Janssen Products

Ketoconazole

Nizoral^TM tablet

Formulation
Each tablet contains 200 mg ketoconazole.

Description
Ketoconazole (Nizoral^TM) is a synthetic broad-spectrum antifungal agent available as tablets.

Each tablet contains 200 mg ketoconazole.

The inactive ingredients in the tablets are maize starch, lactose, polyvidone, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

Properties
Pharmacodynamics
Ketoconazole is a synthetic imidazole dioxolane derivative with a fungicidal or fungistatic activity against dermatophytes, yeasts (Candida, Pityrosporum, Torulopsis, Cryptococcus), dimorphic fungi and eumycetes. Less sensitive are: 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 µg/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 drug. 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 thus requires acidity for dissolution and absorption.

Indications

• Infections of the skin, hair and nails induced by dermatophytes and/or yeasts (dermatophytosis, onychomycosis, Candida perionyxis, pityriasis versicolor, pityriasis capitis, Pityrosporum folliculitis, chronic mucocutaneous candidosis), provided these infections cannot be treated topically because of the site or extension of the lesion, or deep affection of the skin, or if they fail to respond to local therapy;

• Yeast infection of the gastrointestinal tract;

• Chronic, recurrent vaginal candidosis, provided this infection fails to respond to local therapy;

• Systemic fungal infections such as systemic candidosis, paracoccidioidomycosis, histoplasmosis, coccidioidomycosis, blastomycosis;

• Prophylactic treatment of patients with decreased defense mechanisms (inherited, caused by illness or drugs), involving an increased risk of fungal infections.

Ketoconazole does not penetrate well in the CNS. Therefore, fungal meningitis should not be treated with oral ketoconazole. Contraindications
Ketoconazole (Nizoral^TM) should not be administered to patients with acute or chronic liver disease or with a known hypersensitivity to the drug or its components.

Terfenadine, astemizole, cisapride, triazolam, oral midazolam, quinidine, pimozide, CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin and lovastatin are contraindicated with ketoconazole (Nizoral^TM).

Warnings and precautions
Ketoconazole (Nizoral^TM) has a potential for clinically important drug interations (see Interactions).

Decreased gastric acidity: Absorption is impaired when the gastric acidity is decreased. In patients also receiving acid neutralizing medicines (e.g. aluminum hydroxide) these should be administered at least 2 hours after the intake of ketoconazole (Nizoral^TM). In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists, protonpump inhibitors) it is advisable to administer ketoconazole (Nizoral^TM) with a cola beverage.

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

Liver function tests should accompany ketoconazole (Nizoral^TM) treatments which lasts longer than 2 weeks: before treatment, after 2 weeks and later on monthly.

It is important to make the patient on chronic ketoconazole (Nizoral^TM) treatment 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 drug intolerance, long lasting treatment and concomitant use of liver compromising medication.

In case 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 (Nizoral^TM) is used in cases of non-life threatening diseases requiring long treatment periods.

In volunteers on daily doses of 400 mg and more, ketoconazole (Nizoral^TM) 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 (major surgery, intensive care, etc.).

Interactions

• Drugs affecting the metabolism of ketoconazole:
  Enzyme-inducing drugs such as rifampicin, rifabutin, carbamazepine, isoniazid and phenytoin significantly reduce the bioavailability of ketoconazole.
  
  Drugs that affect the 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.
  
  

• Effect of ketoconazole on the metabolism of other drugs:
  Ketoconazole can inhibit the metabolism of drugs metabolized 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:
  Drugs which should not be used during treatment with ketoconazole: Terfenadine, astemizole, cisapride, triazolam, oral midazolam, quinidine, pimozide, CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin and lovastatin.
  
  Drugs whose plasma levels, effects or side effects should be monitored. Their dosage, 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 docetaxel;

  • CYP3A4 metabolized Calcium Channel Blockers such as dihydropyridines and probably verapamil;

  • Certain Immunosuppressive Agents: cyclosporine, tacrolimus;

  • Others: digoxin, carbamazepine, buspirone, alfentanil, sildenafil, alprazolam, midazolam IV, rifabutin, Methylprednisolone and trimetrexate.

  Exceptional cases have been reported of a disulfiram-like reaction to alcohol, characterized by flushing, rash, peripheral edema, nausea and headache. All symptoms completely resolved within a few hours.

Pregnancy and lactation
Ketoconazole (Nizoral^TM) induces syndactylism in rats at a dosage level of 80 mg/kg. No studies are available on its use in pregnant women. Therefore, ketoconazole (Nizoral^TM) may not be administered during pregnancy, unless the potential advantage justifies the possible risk for the fetus.

Since ketoconazole (Nizoral^TM) is excreted in the milk, mothers who are under treatment should not breastfeed.

Effects on driving ability and use of machinery
No effects have been observed.

Dosage and administration
Ketoconazole (Nizoral^TM) should be taken during meals for maximal absorption.

Curative treatment:

Adults

• Skin, gastrointestinal and systemic infections: One tablet (= 200 mg) once daily with a meal. When no adequate response is obtained with this dose, the dose should be increased to 2 tablets (= 400 mg) once daily.

• Vaginal candidosis: two tablets (= 400 mg) once daily with a meal.

Children

• Children weighing more than 30 kg: same as for adults.

In general, this dosage scheme should be continued without any interruption until at least 1 week after all symptoms have disappeared and until all cultures turn out to be negative.

Prophylactic treatment of immunodeficient patients:

• Adults: 2 tablets (= 400 mg) daily

• Children: 4-8 mg/kg

The usual duration of treatment is:

• vaginal candidosis: 5 consecutive days;

• skin mycoses induced by dermatophytes, approx. 4 weeks;

• pityriasis versicolor: 10 days;

• oral and skin mycosis induced by Candida: 2-3 weeks;

• hair infections: 1-2 months;

• nail infections: 6-12 months: also determined by the speed of nail growth; full outgrowth of the affected nail is required;

• systemic candidosis: 1-2 months;

• paracoccidioidomycosis, histoplasmosis, coccidioidomycosis: the optimum duration of therapy is 3-6 months.

Adverse reactions
The most frequently reported adverse experiences in association with the use of ketoconazole (Nizoral^TM) were of gastrointestinal origin, such as dyspepsia, nausea, abdominal pain and diarrhea. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorders, dizziness, photophobia, paresthesia and allergic reactions. Side effects reported with an extremely low frequency are: thrombocytopenia, alopecia, impotence and reversible increased intracranial pressure (e.g. papilloedema, bulging fontanel in infants).

With doses higher than the recommended therapeutic dose of 200 or 400 mg daily, reversible gynecomastia 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 normalize within 24 hours after administration of ketoconazole (Nizoral^TM). During long term therapy at this level of dosage, testosterone levels are usually not significantly different from controls.

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

Overdosage
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.

How supplied
Ketoconazole (Nizoral^TM) tablet is supplied in box of 100 tablets.

Storage conditions
Store at a temperature not exceeding 30°C.
The tablets must be stored in a dry place.
Keep out of reach of children.

CAUTION: Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Manufactured by:
INTERPHIL LABORATORIES, INC.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
For: Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque City
Under license from:
JANSSEN PHARMACEUTICA
Beerse, Belgium
Exclusively distributed by:
ZUELLIG PHARMA CORPORATION
Sen. Gil Puyat Avenue
Makati City