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Ketoconazole (Nizoral Tablets 200 Mg)

Ketoconazole is an antifungal agent that impairs synthesis of ergosterol, allowing increased permeability in fungal cell membrane and leakage of cellular components. It is indicated in the treatment of susceptible systemic and cutaneous fungal infections.

Topical: used for seborrheic dermatitis, tinea corporis, tinea cruris, tinea pedis, and tinea versicolor. Ketoconazole (200 mg daily) is indicated in the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidiomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.

Moreover, it is effective in the treatment of severe recalcitrant cutaneous dermatophyte infections not responding to topical therapy or oral griseofulvin or in patients unable to take griseofulvin.

Ketoconazole (Nizoral Tablets 200 Mg)

Ketoconazole, a broad-spectrum antifungal agent, impairs the synthesis of ergosterol, the main sterol of fungal cell membranes, allowing increased permeability and leakage of cellular components. Ketoconazole dissolves in an acidic solution. Therefore, antacids, histamine2-receptor-blocking agents, or anticholinergic agents reduce its oral absorption and bioavailabihty. Peak plasma concentration of ketoconazole is achieved within 2 hours and is bound to albumin to the extent of 95 to 99%.

Ketoconazole is metabolized in the liver to inactive metabolites and is excreted mainly (90%) in the bile and feces. Renal failure does not alter the dosing regimen. As ketoconazole penetrates poorly into CSF, it is not used in fungal meningitis.

Ketoconazole has been associated with hepatic toxicity, hence necessitating liver function tests before, during, and after termination of the therapy. Ketoconazole reduces the serum level of testosterone, which returns to normal levels after discontinuation of therapy. It increases the plasma levels, bioavailability, or actions of oral anticoagulants, astemizole, terfenidine, corticosteroids, and cyclosporine, but decreases that of theophylline.

Ketoconazole: Organs and Systems

Respiratory

Patients undergoing esophagectomy are at increased risk of acute lung injury, perhaps related to increased concentrations of thromboxane in the postpulmonary circulation. In 38 consecutive patients undergoing esophagectomy, perioperative ketoconazole, which inhibits thromboxane synthesis, reduced the incidence of acute lung injury.

Nervous system

Headache, dizziness, nervousness, and somnolence have been reported. The incidences are low. Encephalopathy can occur as a result of severe liver damage.

Sensory systems

Eyes

Papilledema has been reported in one patient taking ketoconazole. The condition cleared on withdrawal of ketoconazole and recurred on resumption 2 months later.

Psychological, psychiatric

In one patient taking a high dosage for prostate cancer, weakness was associated with mental disturbances, notably confabulation and disorientation in time and space.

Endocrine

Gynecomastia was occasionally observed in men when ketoconazole first became available. Ketoconazole has a marked effect on steroid concentrations, including a change in the testosterone/estradiol ratio, and this is most likely to be the basis of the gynecomastia. A lowering of testosterone serum concentrations and a reduced response of testosterone concentrations to human gonadotropin have been shown. Various studies have shown suppression of testosterone, androstenedione, and dehydroepiandrosterone, with reciprocal increases in gonadotrophins.

Reductions in serum and urinary cortisol concentrations have been reported in patients taking ketoconazole and signs of hypoadrenalism have been seen during high-dose treatment. However, it is not clear whether the asthenia syndrome described in the past (severe muscle weakness, most pronounced in the legs, fatigue, apathy, and anorexia) is related to hypoadrenalism. In some cases, hypoadrenalism has been described shortly after the start of low-dose treatment. Substitution therapy may be required, since simple withdrawal of ketoconazole may not redress hormonal balance quickly enough.

Various studies have shown that ketoconazole interferes with 17- and 20-hydroxylases and inhibits mitochondrial 11-a-hydroxylase and cytochrome P450-dependent steroid hydroxylase enzymes.

Because of its effects on the pituitary/adrenal system, ketoconazole has been used in the long-term control of hypercortisolism of either pituitary or adrenal origin. In seven patients with Cushing's disease and one with an adrenal adenoma, ketoconazole 600-800 mg/day for 3-13 months produced rapid persistent clinical improvement. Plasma dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid and cortisol excretion fell soon after the start of treatment, and remained normal or nearly so throughout treatment. Urinary tetrahydro-11-deoxycortisol excretion rose significantly. Plasma cortisol concentrations fell. Plasma ACTH concentrations did not change and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another. The patients recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment.

The effect of ketoconazole appears to be mediated by inhibition of adrenal 11-P-hydroxylase and 17,20-lyase, and in some unknown way it prevents the expected rise in ACTH secretion in patients with Cushing's disease. It may, however, cause such a rapid reduction in serum cortisol concentrations that a crisis is precipitated, and patients' adrenal function should be carefully monitored. While ketoconazole (400-800 mg/day) may be a good alternative to other adrenal steroid inhibitors, patients should be observed for signs of hepatotoxicity. Acute adrenal crisis occasionally occurs.

Because ketoconazole has antiandrogenic properties, it is particularly suitable for women, in whom it has few effects on menstruation and does not cause hirsutism. In men, however, long-term inhibition of androgen production can be disruptive, especially if it leads to gynecomastia and hypogonadism. Combination with ami-noglutethimide and metyrapone has been advocated in order to avoid these effects.

Ketoconazole (400 mg/day) has been used for the treatment of hirsutism and acne in women, but adverse effects, such as headache, nausea, loss of scalp hair, hepatitis, and biochemical changes, were impressive.

Hematologic

Fatal aplastic anemia has been reported during ketoconazole therapy.

Gastrointestinal

Nausea, mild gastrointestinal symptoms, and vomiting can occur in patients taking ketoconazole; diarrhea has been reported, but the incidence is low. The incidence of gastrointestinal complaints is higher with the use of daily doses above 800 mg.

Liver

Mild and often transient rises in serum liver enzyme activities are not uncommon in patients taking ketoconazole; the incidence is reported to be about 10-15%. This figure is higher than originally thought, the newer figures probably representing a greater awareness of the risk rather than a true increase; it is possible, however, that the use of higher doses plays a role.

The incidence of symptomatic hepatic injury associated with ketoconazole is estimated to be about one in 10 000 treated cases. Biochemically, the pattern was hepatocellular in 54%, cholestatic in 16%, and mixed cholestatic-hepatocellular in 30%. Histology (14 cases) showed a predominantly hepatocellular pattern in 57%, with extensive centrilobular necrosis and mild to moderate bridging. Lethal cases of toxic hepatitis and a case necessitating transplantation have been reported.

  • A girl developed fatal liver failure while taking ketoconazole for Cushing's syndrome. The authors proposed using metyrapone when temporary control of hypercortisolism is required in childhood and adolescence.

A cohort study of the risk of acute liver injury among users of oral antifungal drugs has been performed in the general population of the General Practice Research Database in the UK. The cohort included 69 830 patients, free from liver and systemic diseases, who had received at least one prescription for oral griseofulvin, fluconazole, itraconazole, ketoconazole, or terbinafine between 1991 and 1996. Five cases of acute liver injury occurred during the use of oral antifungal drugs. Two of the patients were taking ketoconazole, another two itraconazole, and one terbinafine. The incidence rates of acute liver injury were 134 (CI per 100 000 person-months for ketoconazole, 10 (CI = 2) for itraconazole, and 2.5 for terbinafine. One case was associated with past use of fluconazole. Ketoconazole was the antifungal drug that was associated with the highest relative risk, 228 compared with the risk among non-users, followed by itraconazole and terbinafine, with relative risks of 18 (CI = 2) and 4.2 respectively.

Skin

The risk of serious skin disorders has been estimated in 61 858 users, aged 20-79 years, of oral antifungal drugs identified in the UK General Practice Research Database. They had received at least one prescription for oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. The background rate of serious cutaneous adverse reactions (corresponding to non-use of oral anti-fungal drugs) was 3.9 per 10 000 person-years (95% CI = 2.9). Incidence rates for current use were 15 per 10 000 person-years for itraconazole, 11.1 for terbinafine, 10 for fluconazole, and 4.6 for griseofulvin. Cutaneous disorders associated with the use of oral antifungal drugs in this study were all mild.

Pruritus and occasional rashes can occur in patients taking ketoconazole. Rare cases of a fixed drug eruption have been reported.

Musculoskeletal

  • Muscle weakness and diffuse myalgia were reported in a 17-year-old man with multiple endocrine neoplasia syndrome type 1 taking ketoconazole for oral candidiasis. The electromyogram showed a distinct myopathic pattern. Withdrawal of the ketoconazole was followed by rapid improvement.

In rats, high doses (80 mg/kg) caused syndactyly in one experiment. There are insufficient data to determine whether there might be a harmful effect in humans.

Ketoconazole: Side Effects

See also Antifungal azoles

Ketoconazole was the first azole available for oral administration. However, it has been supplanted by newer azoles with fewer adverse effects and more reliable absorption from the gastrointestinal tract. Even after years of use, new adverse effects (often related to high doses and/or newer indications) continue to be reported.

Ketoconazole is water-soluble at a pH of below 3. Its oral absorption is influenced by the acidity of the stomach contents, and the concomitant administration of histamine H2 receptor antagonists, proton pump inhibitors, antacids, or food affects its absorption. A high carbohydrate meal ingested with ketoconazole reduces total drug absorption, while a high lipid meal increases it. Erratic absorption is particularly apparent in patients with AIDS. Peak serum concentrations are seen within 2-3 hours. The half-life is about 8 hours. CSF penetration is less than 10%. Ketoconazole is extensively metabolized in the liver and excreted in the bile in an inactive form; less than 1% of the active drug is excreted in the urine. Clearance is not significantly altered by renal dialysis.

In man, higher doses of ketoconazole affect cortisol/ cortisone and androgen/testosterone substrates. This finding has led to the use of ketoconazole in Cushing's disease and prostate cancer, but the phenomenon is also responsible for some of the adverse effects, especially those associated with higher doses and prolonged use. The potency of ketoconazole in inhibiting P450 isozymes (such as CYP3A is a cause of interactions with several other drugs.

Use in non-infective conditions

The efficacy of ketoconazole 400 mg qds in the early treatment of acute lung injury and acute respiratory distress syndrome has been investigated in a randomized, double-blind, placebo-controlled trial in 234 patients. Ketoconazole was safe but had no effects on mortality, lung function, or the duration of mechanical ventilation. Because of its potent inhibitory effects on adrenal steroidogenesis by interference with cytochrome CYP450, ketoconazole controls hypercortisolism when surgery is contraindicated or unsuccessful. The effects of oral ketoconazole 200-1200 mg qds for 65-83 months in three patients who had residual or recurrent Cushing's disease after surgical treatment have been reported. The dosage of ketoconazole was adjusted according to the clinical response and 24-hour urinary excretion of free cortisol. All three patients had good clinical and biochemical responses to therapy with ketoconazole and had no adverse effects.

General adverse effects

Gastrointestinal complaints, including anorexia, nausea, gastralgia, and constipation are the most frequent adverse effects of ketoconazole. Hepatotoxicity, varying in degree from mild disturbances of liver function tests to hepatitis and rare cases of fulminating hepatic necrosis, has been reported. Some cases have been reported in the first weeks of treatment, but duration of treatment is of importance and in prolonged courses of treatment, monitoring is advisable. With the use of high doses, especially for longer periods of time, the effects of interference with hormonal balance should be watched for. Adrenal insufficiency has been reported even with low-dose treatment. Pruritus and skin reactions have been reported, but do not in general cause major problems. Hypersensitivity reactions are rare. Tumor-inducing effects have not been reported.

Ketoconazole: Organs and Systems

Second-Generation Effects

Lactation

Ketoconazole can be found in the milk of lactating dogs receiving ketoconazole; there are insufficient data to decide whether harm might ensue to the breast-fed child.

Susceptibility Factors

Age

Because ketoconazole interferes with steroid synthesis and vitamin D metabolism, ketoconazole should not be used in children. It is not approved for use in children and there is no pediatric dosage range based on pharmacokinetic information in this population.

Sex

Liver complications may be more common in elderly people, in women, or in subjects in whom liver function is already compromised for other reasons.

Other features of the patient

Ketoconazole interferes with steroidogenesis, and those who are critically ill or HIV-positive are particularly susceptible to adrenal insufficiency from the use of ketoconazole.

Ketoconazole: Drug-Drug Interactions

Aciclovir

Ketoconazole seems to have a synergistic antiviral effect when it is taken with aciclovir.

Alcohol

A disulfiram-type reaction of ketoconazole with alcohol has been reported.

Amphotericin

Combination of ketoconazole with amphotericin reportedly leads to antagonism, particularly if ketoconazole therapy precedes amphotericin.

Antacids

Co-administration of antacids reduces the absorption of ketoconazole.

Antihistamines

Ketoconazole can increase the concentrations of astemi-zole and terfenadine by inhibition of CYP3A4. High concentrations of terfenadine can cause cardiac toxicity. Increased plasma concentrations of unmetabolized terfenadine prolong the QT interval and carry the risk of torsade de pointes and other fatal ventricular arrhythmias.

Ebastine (10 and 20 mg/day) had no clinically important effect on QTC interval in adults, including elderly people, children, and patients with hepatic or renal impairment, and co-administration with ketoconazole or erythromycin did not lead to significant changes in the QTC interval.

The pharmacokinetic and pharmacodynamic interactions of emedastine difumarate and ketoconazole have been investigated in 12 healthy volunteers. Emedastine difumarate 4 mg was given orally for 10 consecutive days, and on days 6-10 ketoconazole 200 mg bd was co-administered. Emedastine steady-state phar-macokinetics were slightly altered by ketoconazole: the AUC rose by about 33% and total clearance fell by about 30%, with no change in the half-life, suggesting that the volume of distribution also changed; this pattern could have arisen from protein binding displacement. However, there was no change in the QTC interval after 5 days of co-treatment. The authors concluded that concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals could therefore be undertaken without special precautions.

When single doses of erythromycin (333 mg) or ketoconazole (200 mg) were given to healthy men who used levocabastine, two sprays per nostril (0.05 mg/spray) bd for 6 days, there were no changes in the pharmacokinetics of levocabastine or in the QTC interval.

Ketoconazole affects plasma concentrations of loratadine, a non-sedating antihistamine, but appears to be devoid of any electrocardiographic effects. In a randomized, single-blind, multiple-dose, three-way, crossover study, concomitant administration of loratadine 10 mg qds and ketoconazole 200 mg bd resulted in significantly increased mean loratadine plasma concentration by 307% and desloratadine plasma concentrations by 73%; ketoconazole plasma concentrations were unaffected by loratadine. Despite increased concentrations of loratadine and its metabolite, there were no statistically significant differences in the electrocardiographic QTC interval.

Benzodiazepines

In a double-blind, crossover kinetic and dynamic study of the interaction of ketoconazole with alprazolam and tria-zolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam. By the same mechanism ketoconazole also inhibits the metabolism of midazolam.

Calcium channel blockers

The effects of ketoconazole 200 mg on the pharmacoki-netics of nisoldipine 5 mg have been investigated in a randomized, cross-over trial. Pretreatment with and concomitant administration of ketoconazole resulted in 24-fold and 11-fold increases in the AUC and Cmax of nisoldipine, respectively. The ketoconazole-induced increase in plasma concentrations of the metabolite M9 was of similar magnitude. Thus, ketoconazole and other potent inhibitors of CYP3A should not be used concomi-tantly with nisoldipine.

In an intestinal perfusion study of the effect of ketoconazole 40 µg/ml on the jejunal permeability and first-pass metabolism of (R)- and-verapamil 120 µg/ml in six healthy volunteers, ketoconazole did not alter the jejunal permeability of the isomers, suggesting that it had no effect on the P-glycoprotein mediated efflux. However, the rate of absorption increased, suggesting inhibition by ketoconazole of the gut wall metabolism of (1)-verapamil by CYP3A4.

Carbamazepine

Serum concentrations of ketoconazole are reduced by concomitant use of drugs that induce hepatic micro-somal enzymes, such as carbamazepine. There may at the same time be a change in serum carbamazepine concentration.

Ciclosporin

The fact that ketoconazole inhibits cytochrome P450 accounts for some of its interactions. Ketoconazole increases ciclosporin concentrations, enhancing the risk of renal impairment, as shown by a fall in creatinine clearance.

The effect of ketoconazole in ciclosporin-treated kidney transplant recipients has been the subject of a prospective randomized study. In 51 ketoconazole -treated patients and 49 controls there was a similar frequency of acute rejection episodes. However, in the control group, rejection episodes were more recurrent, with a poorer response to treatment. Acute ciclosporin nephrotoxicity was more common in the ketoconazole group, but this was encountered more at induction and rapidly reversed on further reduction of the dose of ciclosporin. Chronic graft dysfunction was significantly less in the ketoconazole group during the first year, but by the end of the study the difference was not statistically significant. Hepatotoxicity was similar in the two groups. Serum concentrations of cholesterol, low-density lipopro-tein, and triglycerides were lower in the ketoconazole group. The authors concluded that long-term low-dose ketoconazole in ciclosporin-treated kidney transplant recipients is safe and cost-saving.

Citalopram

The effect of ketoconazole on the pharmacokinetics of citalopram has been studied in a double-blind, three-way, crossover trial in 18 men and women. The subjects received three treatments with a 14-day washout period: a single dose of ketoconazole 200 mg plus placebo, a single dose of citalopram 40 mg plus placebo, and a single dose of ketoconazole 200 mg plus a single dose of citalopram 40 mg. There were no changes in the pharmacokinetics of citalopram after co-administration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors can be safely co-administered with citalopram.

Clozapine

The interaction of ketoconazole (400 mg/day for 7 days) with clozapine has been evaluated in five patients with schizophrenia given a single dose of clozapine 50 mg at the end of ketoconazole therapy. Ketoconazole did not significantly change the disposition of clozapine or its metabolism to its principal metabolites, desmethylclozapine and clozapine-N-oxide.

Donepezil

Donepezil 5 mg produced no change in plasma concentrations of ketoconazole 200 mg.

Erythromycin

If erythromycin and ketoconazole, both CYP3A4 inhibitors, are taken in combination, there will be an even more dramatic effect on the metabolism of other drugs, such as terfenadine and astemizole, midazolam and triazolam, and ciclosporin.

Halofantrine

Halofantrine, a highly lipophilic antimalarial drug with poor and erratic absorption, is metabolized to its equi-potent metabolite desbutylhalofantrine and this is inhibited by oral ketoconazole.

Histamine H2 receptor antagonists

Co-administration of histamine H2 receptor antagonists reduces the absorption of ketoconazole.

HIV protease inhibitors

The effects of co-administration of ketoconazole 400 mg and amprenavir 1200 mg, which is mostly metabolized by CYP3A4, have been studied in an open, randomized, balanced, single-dose, three-period, crossover study in 12 healthy men. Co-administration of the two drugs increased the amprenavir AUC by 31% and reduced its Cmax by 16%. Amprenavir increased the AUC of ketoconazole by 44% and increased its half-life and Cmax by 23% and 16% respectively. Thus, co-administration of amprenavir and ketoconazole result in statistically significant increases in the AUCs of both agents, but the clinical significance of these changes remains to be investigated.

The pharmacokinetic interaction of fluconazole 400 mg od and indinavir 1000 mg tds has been evaluated in a placebo-controlled, crossover study for 8 days; there was no significant interaction.

The effect of ketoconazole (200 and 400 mg qds) on plasma and cerebrospinal fluid concentrations of ritonavir (400 mg bd) and saquinavir (400 mg bd) have been investigated in a two-period, two-group, longitudinal pharmacokinetic study in 12 HIV-infected patients. Ketoconazole significantly increased the AUC and trough concentrations of ritonavir and prolonged its half-life (by 29%, 62%, and 31% respectively). It produced similar changes (37%, 94%, and 38% respectively) in the kinetics of saquinavir. Ketoconazole significantly increased the ritonavir CSF concentration at 4-5 hours after the dose by 178% (from 2.4 to 6.6 µg/ml), with no change in the paired unbound plasma concentration (26 µg/ml). The changes were not related to ketoconazole dose or plasma exposure. The corresponding changes in saquinavir CSF concentrations were not significant. The authors concluded that ketoconazole inhibited the systemic clearance of ritonavir and, because of the disproportionate increase in CSF concentrations compared with the increase in plasma concentrations, that there was greater inhibition of drug efflux from the CSF.

A study in seven HIV-infected men who took saquinavir 600 mg tds in addition to two other antiretroviral drugs and concomitant ketoconazole (200 mg qds for 7 days, followed by 400 mg qds for another 7 days) showed no significant differences in peak and trough concentrations of saquinavir after the addition of ketoconazole. There was substantial inter-subject variability in the study, and the authors concluded that saquinavir concentrations may be unpredictable in individual patients and that drug monitoring may be required for optimizing saquinavir treatment.

Ifosfamide

The effect of ketoconazole on the CYP-mediated metabolism of ifosfamide to 4-hydroxyifosfamide and the ultimate cytotoxic ifosforamide mustard, and its deactivation to 2- and 3-dechloroethylifosfamide has been studied in a randomized, crossover study in 16 patients, who received intravenous ifosfamide 3 g/m2/day, either alone or in combination with ketoconazole 200 mg bd 1 day before treatment and during 3 days of concomitant administration. Ketoconazole did not affect the fraction metabolized or exposure to the dechloroethylated metabolites and thus did not alter the pharmacokinetics of ifosfamide or its metabolism.

Isoniazid

Combined administration of ketoconazole with isoniazid can lead to increased concentrations of the latter, and there are possibly also alterations in ketoconazole concentrations.

Methylprednisolone

The effect of ketoconazole on steroid metabolism is reflected in other interactions. Ketoconazole increases the total amount of methylprednisolone in the body.

Oral contraceptives

The reported reduction in the effect of oral contraceptives concurs with the effect of ketoconazole on steroid metabolism; the effect seems to be mild and may be mainly of importance during the use of formulations with low estrogen content.

Phenazone

Ketoconazole reduces the clearance of phenazone (anti-pyrine).

Phenytoin

Serum concentrations of ketoconazole are reduced by concomitant use of drugs that induce hepatic microsomal enzymes, such as phenytoin. There may at the same time be a change in serum phenytoin concentration.

Proton pump inhibitors

Co-administration of proton pump blockers reduces the absorption of ketoconazole.

Reboxetine

Reboxetine is metabolized by CYP3A4. In 11 healthy volunteers, ketoconazole increased the AUC of reboxetine by about 50% and increased its half-life. The adverse effects profile of reboxetine was not altered by ketoconazole.

Rifamycins

Serum concentrations of ketoconazole are reduced by concomitant use of drugs that induce hepatic microsomal enzymes, such as rifampicin. There may at the same time be a change in rifampicin serum concentration.

Ropivacaine

Ketoconazole 400 mg caused a minor reduction in the clearance of ropivacaine, which is mostly metabolized by CYP1A2.

Statins

In two cases, rhabdomyolysis occurred after co-administration of simvastatin 20 mg/day and ketoconazole.

Theophylline

The combination of ketoconazole with theophylline was reported to have reduced theophylline concentrations, suggesting increased metabolism of theophylline. This is surprising, since one would have expected ketoconazole to have inhibited the metabolism of theophylline, if at all. However, in 10 healthy, non-smoking men aged 18-40 years aminophylline 6 mg/kg intravenously before and after they had taken oral ketoconazole 200 mg/day for 7 days caused no change in the half-life or clearance of theophylline, so there is probably no important interaction between these two drugs.

Tolterodine

Tolterodine is eliminated by two different oxidative metabolic pathways: hydroxylation, catalysed by CYP2D6, and D-alkylation, catalysed by CYP3A. The pharmacokinetics and safety of tolterodine and its metabolites in the absence and presence of ketoconazole have been investigated in healthy volunteers with deficient CYP2D6 activity (poor metabolizers). Clearance of tolterodine fell by 60% during co-administration of ketoconazole, resulting in a 2.1-fold increase in AUC. Thus, caution is needed when ketoconazole and other potent inhibitors of CYP3A are used concomitantly with tolterodine.

Tretinoin

A potential interaction of ketoconazole with tretinoin (all-trans retinoic acid), resulting in slowed metabolism, is probably not of importance.

Warfarin

Potentiation of the effects of warfarin has been reported in one case, but absence of interference with anticoagulants was also claimed.

Ziprasidone

Ziprasidone is oxidatively metabolized by CYP3A4, but it does not inhibit CYP3A4 or other isoenzymes at clinically relevant concentrations. The effect of ketoconazole 400 mg qds for 6 days on the single-dose pharmacokinetics of ziprasidone 40 mg has been evaluated in an open, placebo-controlled, crossover study in healthy volunteers. Ketoconazole caused a modest increase in the mean AUC (33%) and the mean Cmax (34%) of ziprasidone. This effect was not considered clinically relevant and suggests that other inhibitors of CYP3A4 are unlikely to affect the pharmacokinetics of ziprasidone significantly. Most of the reported adverse events were mild. The adverse events that were most commonly reported in subjects who took the drugs concomitantly were dizziness, weakness, and somnolence. There were no treatment-related laboratory abnormalities or abnormal vital signs during the study and at the 6-day follow-up evaluation.

Zolpidem

Zolpidem is metabolized by CYP3A. Ketoconazole 200 mg bd impaired the clearance of zolpidem 5 mg and enhanced its benzodiazepine-like pharmacodynamic effects. In contrast, itraconazole 100 mg bd and fluconazole 100 mg bd had small effects on zolpidem kinetics and dynamics.

Ketoconazole: Cautions

GI Effects

The most frequent adverse reactions to ketoconazole are nausea and/or vomiting which have been reported in 3-10% of patients receiving the drug. Abdominal pain, constipation, flatulence, GI bleeding, and diarrhea have also been reported in 1% or less of patients receiving the drug. Adverse GI effects appear to be dose related, are reported less frequently when ketoconazole is administered with food, and usually subside with continued therapy with the drug.

 Nizoral Hepatic Effects

Hepatic Effects

Transient increases in serum AST (SGOT), ALT (SGPT), and alkaline phosphatase concentrations have been reported during ketoconazole therapy. Hepatotoxicity, which may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury, has been reported rarely.

Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and rarely death has occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy, but occasionally may be apparent within the first week of therapy.

Most cases of hepatotoxicity have been reported in patients receiving the drug for tinea unguium (onychomycosis), and many others were receiving the drug for chronic, refractory dermatophytoses. Several cases of ketoconazole-induced hepatitis have been reported in children.

Endocrine and Metabolic

Effects Bilateral gynecomastia with breast tenderness has occurred in some men during therapy with ketoconazole. In some patients, gynecomastia and breast pain abated after several weeks of continued therapy with ketoconazole. In other patients, gynecomastia persisted until the drug was discontinued.

Limited data suggest that gynecomastia occurs because ketoconazole decreases serum testosterone concentrations and to a lesser extent serum estradiol concentrations, resulting in an increased estradiol:testosterone ratio. Although it has been suggested that gynecomastia may be caused by a direct effect on breast tissue since serum hormone concentrations were normal in several patients, ketoconazole only transiently inhibits testosterone synthesis and testosterone concentrations may have returned to baseline values depending on when the serum samples were obtained.

Ketoconazole may inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosages or divided daily dosing of the drug. The adrenocortical response to corticotropin (ACTH) may be at least transiently diminished and a reduction in urinary free and serum cortisol concentrations may occur during therapy with the drug; however, adrenocortical insufficiency has been reported only rarely. In clinical trials in Europe in patients receiving high-dose (i.e., 1.2 g daily) ketoconazole therapy for metastatic prostatic carcinoma, death occurred within 2 weeks after initiating therapy with the drug in 3% of patients.

Although these deaths could not be attributed definitely to the drug, in part because of the serious nature of the underlying disease, the possibility exists that ketoconazole-induced adrenocortical insufficiency may have been a contributing factor in some patients. When adrenocortical hypofunction does occur in patients receiving ketoconazole, the condition generally is reversible following discontinuance of the drug but rarely may be persistent.

Although the clinical importance is unclear, a transient decrease (of approximately 20% of pretreatment concentrations) in serum cholesterol concentrations and alterations in serum triglyceride concentrations (e.g., hypertriglyceridemia) have been reported in a few patients during ketoconazole therapy.

Dermatologic and Sensitivity Reactions

Pruritus has been reported in about 2% of patients receiving ketoconazole. Rash, dermatitis, purpura, and urticaria have been reported in less than 1% of patients receiving ketoconazole, and in some cases these effects may have been manifestations of a hypersensitivity reaction to the drug. Anaphylactic reactions occurring after the first dose of ketoconazole have been reported rarely.

Nervous System Effects

Headache, dizziness, somnolence, lethargy, asthenia, nervousness, insomnia, abnormal dreams, photophobia, and paresthesia have been reported in less than 1% of patients receiving ketoconazole. Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely in patients receiving ketoconazole.

 Nizoral Hepatic Effects

Cardiovascular Effects

Hypertension has been reported in several patients receiving high-dose (e.g., 400 mg every 6-8 hours) ketoconazole therapy for metastatic prostatic carcinoma. Although not clearly established, it has been suggested that ketoconazole-induced increases in mineralocorticoid activity may have caused the increase in blood pressure observed in these patients.

Other Adverse Effects

Arthralgia, fever and chills, dyspnea, hemolytic anemia, tinnitus, impotence, changes in sweat patterns, thrombocytopenia, leukopenia, alopecia, and signs of increased intracranial pressure including bulging fontanelles and papilledema have also occurred in less than 1% of patients receiving ketoconazole. Fragility and fractures of long bones have occurred in female rats following daily oral administration of ketoconazole doses of 80 mg/kg or more for 3-6 months; these effects did not occur with daily doses of 20 mg/kg or less. Limited studies have not demonstrated these effects on the metacarpals or ribs of dogs, and these effects have not been reported in humans to date.

Precautions and Contraindications

Ketoconazole has been associated with hepatotoxicity, which rarely has resulted in death. Patients receiving the drug should be informed of the risk of hepatotoxicity and should be instructed to report any signs or symptoms of possible hepatic dysfunction (e.g., unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, pale feces) to their physician. Patients receiving the drug should be closely monitored clinically and biochemically.

Liver function tests, including determinations of serum AST (SGOT), ALT (SGPT), alkaline phosphatase, Gamma-glutamyltransferase (b-glutamyltranspeptidase, GGT, GGTP), and bilirubin, should be performed prior to initiation of ketoconazole therapy and frequently (e.g., biweekly during the first 2 months of therapy and monthly or bimonthly thereafter) during therapy, particularly in patients receiving prolonged therapy or other potentially hepatotoxic drugs and in those with a history of hepatic disease. Minor, asymptomatic elevations in liver function test results may return to pretreatment concentrations during continued therapy with ketoconazole.

However, if liver function test results are substantially elevated or if such abnormalities persist, worsen, or are accompanied by other manifestations of hepatic dysfunction, ketoconazole therapy should be discontinued. The possibility that ketoconazole may depress adrenocortical function should be considered, particularly in patients receiving relatively high dosages of the drug. (See Cautions: Endocrine and Metabolic Effects.) Similarly, the possibility that the drug may reduce serum testosterone concentrations should be considered. To minimize the risk of these endocrine effects, the manufacturer states that the recommended dosage (i.e., 200-400 mg daily in adults) should be followed closely. Ketoconazole is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Ketoconazole has not been systematically studied in children of any age, and there is essentially no information to date on use of the drug in children younger than 2 years of age. Although ketoconazole has been used in a limited number of children older than 2 years of age, the drug should be used in pediatric patients only when the potential benefits justify the possible risks.

Mutagenicity and Carcinogenicity

In vitro studies using ketoconazole in a microbial system (i.e., Ames test) have not shown the drug to be mutagenic. In addition, there was no evidence of mutagenicity in any stage of germ cell development in a dominant lethal mutation test in mice who received single oral doses of ketoconazole as high as 80 mg/kg. There was no evidence of ketoconazole-induced carcinogenicity in a long-term feeding study in mice and rats.

 Nizoral Hepatic Effects

Pregnancy, Fertitlity and Lactation

Ketoconazole has caused webbing of the feet or the absence of toes in the fetus when given orally to pregnant rats in daily doses of 80 mg/kg (10 times the maximum recommended human oral dosage). The drug has also been embryotoxic in rats when given during the first trimester of pregnancy and has caused dystocia in rats when given during the third trimester of pregnancy.

Although these effects may be a reflection of the particular sensitivity of female rats to ketoconazole (maternal toxicity), there are no adequate and controlled studies to date using ketoconazole in pregnant women.

Ketoconazole should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Oligospermia and, rarely, azoospermia have been reported in adult males receiving ketoconazole dosages greater than 400 mg daily. Although oligospermia has not been reported to date in patients receiving lower dosages, sperm counts have been obtained infrequently in such patients. Because ketoconazole is probably distributed into human milk, lactating women receiving the drug should not breast-feed.

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