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Nizoral Tablets - Information Nizoral Tablets - Information

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. Ketoconaole 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

NIZORAL tablets are indicated for the treatment of:

Systemic and deep mycoses (attributable to susceptible fungi) where other forms of therapy have failed or are contraindicated.
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

Nail infections: 6 to 12 months (also determined by the speed of nail growth; full outgrowth of the affected nail is required)

Systemic candidiosis: 1 to 2 months

Contraindications

Patients with a known hypersensitivity to ketoconazole or any components of NIZORAL tablets. NIZORAL tablet is also contraindicated in pregnant women and patients with hepatic failure or those recovering from hepatitis (see Warnings and Precautions ).

Terfenadine and astemizole should not be used by patients taking ketoconazole. Concomitant administration of these medicines has been associated with increased blood levels of terfenadine and astemizole and an increased risk of serious cardiac arrhythmias.

The concomitant use of mizolastine, cisapride, dofetilide, oral midazolam or oral triazolam with oral ketoconazole is also contraindicated.

Quinidine, pimozide and CYP3A4 metabolised HMG-Co A reductase inhibitors (such as simvastatin and lovastatin) can interact with oral ketoconazole. As these interactions are of potential clinical significance, the concomitant use of these medicines with oral ketoconazole is contraindicated (see Interactions ).

Warnings and Precautions

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.

A mild transient asymptomatic increase of transaminases or alkaline phosphatase sometimes occurs. This does not necessarily require a discontinuation of the therapy but these patients should be monitored.

It is desirable to perform liver function tests before the commencement of treatment, after 2 weeks of treatment and then on a monthly basis, particularly in patients who are on prolonged therapy (beyond 2 weeks).

It is important that patients on chronic NIZORAL treatment are made aware of symptoms of liver disease such as abnormal fatigue, fever, dark urine, pale stools or jaundice. Factors increasing the risk of hepatitis are: women over 50, history of liver disease, known intolerance to medicines, long lasting treatment and concomitant use of liver compromising medication.

If symptoms of hepatitis occur or when liver function tests confirm liver disease, treatment should be promptly discontinued.

A risk/benefit evaluation should be made before ketoconazole is used in cases of non life threatening diseases requiring long treatment periods.

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.

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

The most frequently reported adverse experiences associated with the use of NIZORAL tablet were of gastrointestinal origin, such as dyspepsia, nausea, abdominal pain and diarrhoea. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorders, dizziness, photophobia, paraesthesia, and allergic reactions. Side effects reported with an extremely low frequency are thrombocytopenia, alopecia, impotence and reversible increased intracranial pressure (e.g. papilloedema, bulging fontanelle in infants).

With doses higher than the recommended therapeutic dose of 200 mg or 400 mg daily, reversible gynaecomastia and oligospermia have been observed in rare cases.

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.

During treatment with NIZORAL, hepatitis (most probably idiosyncratic) has been reported. This is usually reversible if the treatment is promptly discontinued.

Interactions

Medicines affecting the metabolism of ketoconazole

Enzyme inducing medicines such as rifampicin, rifabutin, carbamazepine, isoniazid and phenytoin significantly reduce the bioavailability of ketoconazole.

Medicines that affect gastric acidity (see Warnings and Precautions ).

Ritonavir increases the bioavailability of ketoconazole. Therefore when it is given concomitantly, a dose reduction of ketoconazole should be considered.

Effects of ketoconozole 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 side effects.

Examples are:

Medicines which should not be used during treatment with ketoconazole

Terfenadine, astemizole, mizolastine, cisapride, oral midazolam and triazolam, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors, such as simvastatin and lovastatin.

Medicines whose plasma levels, effects or side effects should be monitored. The dosage of these medicines, if co-administered with ketoconazole should be reduced if necessary.

Oral anticoagulants
HIV protease inhibitors, such as indinavir, saquinavir
Certain antineoplastic agents, such as vinca alkaloids, busulphan and docetaxal
CYP3A4 metabolised calcium channel blockers, such as dihydropyridines and probably verapamil
Certain immunosuppressive agents, such as cyclosporin, sirolimus (also known as rapamycin) and tacrolimus
Others: digoxin, carbamazepine, buspirone, alfentanil, sildenafil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, trimetrexate, ebastine and reboxetine.

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

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.