Nizoral 200 mg Tablets.

Each tablet contains 200 mg ketoconazole.

Excipient: Each tablet contains 19 mg lactose.

For a full list of excipients, see 6.1.

Tablet.

White, circular, flat bevelled-edge, half scored tablet marked 'JANSSEN' on one side and 'K/200' on the other side.

Because of the risk for serious hepatic toxicity, Nizoral 200 mg 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.

Indications are:

Treatment of dermatophytosis and Malassezia (previously called Pityrosporum) folliculitis that cannot be treated topically because of the site, extent of the lesion or deep infection of the skin, in patients resistant to, or intolerant of, fluconazole, terbinafine and itraconazole.

Treatment of chronic mucocutaneous candidosis, cutaneous candidosis, and oropharyngeal candidosis that cannot be treated topically because of the site, extent of the lesion or deep infection of the skin, in patients resistant to or intolerant of both fluconazole and itraconazole.

Method of administration:

Oral.

Nizoral 200 mg tablets should be taken during meals for maximal absorption.

Dosage:

Adults

One tablet (= 200 mg) once daily with a meal. If no adequate response is obtained with this dose, the dose should be increased to 2 tablets (= 400 mg) once daily.

Children

- Children weighing from 15 to 30 kg: half a tablet (=100 mg) once daily with a meal.

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

Duration of Treatment

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, the risk of serious hepatic toxicity increases with longer duration of treatment; courses of greater than 10 days should only be given after full consideration of the extent of treatment response and the risk benefit of continuing treatment, and liver function should be closely monitored (see section 4.4 Special warnings and precautions for use)

For the treatment of Malassezia infections, treatment should not normally exceed 4 weeks.

Special Patient Population: Hepatic Impairment (see 4.3 Contraindications)

Nizoral 200 mg tablets are contraindicated in the following situations:

- in patients with a known hypersensitivity to ketoconazole, to any of the other excipients, or to any other imidazole antifungal.

- In patients with acute or chronic liver disease.

- Co-administration of the CYP3A4 substrates astemizole, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine with Nizoral 200 mg tablets is contraindicated since increased plasma concentrations of these medicinal products can lead to QT prolongation and rare occurrences of torsades de pointes.

- Co-administration of triazolam and oral midazolam.

- Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin.

- Co-administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Co-administration of nisoldipine

- Co-administration of eplerenone

- Co-administration of irinotecan

- Co-administration of everolimus and sirolimus (= rapamycin)

See also 4.5 Interaction with other medicinal products and other forms of interaction.

Because of the risk for serious hepatic toxicity, Nizoral 200 mg 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.

Hepatic toxicity

Very rare cases of serious hepatic toxicity, including cases with a fatal outcome or requiring liver transplantation, have occurred with the use of oral ketoconazole (see 4.8 Undesirable effects). 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 risk of serious hepatic toxicity increases with longer duration of treatment; courses of greater than 10 days should only be given after full consideration of the extent of treatment response and the risk benefit of continuing treatment

All patients should be counselled at the start of treatment with basic knowledge of the signs and symptoms suggestive of liver toxicity. The patient should be informed to discontinue treatment if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function testing should be conducted.

Monitoring of hepatic function

Liver function must be monitored in all patients receiving treatment with Nizoral 200 mg tablets.

Monitor liver function prior to treatment to rule out acute or chronic liver disease (see 4.3 Contraindications).

Liver function must be monitored at weeks 2 and 4 of treatment, then continued monthly, with discontinuation of treatment if any liver parameters are elevated above 3 times the normal limit.

In patients with raised liver enzymes, or those who have experienced liver toxicity with other drugs, treatment should only be started in exceptional cases, where the expected benefit exceeds the risk of hepatic injury, and consideration should be given to monitoring liver function tests (LFTs) more frequently.

Decreased gastric acidity

Absorption is impaired when gastric acidity is decreased. Acid neutralising medicines (e.g. aluminium hydroxide), should not be administered for at least 2 hours after the intake of Nizoral 200 mg tablets. 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 200 mg tablets with a cola beverage.

Monitoring of adrenal function

In volunteers on daily doses of 400 mg and more, ketoconazole has been shown to reduce the cortisol response to ACTH stimulation. Therefore, adrenal function should be monitored in patients with Addison's Disease, adrenal insufficiency or borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.), and in patients on prolonged therapy presenting signs and symptoms suggestive of adrenal insufficiency.

Documented use of Nizoral 200 mg tablets in children weighing less than 15 kg is very limited. Therefore it is not recommended to administer Nizoral 200 mg tablets to small children.

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

Drug interaction potential

Nizoral 200 mg has a potential for clinically important drug interactions (see 4.5 Interaction with other medicinal products and other forms of interaction).

Use with domperidone

A slight increase of QT interval (mean less than 10msec) was reported in a drug-drug interaction study with oral domperidone. Even if the significance of this study is not fully clear, alternative therapeutic options should be considered if oral ketoconazole treatment is required (see also sections 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

1. Drugs affecting the absorption of ketoconazole

Drugs affecting gastric acidity impair the absorption of ketoconazole: see 4.4 Special warnings and precautions for use.

2. Drugs affecting the metabolism of ketoconazole

Ketoconazole is mainly metabolised through the cytochrome CYP3A4.

Enzyme-inducing drugs such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine and phenytoin significantly reduce the bioavailability of ketoconazole. As plasma levels are lower than those expected if ketoconazole is used alone (no co-medication), it is not really necessary to monitor plasma levels. The combination of ketoconazole with potent enzyme inducers is not recommended.

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

3. 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 CYP3A family. This can result in an increase and/or prolongation of their effects including adverse effects.

Co-administration of ketoconazole and domperidone is not recommended since the combination can lead to increased plasma concentrations of domperidone and QT prolongation.

Drugs that are contraindicated during treatment with ketoconazole (see 4.3 Contraindications):

Co-administration of the CYP3A4 substrates astemizole, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine with Nizoral 200 mg tablets is contraindicated since increased plasma concentrations of these medicinal products can lead to QT prolongation and rare occurrences of torsades de pointes.

Co-administration of triazolam and oral midazolam is contraindicated because of an exaggerated and prolonged pharmacodynamic response.

Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin.

Co-administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine))

Co-administration of nisoldipine.

Co-administration of eplerenone.

Co-administration of irinotecan

Co-administration of everolimus and sirolimus (= rapamycin)

When co-administered with oral ketoconazole the following drugs should be used with caution and their plasma concentrations, effects or adverse effects should be monitored. Their dosage, if coadministered with ketoconazole, should be reduced if necessary. This should be considered when prescribing concomitant medication.

Examples include:

• 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 the dihydropyridines and probably verapamil.

• Certain immunosuppressive agents: ciclosporin and tacrolimus

• Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin

• Certain glucocorticoids such as budesonide, fluticasone, dexamethasone and methylprednisolone

• Digoxin (via inhibition of P-glycoprotein)

• Others: cilostazol, buspirone, alfentanil, fentanyl, sildenafil, solifenacin, alprazolam, brotizolam, intravenous midazolam, quetiapine, , repaglinide, tolterodine, trimetrexate, ebastine, eletriptan and reboxetine

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

Pregnancy

There is limited information on the use of Nizoral 200 mg tablets during pregnancy. Animal studies have shown reproductive toxicity (see 5.3 Preclinical safety data). The potential risk to humans is unknown. Therefore, Nizoral 200 mg tablets should not be used during pregnancy unless the potential benefit to the mother outweighs the possible risk to the foetus.

Lactation

Since ketoconazole is excreted in the milk, mothers who are under treatment should not breast-feed whilst being treated with Nizoral 200 mg tablets.

No studies on the effects on the ability to drive and use machines have been performed.

Clinical trials

In a multinational multi-centre, open label study in patients with various superficial and deep mycoses, adverse events during ketoconazole treatment were evaluable in 1361 cases, 149 (11%) reported adverse events. The adverse events were summarised 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.

Postmarketing Experience

Including the above mentioned Adverse Drug Reactions (ADRs), the following ADR's have been observed from post-markleting experiences reported with the use of Nizoral 200 mg tablets. Unlike for clinical trials, precise frequencies cannot be provided for spontaneous reports. The frequency for these reports is therefore classified as 'not known'.

There is no known antidote to ketoconazole.

In the event of accidental overdose, treatment consists of supportive measures. Within the first hour after ingestion gastric lavage may be performed. Activated charcoal may be given if considered appropriate.

Pharmacotherapeutic classification: Antimycotics for systemic use, imidazole derivatives

ATC code: J02A B02

Ketoconazole is an imidazole-dioxolane anti-mycotic, which is effective after oral administration and has a broad spectrum of activity against dermatophytes, yeasts and other pathogenic fungi.

In vitro studies have demonstrated that ketoconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3-7 days can result in a small increase of the QTc interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma levels, about 1-4 hours after ketoconazole administration. This small prolongation of the QTc interval, however, is not considered to be clinically relevant.

At the therapeutic dosage of 200 mg once daily, a transient decrease in the plasma concentrations of testosterone can be observed. Testosterone concentrations return to pre-dose concentrations within 24 hours after administration of ketoconazole has stopped. During long-term therapy at this dosage, testosterone concentrations are usually not significantly different from controls.

In volunteers on daily doses of 400 mg and more, ketoconazole has been shown to reduce the cortisol response to ACTH stimulation (see 4.4 Special warnings and precautions for use).

Absorption

Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations 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.

Distribution

In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid.

Metabolism

Following absorption from the gastro-intestinal 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.

Excretion

Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. 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.

Conditions in special populations

In patients with hepatic or renal insufficiency the overall pharmacokinetics of ketoconazole were not significantly different when compared with healthy subjects. See 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Slight pathological changes in the kidney, 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 (NOAEL) in both these studies was 10 mg/kg/day.

In reproduction studies, at very high, maternally toxic doses (80 mg/kg/day and higher), ketoconazole impaired female fertility in the rat, and produced embryotoxic and teratogenic (oligodactylia and syndactylia) effects in pups. At 40 mg/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 up to a maximum of 160 mg/kg. In pre-clinical studies, ketoconazole was not carcinogenic or genotoxic.

Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT interval.

Maize starch

Lactose

Polyvidone K90

Microcrystalline cellulose

Colloidal anhydrous silica

Magnesium stearate

Not Applicable

36 months.

Do not store above 30°C.

Store in the original package to protect from moisture.

PVC/aluminium blister packs containing 30 tablets

Not applicable.

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Bucks

HP12 4EG

UK

PL 00242/0083

Date of First Authorisation: 22 December 1980

Date of renewal: 25 March 2003

25 June 2010