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

Logo NIZORAL® 200 mg tablet

SCHEDULING STATUS
Schedule 4.

PROPRIETARY NAME
(and dosage form)

NIZORAL® 200 mg tablet

COMPOSITION
Each tablet contains
ketoconazole 200 mg.

PHARMACOLOGICAL CLASSIFICATION
A.20.2.2 Antimicrobial (chemotherapeutic) agents. Fungicides.

PHARMACOLOGICAL ACTION
NIZORAL is a synthetic imidazole dioxolane derivative, active in vitro against dermatophytes, yeasts and other pathogenic fungi.
Invitro NIZORAL is fungicidal and, therefore, suppresses the formation of mycelia. In vivo, at therapeutic levels however, it is primarily fungistatic.
NIZORAL 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 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 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 cerebral-spinal 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;
- Coccidioidomycosis.

CONTRA-INDICATIONS
Patients with existing liver disease.
NIZORAL is contra-indicated in those patients who have shown hypersensitivity to ketoconazole or to any of the excipients.
Terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin are contra-indicated with NIZORAL.
Pregnancy: Ketoconazole is teratogenic in small laboratory animals. No studies are available on its use in pregnant women. Therefore NIZORAL must not be administered during pregnancy.
Lactation: Since NIZORAL is excreted in the milk, mothers who are under treatment should not breast feed.
Not intended for children, as safety has not been proven.

WARNINGS
NIZORAL has a potential for clinically important drug interactions. (See the section on “Interactions”).
Decreased gastric acidity: Absorption is impaired when the gastric acidity is decreased. In patients also receiving acid neutralizing medicines (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 (H2-antagonists, proton pump inhibitors) it is advisable to administer NIZORAL with a cola beverage.
The concomitant administration of terfenadine and astemizole with NIZORAL is contra-indicated. For combinations with other drugs see Interactions.
During NIZORAL treatment hepatitis has been reported. If symptoms or signs suggestive of hepatic dysfunction are detected, medication should be stopped at once. Patients on NIZORAL 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.
A risk/benefit evaluation should be made before ketoconazole in cases of non-life threatening diseases requiring long treatment periods.
Factors increasing the risk of hepatitis are: females over 50 years of age, previous long-term treatment with griseofulvin, history of liver disease, known drug intolerance, long lasting treatment and concomitant use of liver compromising medication.
A mild transient asymptomatic increase in 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.
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.
After long-term griseofulvin treatment, it is advisable to wait for one month before starting NIZORAL treatment.

DOSAGE AND DIRECTIONS FOR USE
NIZORAL should be taken with meals for maximal absorption.
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 as follows:
- Serious chronic mycoses of the skin and hair: 1 to 2 months;
- Systemic candidiasis: 1 to 2 months;
- Serious chronic mucocutaneous candidiasis: 6 to 12 months;
- Paracoccidioidomycosis and histoplasmosis: 2 to 6 months;
- Dermatophytes: 4 weeks.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The most frequently reported adverse experiences in association with the use of NIZORAL were of gastro-intestinal origin, such as dyspepsia, nausea, vomiting, abdominal pain and diarrhoea. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorder, dizziness, photophobia, paraesthesia and allergic reactions, rash and pruritus. Side-effects reported with an extremely low frequency are: thrombocytopenia, alopecia, impotence and reversible intracranial pressure (e.g. papilloedema, bulging fontanel in infants).
Transient decreased libido, reversible gynaecomastia and oligospermia may occur. Somnolence has been reported.
During treatment with NIZORAL, hepatitis (most probably idiosyncratic) has been reported. This is usually reversible if the treatment is promptly discontinued but fatalities have occurred.
Decreased plasma testosterone values which normalise within 24 hours after administration of NIZORAL may also occur, during long term therapy at this level of dosage, testosterone levels are usually not significantly different from controls.
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:
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 under “Warnings”.
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 metabolised by certain hepatic P450 enzymes, especially of the CYP 3A family. This can result in an increase and/or prolongation of their effects including side-effects.
Examples are:
Drugs which should not be used during treatment with ketoconazole:
Terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-Co A reductase inhibitors such as simvastatin and lovastatin.
Drugs whose plasma levels, effects or side-effects should be monitored. Their dosage 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 metabolised Calcium Channel Blockers such as dihydropropyridines and probably verapamil.
Certain immunosuppressive Agents: cyclosporine, tacrolimus rapamycin = sirolimus;
Others: digoxin, carbamazepine, buspirone, alfentanil, sildenafil, alprazolam, brotizolam, midazolam IV, rifabutin, methyl prednisolone and trimetrexate, ebastine, reboxetine.
Cases have been reported of a disulfiram-like reaction to alcohol, characterised by flushing, peripheral oedema, nausea and headache.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In the event of accidental overdosage, supportive measures including gastric lavage with sodium bicarbonate, should be employed.

IDENTIFICATION
White, circular, flat, bevelled edge, scored tablets (local) inscribed “K”above “200”on one 200 side and "JANSSEN" on the other side.

PRESENTATION
Carton containing one or more blister packs of 10 tablets each.

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

REGISTRATION NUMBER
P/20.2.2/36

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/11122/07)
15th Road, HALFWAY HOUSE 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
4 September 1992

                        024232 - 2002D
                        Britepak
® = TRADEMARK

Updated on this site: November 2002
Current: November 2005
Source: Community Pharmacy

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