiency.
Pregnancy and lactation
Use in pregnancy
Category B3. Ketoconazole induces syndactylism in rats at a dosage level of 80 mg/kg. No studies are available on its use in pregnant women. Therefore, NIZORAL tablets may not be administered during pregnancy, unless the potential advantage justifies the possible risk for the foetus.
Use in lactation
As ketoconazole is excreted in the milk, mothers who are taking ketoconazole should not breastfeed.
Effects on ability to drive and use machines
No effects have been observed.
Adverse Effects
Clinical Trials
In a multinational multicentre, open-label study in patients with various superficial and deep mycosis, adverse events during ketoconazole treatment were evaluable in 1361 cases, 149 (11%) reported adverse events were summarized regardless of the causality assessment of the investigator. The most frequently reported adverse events were of gastrointestinal origin, i.e. nausea and vomiting. Adverse events that were reported with an incidence of ≥ 0.5% are presented in Table 1.
Table 1: Adverse Experiences with an incidence ≥ 0.5% during ketoconazole treatment in 1361 cases with various superficial and deep mycosis
| System Organ Class AE Preferred term |
Superficial Mycosis % (N=1,026) |
Deep Mycosis % (N=335) |
Total % (N=1361) |
|---|---|---|---|
| Nervous System disorder | |||
| Headache | 0.7 | 0.9 | 0.7 |
| Dizziness | 0.5 | 1.2 | 0.7 |
| Somnolence | 0.5 | 1.2 | 0.7 |
| Gastrointestinal disorders | |||
| Nausea/Vomiting | 1.8 | 6.9 | 3.0 |
| Abdominal pain | 1.2 | 1.2 | 1.2 |
| Diarrhoea | 0.7 | 0.6 | 0.7 |
| Skin & subcutaneous tissue disorders | |||
| Pruritus | 0.8 | 3.3 | 1.4 |
| Rash | 0.6 | 0.6 | 0.6 |
Based upon post-marketing experience the following adverse
events have also been reported. The adverse drug reactions are ranked by
frequency, using the following convention:
- Very common: ≥ 1/10
- Common: ≥ 1/100 and < 1/10
- Uncommon: ≥ 1/1,000 and < 1/100
- Rare: ≥ 1/10,000 and < 1/1,000
- Very rare: < 1/10,000 including isolated reports
Immune system disorders
Very rare: allergic conditions including anaphylactic shock, anaphylactoid and anaphylactic reactions and angioneyrotic oedema.
Nervous system disorders
Very rare: intracranial pressure increased (e.g. papilloedema, fontanelle bulging in infants), dizziness, headache, paraesthesia
Hepato-biliary disorders
Very rare: serious hepatotoxicity, including jaundice, hepatitis, biopsy confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death (see WARNINGS AND PRECAUTIONS), liver function test abnormal.
Skin and subcutaneous tissue disorders
Very rare: urticaria, pruritus, rash, alopecia, photosensitivity
Reproductive system and breast disorders
Very rare: erectile dysfunction, gynaecomastia, menstrual disorders, with doses higher than the recommended therapeutic dose of 200 to 400mg daily azoospermia.
Blood and the lymphatic system disorder
Very rare: thrombocytopenia
Endocrine disorders
Very rare: adrenocortical insufficiency
Eye disorder
Very rare: photophobia
Gastrointestinal disorders
Very rare: vomiting, abdominal pain, diarrhoea, dyspepsia, nausea
At the therapeutic dosage level of 200 mg once daily, a transient decrease in the plasma levels of testosterone can be observed. Testosterone levels normalise within 24 hours after administration of NIZORAL tablet. During long-term therapy at this level of dosage, testosterone levels are usually not significantly different from controls.
Interactions
- Medicines affecting the metabolism of ketoconazole
Enzyme inducing medicines such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine and phenytoin significantly reduce the bioavailability of ketoconazole.
Ritonavir increases the bioavailability of ketoconazole. Therefore when it is given concomitantly, a dose reduction of ketoconazole should be considered. - Effects of ketoconazole on the metabolism of other medicines
Ketoconazole can inhibit the metabolism of medicines metabolised by certain hepatic P450 enzymes, especially of the CYP 3A family. This can result in an increase and/or a prolongation of their effects, including adverse effects.
Examples are:
Medicines that are contraindicated during treatment with NIZORAL tablets- Co-administration of the CYP3A4 substrates terfenadine, astemizole, bepridil, mizolastine, cisapride, disopyramide, dofetilide, halofantrine, levacetylmethadol (levomethadyl), quinidine, sertindole or pimozide, with NIZORAL tablets is contraindicated since the increased plasma concentrations of these drugs caused by the interaction can lead to QTc prolongation and rare occurrences of torsades de pointes
- Co-administration of domperidone is contraindicated since the combination can lead to QTc prolongation
- Co-administration of triazolam and oral midazolam is contraindicated because of an exaggerated and prolonged pharmacodynamic response
- CYP3A4 metabolised HMG-CoA reductase inhibitors, such as simvastatin and lovastatin
- Co-administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergotamine (methylergonovine)
- Co-administration of nisoldipine
- Co-administration of eplerenone
- Co-administration of irinotecan
- Co-administration of everolimus
Medicines whose plasma levels, effects or side effects should be monitored. The dosage of these medicines, if coadministered with ketoconazole should be reduced if necessary. This should be considered when prescribing concomitant medication.
- Oral anticoagulants
- HIV protease inhibitors, such as indinavir, saquinavir
- Certain antineoplastic agents, such as vinca alkaloids, busulphan, docetaxel, erlotinib and imatinib
- CYP3A4 metabolised calcium channel blockers, such as dihydropyridines and probably verapamil
- Certain immunosuppressive agents, such as cyclosporin, sirolimus (also known as rapamycin) and tacrolimus
- Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as atrovastatin
- Certain glucocorticoids such as budesonide, fluticasone, dexamethasone and methylprednisolone
- Digoxin (via inhibition of P-glycoprotein)
- Others: alprazolam, carbamazepine, cilostazol, buspirone, alfentanil, fentanyl, midazolam IV, sildenafil, repaglinide, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, tolterodine, trimetrexate, ebastine, eletriptan reboxetine, quetiapine and solifenacin.
Exceptional cases have been reported of a disulfiram-like reaction to alcohol, characterised by flushing, rash, peripheral oedema, nausea and headache. All symptoms completely resolve within a few hours.
Overdosage
Treatment
There is no known antidote to ketoconazole. In the event of accidental overdosage, treatment consists of supportive measures. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate.
Pharmaceutical Precautions
Shelf Life
5 years when stored below 25°C.
Special Precautions for Storage
Store in a dry place.
Medicine Classification
Prescription Medicine
Package Quantities
Blisters in a carton of 30 tablets.
Further Information
NIZORAL tablets contain maize starch, lactose, povidone, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.
Ketoconazole has been tested in a standard battery of non-clinical safety studies.
Hepatotoxic effects were seen in a twelve month repeated dose dog study. Slight pathological changes in the kidneys, adrenals, and ovaries were noted in an 18 month repeated dose rat study. In addition, female rats showed an increase in bone fragility. The No Observed Adverse Effect Level (NPAEL) in both studies was 10mg/kg/day.
In reproduction studies, at very high maternally toxic doses (80mg/kg/day and higher) ketoconazole impaired female fertility in the rat and produced embryotoxic and teratogenic (oligodactylia and syndactylia) effects in pups. At 40mg/kg in rats and rabbits, ketoconazole was devoid of embryotoxicity, teratogenicity and effects on fertility. No teratogenic effects were observed in mice at any dose level tested to a maximum of 160mg/kg.
Ketoconazole is not carcinogenic or genotoxic.
Name and Address
New Zealand Sponsor
Johnson & Johnson (New Zealand) Ltd,
Ground Floor, Ericsson House
105 Carlton Gore Road, Newmarket
Auckland, NEW ZEALAND
Distributed by
Janssen-Cilag Pty Ltd, PO Box 9222, Newmarket, Auckland, New Zealand
Tel: (09) 524 5012
Fax: (09) 523 1646
Date of Preparation
5 May 2008