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Ketoconazole
Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine. Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44. Tablets: Ketoconazole is a synthetic broad-spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Shampoo: Ketoconazole 2% Shampoo is a red-orange liquid for topical application, containing the broad-spectrum synthetic antifungal agent ketoconazole in a concentration of 2% in an aqueous suspension. It also contains: coconut fatty acid diethanolamide, disodium monolauryl ether sulfosuccinate, FD&C Red No. 40, hydrochloric acid, imidurea, laurdimonium hydrolyzed animal collagen, macrogol 120 methyl glucose dioleate, perfume bouquet, sodium chloride, sodium hydroxide, sodium lauryl ether sulphate, and purified water. Cream: Ketoconazole 2% cream contains the broad-spectrum synthetic antifungal agent ketoconazole 2% formulated in an aqueous cream vehicle consisting of propylene glycol, stearyl and cetyl alcohols, sorbitan monostearate, polysorbate 60, isopropyl myristate, sodium sulfite anhydrous, polysorbate 80 and purified water.
TABLETS Mean peak plasma levels of approximately 3.5 mcg/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 half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the gastrointestinal 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. 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. 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 weak dibasic agent and thus requires acidity for dissolution and absorption. Ketoconazole Tablets are active against clinical infections withBlastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. Ketoconazole Tablets are also active againstTrichophyton spp., Epidermophyton spp., and Microsporum spp. Ketoconazole is also active in vitro against a variety of fungi and yeast. In animal models, activity has been demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Coccidioides immitis, and Cryptococcus neoformans. Mode of Action In vitro studies suggest that Ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. SHAMPOO When ketoconazole 2% shampoo was applied dermally to intact or abraded skin of rabbits for 28 days at doses up to 50 mg/kg and allowed to remain one hour before being washed away, there were no detectable plasma ketoconazole levels using an assay method having a lower detection limit of 5 ng/ml. Ketoconazole was not detected in plasma in 39 patients who shampooed 4-10 times per week for 6 months or in 33 patients who shampooed 2-3 times per week for 3-26 months (mean: 16 months). Twelve hours after a single shampoo, hair samples taken from six patients showed that high amounts of ketoconazole were present on the hair but only about 5% had penetrated into the hair keratin. Chronic shampooing (twice weekly for two months) increased the ketoconazole levels in the hair keratin to 20%, but did not increase levels on the hair. There were no detectable plasma levels. An exaggerated use washing test on the sensitive antecubital skin of 10 subjects twice daily for five consecutive days showed that the irritancy potential of ketoconazole 2% shampoo was significantly less than that of 2.5% selenium sulfide shampoo. A human sensitization test, a phototoxicity study, and a photoallergy study conducted in 38 male and 22 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no phototoxicity and no photoallergic potential due to ketoconazole 2% shampoo. Mode of Action Interpretations of in vivo studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in dandruff is due to the reduction ofPityrosporum ovale (Malassezia ovale), but this has not been proven. Support for this hypothesis comes from a 4-week double-blind, placebo controlled clinical trial in which the decrease in P. ovale on the scalp was significantly greater with ketoconazole (36 patients) than with placebo (20 patients) and was comparable to that with selenium sulfide (42 patients). In the same study, ketoconazole and selenium sulfide reduced the severity of adherent dandruff significantly more than placebo did. Ketoconazole produced significantly higher proportions of patients with at least 50% reductions in adherent dandruff (50% vs. 15%) and in loose dandruff (67% vs. 15%) than did the placebo. Microbiology Ketoconazole is a broad-spectrum synthetic antifungal agent which inhibits the growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, C. tropicalis, Pityrosporum ovale (Malassezia ovale) and Pityrosporum orbiculare (M. furfur). Development of resistance by these microorganisms to ketoconazole has not been reported. CREAM When ketoconazole 2% cream was applied dermally to intact or abraded skin of Beagle dogs for 28 consecutive days at a dose of 80 mg, there were no detectable plasma levels using an assay method having a lower detection limit of 2 ng/ml. After a single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the 5 ng/ml level in blood over a 72-hour period. Two dermal irritancy studies, a human sensitization test, a phototoxicity study and a photoallergy study conducted in 38 male and 62 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity and no photoallergic potential due to ketoconazole 2% cream. Microbiology Ketoconazole is a broad spectrum synthetic antifungal agent which inhibits the in vitro growth of the following common dermatophytes and yeast by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, Malassezia ovale (pityrosporum ovale) and C. tropicalis; and the organism responsible for tinea versicolor,Malassezia furfur (Pityrosporum orbiculare). Only those organisms listed in the INDICATIONS AND USAGE have been proven to be clinically affected. Development of resistance to ketoconazole has not been reported. Mode of Action In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in seborrheic dermatitis is due to the reduction of M. ovale, but this has not been proven.
Tablets Ketoconazole tablets are indicated for the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole should not be used for fungal meningitis because it penetrates poorly into the cerebral-spinal fluid. Ketoconazole tablets are also indicated for the treatment of patients with severe recalcitrant cutaneous dermatophyte infections who have not responded to topical therapy or oral griseofulvin, or who are unable to take griseofulvin. Shampoo Ketoconazole 2% shampoo is indicated for the reduction of scaling due to dandruff. Cream Ketoconazole 2% cream is indicated for the topical treatment of tinea corporis, tinea cruris and tinea pedis caused by Trichophyton rubrum, T. mentagrophytes, (efficacy for this organism in this organ system was studied in fewer than ten infections), and Epidermophyton floccosum; in the treatment of tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare); in the treatment of cutaneous candidiasis caused by Candida spp. and in the treatment of seborrheic dermatitis.
Tablets Adults: The recommended starting dose of ketoconazole Tablets is a single daily administration of 200 mg (one tablet). In very serious infections or if clinical responsiveness is insufficient within the expected time, the dose of ketoconazole may be increased to 400 mg (two tablets) once daily. Children: In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg has been used. Ketoconazole tablets have not been studied in children under 2 years of age. There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole therapy. Treatment should be continued until tests indicate that active fungal infection has subsided. Inadequate periods of treatment may yield p.o. response and lead to early recurrence of clinical symptoms. Minimum treatment for candidiasis is one or two weeks. Patients with chronic mucocutaneous candidiasis usually require maintenance therapy. Minimum treatment for the other indicated systemic mycoses is six months. Minimum treatment for recalcitrant dermatophyte infections is four weeks in cases involving glabrous skin. Palmar and plantar infections may respond more slowly. Apparent cures may subsequently recur after discontinuation of therapy in some cases. Shampoo Moisten hair and scalp thoroughly with water. Apply sufficient shampoo to produce enough lather to wash the scalp and hair gently massage it over the entire scalp area for approximately one minute. Rinse the hair thoroughly with warm water. Repeat, leaving the shampoo on the scalp for an additional 3 minutes. After the second thorough rinse, dry the hair with a towel or warm air flow. Shampoo twice a week for four weeks with at least three days between each shampooing and then intermittently as needed to maintain control. Cream Cutaneous candidiasis, tinea corporis, tinea cruris, and tinea (pityriasis) versicolor: It is recommended that ketoconazole 2% cream be applied once daily to cover the affected and immediate surrounding area. Clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks in order to reduce the possibility of recurrence. Patients with tinea versicolor usually require two weeks of treatment. Patients with tinea pedis require six weeks of treatment. Seborrheic Dermatitis: Ketoconazole 2% cream should be applied to the affected area twice daily for four weeks or until clinical clearing. If a patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined. HOW SUPPLIED Tablets Nizoral is available as white, scored tablets containing 200 mg of ketoconazole debossed "JANSSEN" and on the reverse side debossed "NIZORAL". Storage: Store at room temperature (59°-86°F/15°-30°C). Protect from moisture. Shampoo Nizoral 2% shampoo is a red-orange liquid supplied in a 4-fluid ounce nonbreakable plastic bottle. Storage: Store at a temperature not above 25°C (77°F). Protect from light. Cream Nizoral 2% cream is supplied in 15, 30 and 60 gm tubes.
Tablets In rare cases anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported. However, the most frequent adverse reactions were nausea and/or vomiting in approximately 3%, abdominal pain in 1.2%, pruritus in 1.5%, and the following in less than 1% of the patients: headache, dizziness, somnolence, fever and chills, photophobia, diarrhea, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, and bulging fontanelles. Oligospermia has been reported in investigational studies with the drug at dosages above those currently approved. Oligospermia has not been reported at dosages up to 400 mg daily, however, sperm counts have been obtained infrequently in patients treated with these dosages. Most of these reactions were mild and transient and rarely required discontinuation of ketoconazole tablets. In contrast, the rare occurrences of hepatic dysfunction require special attention (see WARNINGS.) Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely in patients using ketoconazole Tablets. Ventricular dysrhythmias (prolonged QT intervals) have occurred with the concomitant use of terfenadine with ketoconazole tablets. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS.) Shampoo In 11 double-blind trials in 264 patients using ketoconazole 2% shampoo, an increase in normal hair loss and irritation occurred in less than 1% of patients. In three open-label safety trials in which 41 patients shampooed 4-10 times weekly for six months, the following adverse experiences each occurred once: abnormal hair texture, scalp pustules, mild dryness of the skin, and itching. As with other shampoos, oiliness and dryness of hair and scalp have been reported. Cream During clinical trials 45 (5.0%) of 905 patients treated with ketoconazole 2% Cream and 5 (2.4%) of 208 patients treated with placebo reported side effects consisting mainly of severe irritation, pruritus and stinging. One of the patients treated with ketoconazole Cream developed a painful allergic reaction.
Tablets When taken orally, imidazole compounds like ketoconazole may enhance the anticoagulant effect of coumarin-like drugs. In simultaneous treatment with imidazole drugs and coumarin drugs, the anticoagulant effect should be carefully titrated and monitored. Concomitant administration of rifampin with ketoconazole reduces the blood levels of the latter. INH (isoniazid) is also reported to affect ketoconazole concentrations adversely. These drugs should not be given concomitantly. Ketoconazole tablets may alter the metabolism of cyclosporine and methylprednisolone, resulting in elevated plasma concentrations of the latter drugs. Dosage adjustment may be required if cyclosporine or methylprednisolone are given concomitantly with ketoconazole tablets. Concomitant administration of ketoconazole with phenytoin may alter the metabolism of one or both of the drugs. It is suggested to monitor both ketoconazole and phenytoin. Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole (an imidazole) and oral hypoglycemic agents, such a potential interaction involving the latter agents when used concomitantly with ketoconazole (an imidazole) can not be ruled out. Ketoconazole tablets inhibit the metabolism of terfenadine, resulting in an increased plasma concentration of terfenadine ad a delay in the elimination of its acid metabolite. Increased plasma concentration of terfenadine or its acid metabolite may result in prolonged QT intervals. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS.) Pharmacokinetic data indicate that oral ketoconazole inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals. Coadministration of astemizole with ketoconazole tablets is therefore contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS.) After the coadministration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11 subjects, the AUC and Cmax of loratadine averaged 302% (± 142 S.D.) and 251% (± 68 S.D.), respectively, of those obtained after co-treatment with placebo. The AUC and Cmax of descarboethoxyloratadine, an active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively. However, no related changes were noted in the QT0 on ECG taken at 2, 6, and 24 hours after the coadministration. Also, there were no clinically significant differences in adverse events when loratadine was administered with or without ketoconazole. Rare cases of a disulfiram-like reaction to alcohol have been reported. These experiences have been characterized by flushing, rash, peripheral edema, nausea, and headache. Symptoms resolved within a few hours.
Tablets Hepatotoxicity, primarily of the hepatocellular type, has been associated with the use of Ketoconazole Tablets, including rare fatalities. The reported incidence of hepatotoxicity has been about 1:10,000 exposed patients, but this probably represents some degree of under-reporting, as is the case for most reported adverse reactions to drugs. The median duration of ketoconazole therapy in patients who developed symptomatic hepatotoxicity was about 28 days, although the range extended to as low as 3 days. The hepatic injury has usually, but not always, been reversible upon discontinuation of ketoconazole treatment. Several cases of hepatitis have been reported in children. Prompt recognition of liver injury is essential. Liver function tests (such as SGGT, alkaline phosphatase, SGPT, SGOT and bilirubin) should be measured before starting treatment and at frequent intervals during treatment. Patients receiving ketoconazole concurrently with other potentially hepatotoxic drugs should be carefully monitored, particularly those patients requiring prolonged therapy or those who have had a history of liver disease. Most of the reported cases of hepatic toxicity have to date been in patients treated for onychomycosis. Of 180 patients worldwide developing idiosyncratic liver dysfunction during ketoconazole tablet therapy, 61.3% had onychomycosis and 16.8% had chronic recalcitrant dermatophytoses. Transient minor elevations in liver enzymes have occurred during ketoconazole treatment. The drug should be discontinued if these persist, if the abnormalities worsen, or if the abnormalities become accompanied by symptoms of possible liver injury. In rare cases anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported. Coadministration of ketoconazole tablets and terfenadine has led to elevated plasma concentrations of terfenadine which may prolong QT intervals, sometimes resulting in life-threatening cardiac dysrhythmias. Cases of torsades de pointes and other serious ventricular dysrhythmias, in rare cases leading to fatality, have been reported among patients taking terfenadine concurrently with ketoconazole tablets. Coadministration of ketoconazole tablets and terfenadine is contraindicated. Coadministration of astemizole with ketoconazole tablets is contraindicated.
(See BOXED WARNING, CONTRAINDICATIONS,
and In European clinical trials involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high dose of ketoconazole (1200 mg/day). It is not possible to ascertain from the information available whether death was related to ketoconazole therapy in these patients with serious underlying disease. However, high doses of ketoconazole tablets are known to suppress adrenal corticosteroid secretion. In female rats treated three to six months with ketoconazole at dose levels of 80 mg/kg and higher, increased fragility of long bones, in some cases leading to fracture, was seen. The maximum "no effect" dose level in these studies was 20 mg/kg (2.5 times the maximum recommended human dose). The mechanisms responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrated such an effect on the metacarpals and ribs. Cream Ketoconazole 2% cream is not for ophthalmic use. Ketoconazole 2% cream contains sodium sulfite anhydrous, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown, and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
General Shampoo: If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Tablets: Ketoconazole tablets have been demonstrated to lower serum testosterone. Once therapy with ketoconazole has been discontinued, serum testosterone levels return to baseline values. Testosterone levels are impaired with doses of 800 mg per day and abolished by 1600 mg per day. Ketoconazole also decrease ACTH induced corticosteroid serum levels at similar high doses. The recommended dose of 200 mg - 400 mg daily should be followed closely. In four subjects with drug-induced achlorhydria, a marked reduction in ketoconazole absorption was observed. Ketoconazole tablets require acidity for dissolution. If concomitant antacids, anticholinergics, and H2-blockers are needed, they should be given at least two hours after administration of ketoconazole Tablets. In cases of achlorhydria, the patients should be instructed to dissolve each tablet in 4 ml aqueous solution of 0.2 N HCl. For ingesting the resulting mixture, they should use a drinking straw so as to avoid contact with the teeth. This administration should be followed with a cup of tap water. Information for the Patient Shampoo: May be irritating to mucous membranes of the eyes and contact with this area should be avoided. There have been reports that use of the shampoo resulted in removal of the curl from permanently waved hair. Tablet: Patients should be instructed to report
any signs and symptoms which may suggest liver
dysfunction so that
appropriate biochemical
testing can be done. Such signs and symptoms may include unusual
fatigue, anorexia, nausea
and/or vomiting, jaundice,
dark urine or pale stools
(see Carcinogenesis, Mutagenesis, and Impairment of Fertility The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produce no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative. A long term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. Pregnancy Teratogenic Effects, Pregnancy Category C Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rate when given in the diet at 80 mg/kg/day, (10 times the maximum recommended human dose). However, these effects may be related to maternal toxicity, evidence of which also was seen at this and higher dose levels. There are no adequate and well controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Shampoo: Ketoconazole is not detected in plasma after chronic shampooing. Tablets: Nonteratogenic Effects: Ketoconazole has also been found to be embryotoxic in the rat when given in the diet at doses higher than 80 mg/kg during the first trimester of gestation. In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole during the third trimester of gestation. This occurred when ketoconazole was administered at doses higher than 10 mg/kg (higher than 1.25 times the maximum human dose). It is likely that both the malformations and the embryotoxicity resulting from the administration of oral ketoconazole during gestation are a reflection of the particular sensitivity of the female rat to this drug. For example, the oral LD50, of ketoconazole given by gavage to the female rat is 166 mg/kg whereas in the male rat the oral LD50 is 287 mg/kg. Nursing Mothers Cream: It is not known whether ketoconazole 2% cream administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Shampoo: Ketoconazole is not detected in plasma after chronic shampooing. Nevertheless, caution should be exercised when ketoconazole 2% shampoo is administered to a nursing woman. Tablets: Since ketoconazole is probably excreted in the milk, mothers who are under treatment should not breast feed. Pediatric Use Cream: Safety and effectiveness in children have not been established. Shampoo: Safety and effectiveness in children have not been established. Tablets: Ketoconazole Tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. Ketoconazole should not be used in pediatric patients unless the potential benefit outweighs the risks.
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