CONTRAINDICATIONS
Tablets, Shampoo, and Cream: Ketoconazole is contraindicated in patients who have shown
hypersensitivity to the drug or excipients of the formulation(s).
Tablets: Coadministration of terfenadine or astemizole with ketoconazole tablets is contraindicated.
(See BOXED WARNING, WARNINGS, and PRECAUTIONS.)
Concomitant administration of ketoconazole tablets with cisapride is contraindicated. (See BOXED
WARNING, WARNINGS, and PRECAUTIONS.)
WARNINGS
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 hepatotoxicity 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 PRECAUTIONS.)
Concomitant administration of ketoconazole tablets with cisapride is contraindicated in markedly
elevated cisapride plasma concentrations and prolonged QT interval, and has rarely been associated
with ventricular arrhythmias and torsades de pointes. (See BOXED WARNING,
CONTRAINDICATIONS, and PRECAUTIONS.)
In European clinical trials involving 350 patients with metastatic prostatic cancer, 11 deaths were
reported within 2 weeks of starting treatment with a 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 3-6 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 demonstrate 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.
PRECAUTIONS
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/day and abolished by 1600 mg/day.
Ketoconazole tablets also decrease ACTH-induced corticosteroid serum levels at similar high
doses. The recommended dose of 200-400 mg daily should be followed closely.
In 4 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 2 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.
Tablets: 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 WARNINGS).
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 produced 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 Category C
Teratogenic Effects
Tablets: Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat
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.
Nonteratogenic Effect
Tablets: 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
Shampoo and Cream: 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 tablets should not be
used in pediatric patients unless the potential benefit outweighs the risks.