Formulation:

Each uncoated tablet contains;

Ketoconazole…………….200 mg

Indications:

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.

Dosage and Administration:

Oral

Ketoconazole 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 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.

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

ADVERSE REACTIONS:

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 summarized 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 the table below:

Post-marketing Experience

Including the above mentioned Adverse Drug Reactions (ADRs), the following ADRs have been observed from post-marketing experiences reported with the use of Ketoconazole 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’.

Pregnancy and lactation:

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

Precautions:

Because of the risk for serious hepatic toxicity, Ketoconazole 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. 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 greater than 10 days should only be given after full consideration of the extent of treatment response and the riskbenefit of continuing treatment

All patients should be counseled 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 Ketoconazole 200 mg tablets. Monitor liver function prior to treatment to rule out acute or chronic liver disease. 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 Ketoconazole 200 mg tablets. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H -antagonists, proton pump inhibitors), it is advisable to administer Ketoconazole 2 200 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 Ketoconazole 200 mg tablets in children weighing less than 15 kg is very limited. Therefore it is not recommended to administer Ketoconazole 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

Ketoconazole 200 mg has a potential for clinically important drug interactions.

Use with domperidone

A slight increase of QT interval (mean less than 10 milliseconds) 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.

Pharmacokinetics:

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 cerebrospinal 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.

Elimination

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.

Storage Condition:

Store at temperatures not exceeding 30 °C.

Caution:

Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Availability:

Aluminium foil strip of 10 tablets (box of 10’s and 30’s).

Manufactured By:

Kusum Healthcare Pvt. Ltd.

SP-289 (A), RIICO Indl. Area, Chopanki (Bhiwadi), Distt- Alwar (Rajasthan), INDIA

Imported and Distributed By:

S.M.H.P Marketing & Consultancy

G/F Manor Bldg. 2629 Taft Avenue

Malate, Manila, Philippines