INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo KETAZOL Tablets
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

KETAZOL Tablets

COMPOSITION:
Each tablet contains 200 mg of ketoconazole.
Antioxidant: sodium sulphite, anhydrous.

PHARMACOLOGICAL CLASSIFICATION:
A.20.2.2 Antimicrobial (Chemotherapeutic) agents: Fungicides.

PHARMACOLOGICAL ACTION:
Ketoconazole is a synthetic imidazole dioxolane derivative, active (in vitro) against dermatophytes, yeasts and other pathogenic fungi. In vitro Ketazol is fungicidal and, therefore, suppresses the formation of mycelia. In vivo, at therapeutic levels, however, it is primarily fungistatic. Ketazol acts in the case of C. albicans by inhibiting lanosterol demethylation in the biosynthesis of ergosterol, resulting in cell membrane defects.
Mean peak plasma levels of approximately 3,5 mg/mL are reached within 1 - 2 hours following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with a rapid elimination phase with a half-life of 2 hours, followed by a slower elimination phase with a half-life of 8 hours. Following absorption from the gastro-intestinal tract, ketoconazole is converted into several inactive metabolites. The major identified metabolic pathways appear to be oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. Concentrations of active drug in the urine is very low. The major route of excretion is through the bile into the faeces. In vitro, the plasma protein binding is about 99%, mainly to the albumin fraction. Only a negligible proportion of ketoconazole reaches the cerebrospinal fluid. Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.

INDICATIONS:
Treatment of superficial and deep mycoses:
• Systemic mycotic infections such as systemic candidiasis;
• Chronic and recurrent vaginal candidiasis not responding to topical treatment;
• Serious chronic infections of the skin, hair and nails caused by sensitive dermatophytes e.g. Trichophyton rubrum, T mentagrophytes; and/or yeasts (dermatomycoses, paronychia, serious chronic mucocutaneous candidiasis etc.);
• When topical treatment is ineffective owing to the involvement of large areas of the skin, or lesions penetrating the deeper dermal layers, nails and hair;
• Serious mycoses of the gastro-intestinal tract not responsive to other therapy or when the organism is resistant to other therapy;
• Serious chronic mucocutaneous candidiasis not responsive to other therapy or when the organism is resistant to other therapy;
• Paracoccidioidomycosis;
• Pulmonary, oral and/or disseminated histoplasmosis; and
• Coccidioidomycosis.

CONTRA-INDICATIONS:
Ketazol is contra-indicated in patients who have shown hypersensitivity to it or any of its ingredients.
Ketazol should not be given to patients with pre-existing liver disease.
Ketazol is not recommended during pregnancy, as ketoconazole has been shown to be teratogenic in animals.
Ketazol should not be used by breastfeeding mothers.
Ketazol is not intended for use in children, as safety has not been proven.
The concomitant administration of terfenadine and astemizole with Ketazol is contra-indicated.

WARNINGS:
Patients taking Ketazol should avoid alcohol. Cases have been reported of a disulfiram-like reaction to alcohol, characterised by flushing, peripheral oedema, nausea and headache.
Hepatitis has been reported during treatment with Ketazol. If symptoms or signs suggestive of hepatic dysfunction are detected, medication should be stopped at once. Patients on Ketazol should be instructed to report any of the prodromal symptoms of hepatitis, such as fatigue associated with nausea or vomiting, jaundice, dark urine or pale stools, immediately and stop treatment.
Factors increasing the risk of hepatitis are: females over 50 years of age, previous treatment with griseofulvin, history of liver disease, known drug intolerance, long-lasting treatment and concomitant use of liver compromising medication.
Patients on prolonged therapy (longer than 2 weeks) should have regular monitoring of liver function (before treatment, after 2 weeks and, later on, monthly), particularly those patients with a known history of prior liver disease or an idiosyncrasy to other medicines.
Should liver disease be confirmed, the therapy is to be discontinued. It should be noted, however, that in patients with fungal infections whether they are treated with Ketazol or not, a mild transient asymptomatic increase of transaminase or alkaline phosphatase may occur. In most instances, enzyme levels return to normal without the need to discontinue medication.
After long-term griseofulvin treatment, it is advisable to wait for one month before starting treatment with Ketazol.

DOSAGE AND DIRECTIONS FOR USE:
Chronic and recurrent vaginal candidiasis not responding to topical treatment:
Two tablets (400 mg) once daily with a meal for 5 days.
All other indications:
One tablet (200 mg) once daily with a meal until at least one week after the symptoms have disappeared and until all cultures have become negative. The dose of ketoconazole may be doubled to 400 mg if the clinical response is insufficient after a reasonable period of treatment.
The usual duration of treatment is a follows:
Serious chronic mycoses of the skin and hair: 1 - 2 months.
Systemic candidiasis: 1 - 2 months
Serious chronic mucocutaneous candidiasis: 6 - 12 months.
Paracoccidioidomycosis and histoplasmosis: 2 - 6 months.
Dermatophytes: 4 weeks.

Note: Ketazol should be taken with meals for maximal absorption. Effective absorption depends upon intact gastric activity, hence concomitant administration with drugs that reduce gastric secretion (anticholinergic drugs, antacids and H2 blockers) should be avoided. When indicated, these drugs should not be taken within two hours after Ketazol.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Nausea, vomiting, gastro-intestinal complaints, constipation, headache, dizziness, somnolence or drowsiness, photophobia, paraesthesia, thrombocytopenia, exanthema or itching have been reported. Increases in serum liver enzymes may occur. Anaphylactoid reactions, alopecia, urticaria, rash, transient decreased libido, reversible gynaecomastia and oligospermia may occur.
Decreased plasma testosterone values which normalise within 24 hours after administration of Ketazol may also occur. During long-term therapy at this level of dosage, testosterone levels are usually not significantly different from controls.
Special Precautions:
Serum cortisol levels may decrease and response of cortisol on ACTH may be blunted. The adrenal function should therefore 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:
The concomitant administration of rifampicin or isioniazid with ketoconazole reduces the blood levels of the latter. Both drugs should not be administered concomitantly.
Since ketoconazole inhibits certain hepatic oxidase enzymes, it may decrease the elimination of co-administered drugs whose metabolism depends on such enzymes. Increased levels of such drugs, when used together with ketoconazole, have been associated with an increase in side-effects.
Known examples of serious interactions include those with cyclosporin, terfenadine, astemizole, cisapride, oral midazolam, triazolam, anticoagulants (e.g. warfarin), methylprednisolone, phenytoin and, possibly, busulphane and tacrolimus. The dosage of cyclosporin, anticoagulants, methylprednisolone, tacrolimus and busulphane, if co-administered with ketoconazole, should be reduced if necessary. Terfenadine, astemizole, cisapride, oral midazolam and triazolam should not be used by patients using ketoconazole. If midazolam is administered intravenously, special precaution is required since the sedative effect may be prolonged.
Ketoconazole interacts with certain anti-retroviral agents, namely didanosine, saquinavir, ritonavir and indinavir. If used together with didanosine, ketoconazole should be administered approximately 2 hours before didanosine administration to aid absorption. When administered with indinavir, the concentration of indinavir increases, thus the dosage of indinavir should be reduced. Ketoconazole also increases the concentrations of saquinavir and ritonavir and although these increases are minimal, care should be taken with these patients.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See Side-effects and Special Precautions.
In the event of accidental overdosage, supportive and symptomatic measures including gastric lavage with sodium bicarbonate, should be employed.

IDENTIFICATION:
A round, white tablet with bevelled edges, bisected on one side.

PRESENTATION:
Blister packs of 10's, 30’s and 100's.

STORAGE INSTRUCTIONS:
Store below 25°C in a dry place. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
33/20.2.2/0309

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacare Limited
7 Fairclough Road
Korsten
Port Elizabeth
6020

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
3 September 1999

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New addition to this site: May 2005
Source: Hospital Pharmacy

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