Each tablet contains: Ketoconazole 200 mg.
Pharmacology: Mechanism of Action: Fungistatic; may be fungicidal, depending on concentration; azole antifungals interfere with cytochrome P450 enzyme activity, which is necessary for the demethylation of 14-alpha-methylsterols to ergosterol. Ergosterol, the principal sterol in the fungal cell membrane, becomes depleted. This damages the cell membrane, producing alterations in membrane functions and permeability. In Candida albicans, azole antifungals inhibit transformation of blastospores into invasive mycelial form.
High dose Ketoconazole therapy may interfere with conversion of lanosterol to cholesterol, a major precursor of several hormones. It has been shown to suppress corticosteroid secretion and lower serum testosterone concentrations, which return to baseline values when Ketoconazole is discontinued.
Pharmacokinetics: Bioavailability (%): 75 (with food); VolD: 0.36 L/kg.
Serum concentrations (CSF): <10%.
Protein binding: 99%.
Half-life (hr): Normal renal function- 8.
Time to peak serum concentration (hr): 1-4.
Peak serum concentration after dose: 3.5 mcg/mL; dose-200 mg (with food).
Renal excretion (% unchanged): 2-4.
Biliary excretion: Yes; primary route of elimination.
Well distributed; distributed to inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissue, and testes (small amounts); crosses the placenta; crosses the blood-brain barrier poorly; only negligible amounts reach the CSF. Although concentrations of 2.2 to 3 mcg per mL have been reported in the CSF with corresponding serum concentrations of 9 to 12 mcg per mL, most studies indicate that CSF concentrations >1 mcg per mL are rare, regardless of dose.
Indicated for the treatment of esophageal and oropharyngeal candidiasis (thrush); Disseminated candidiasis including peritonitis, pneumonia, and urinary tract infections; Severe, chronic extensive mucocutaneous candidiasis; Chromomycosis; Paracoccidioidomycosis caused by Paracoccidioides brasiliensis; Pityriasis versicolor, Tinea corporis, Tinea cruris, and Tinea pedis infections.
Usual adult and adolescent dose: Pityriasis versicolor- 200 mg once a day for five to ten days.
For all other antifungal indications- 200 to 400 mg once a day.
Usual adult prescribing limits: 1 g a day.
Usual pediatric dose: For all other antifungal indications- Children 2 years of age and older: 3.3 to 6.6 mg per Kg of body weight once a day.
Infants and children up to 2 years of age: Dosage has not been established.
Except under special circumstances, this medication should not be used when the following medical problem exists: Hypersensitivity to azole antifungals.
Risk-benefit should be considered when the following medical problems exist: Achlorhydria or Hypochlorhydria (may cause marked reduction in absorption of Ketoconazole; patients with acquired immunodeficiency syndrome [AIDS] may have reduced Ketoconazole absorption due to hypochlorhydria).
Alcoholism, active or in remission or Hepatic function impairment (azole antifungals are metabolized in the liver and may infrequently be hepatotoxic; azole antifungals, especially Ketoconazole, should be used with caution in patients with pre-existing liver function impairment, those who have experienced liver toxicity with other medications, or a history of alcoholism). Ketoconazole has also been reported to cause a disulfiram-like reaction to alcohol, characterized by flushing, rash, peripheral edema, nausea and headache; symptoms resolved within a few hours.
Carcinogenicity/Tumorigenicity: Long-term feeding studies in Swiss albino mice and in Wistar rats have not shown evidence of oncogenesis.
Mutagenicity: Dominant lethal mutation tests have not shown mutation in any stage of germ cell development in male and female mice given single, oral doses of Ketoconazole as high as 80 mg/Kg. In addition, the Ames/salmonella microsomal activator tests have not shown evidence of mutagenicity.
Fertility: Ketoconazole has been shown to decrease or abolish serum testosterone concentrations when used in high doses (e.g., 800 mg to 1.6 g daily). Ketoconazole has also been shown to cause menstrual irregularities, oligospermia, azoospermia, impotence, and decreased male libido.
Use in Children: Several cases of hepatitis have been reported in children who have taken Ketoconazole. Appropriate studies on the relationship of age to the effects of Ketoconazole have not been performed in children up to 2 years of age. However, no pediatrics-specific problems have been documented to date in children over 2 years of age.
Use in Elderly: No information is available on the relationship of age to the effects of azole antifungals in geriatric patients.
Pregnancy: Ketoconazole crosses the placenta. Adequate and well-controlled studies in humans have not been done.
Studies in rats given doses of 80 mg/Kg per day (10 times the MRHD) have shown Ketoconazole to be teratogenic, causing syndactyly and oligodactyly.
Ketoconazole has also been shown to be embryotoxic in rats given doses greater than 80 mg/Kg during the first trimester.
Labor: Ketoconazole has also been shown to cause dystocia in rats given doses greater than 10 mg/Kg (greater than 1.25 times the MRHD) during the third trimester.
Breastfeeding: Ketoconazole is distributed into breast milk.
Those indicating need for medical attention:
Incidence less frequent: Hypersensitivity (fever and chills; skin rash or itching).
Those indicating need for medical attention only if they continue or are bothersome:
Incidence less frequent: Central nervous system (CNS) effects (dizziness; drowsiness; headache); gastrointestinal disturbances (abdominal pain; constipation; diarrhea; loss of appetite; nausea; vomiting).
Incidence rare: Gynecomastia (enlargement of the breasts in males); impotence (decreased sexual ability in males); menstrual irregularities; photophobia (increased sensitivity of the eyes to light).
Note: Gynecomastia and impotence are due to inhibition of testosterone and adrenal steroid synthesis.
Alcohol or Hepatotoxic medications, other (concurrent use with Ketoconazole may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with history of liver disease, should be monitored carefully and should be advised to avoid alcoholic beverages and other hepatotoxins) (concurrent ingestion of alcohol with Ketoconazole has been reported to result disulfiram-like reaction, characterized by facial flushing; other symptoms may include difficult breathing, slight fever, and tightness of the chest; these effects subsided spontaneously within 24 hours with no lasting ill effects).
Alprazolam; Diazepam; Midazolam; Triazolam (concurrent use with Ketoconazole elevates the plasma concentration of oral Midazolam or Triazolam, which may potentiate and prolong their hypnotic and sedative effects; oral Midazolam and Triazolam should not be used in patients treated with Ketoconazole).
Antacids or Anticholinergics/antispasmodic; Histamine H2-receptor antagonists or Omeprazole and Sucralfate (these medications increase gastrointestinal pH; this may result in a marked reduction in absorption of Ketoconazole; Ketoconazole depends on stomach acid for dissolution and subsequent absorption; patients should be advised to take these medications at least 2 hours after taking Ketoconazole).
Astemizole and Terfenadine (concurrent use of these medications with Ketoconazole is contraindicated; concurrent use of these antihistamines with Ketoconazole may result in elevated plasma concentrations of Astemizole or Terfenadine by inhibiting the cytochrome P450 enzyme metabolic pathways; this has led to cardiac arrhythmias, including QT prolongation, ventricular tachycardia, torsades de pointes, and death).
Cisapride (concurrent use of Cisapride with oral Ketoconazole is contraindicated; concurrent use of Cisapride with these antifungals may inhibit the cytochrome P450 enzyme metabolic pathways, resulting in elevated plasma concentrations of Cisapride; this has led to ventricular arrhythmias, including torsades de pointes and QT prolongation, in patients taking Cisapride and oral Ketoconazole).
Cyclosporin and Tacrolimus (Ketoconazole has been reported to inhibit the metabolism of Cyclosporin and Tacrolimus; this may increase the plasma concentration of Cyclosporin or Tacrolimus to potentially toxic levels; plasma concentrations should be monitored carefully in patients receiving any of the azole antifungals; the dose of Cyclosporin may need to be reduced).
Didanosine (ddl) (Didanosine contains a buffer that increases gastrointestinal pH in order to increase its absorption; Ketoconazole require an acidic environment for their optimal absorption; concurrent administration may result in a marked reduction in absorption of any of these medications; Ketoconazole should be administered at least 2 hours before or 2 hours after Didanosine is given).
Digoxin (Ketoconazole may increase serum Digoxin concentrations, leading to toxicity; Digoxin concentrations should be monitored).
Indinavir; Ritonavir; Saquinavir (concurrent use of Ketoconazole with Indinavir increases the AUC for Indinavir by 68 + 48%; a dose reduction of Indinavir to 600 mg every 8 hours is recommended).
Isoniazid or Rifampin (concurrent use of Rifampin may increase metabolism of Ketoconazole, lowering their plasma concentrations; this may lead to clinical failure or relapse; concurrent use of Isoniazid with Ketoconazole has also been reported to decrease serum concentrations of Ketoconazole; Isoniazid or Rifampin is not recommended to be given concurrently with azole antifungals).
Warfarin (anticoagulant effects may be increased when Warfarin is used concurrently with any azole antifungal, resulting in an increase in prothrombin time [PT]; PT must be monitored carefully in patients receiving Warfarin and azole antifungals.
Store at temperature not more than 30°C.
J02AB02 - ketoconazole ; Belongs to the class of imidazole derivatives. Used in the systemic treatment of mycotic infections.