Nizoral mpi (8.5"x11") (page 1)
in markedly elevated cisapride plasma concentrations and prolonged QT interval, and has rarely beenassociated with ventricular arrhythmias and torsades de pointes. (See BOX WARNING, CONTRAINDICA-TIONS, and PRECAUTIONS sections.)In European clinical trials involving 350 patients with metastatic prostatic cancer, eleven deaths werereported within two weeks of starting treatment with high doses of ketoconazole tablets (1200 mg/day). It isnot possible to ascertain from the information available whether death was related to ketoconazole therapyin these patients with serious underlying disease. However, high doses of ketoconazole tablets are known
When used orally, ketoconazole has been associated with hepatic toxicity, including some
to suppress adrenal corticosteroid secretion.
fatalities. Patients receiving this drug should be informed by the physician of the risk and should be
In female rats treated three to six months with ketoconazole at dose levels of 80 mg/kg and higher,
closely monitored. See WARNINGS and PRECAUTIONS sections.
increased fragility of long bones, in some cases leading to fracture, was seen. The maximum "no-effect"
Coadministration of terfenadine with ketoconazole tablets is contraindicated. Rare cases of serious
dose level in these studies was 20 mg/kg (2.5 times the maximum recommended human dose). The mech-
cardiovascular adverse events, including death, ventricular tachycardia and torsades de pointes have
anism responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrate such an
been observed in patients taking ketoconazole tablets concomitantly with terfenadine, due to increased
terfenadine concentrations induced by ketoconazole tablets. See CONTRAINDICATIONS, WARNINGS,
General: NIZORAL® (ketoconazole) Tablets have been demonstrated to lower serum testosterone. Once
Pharmacokinetic data indicate that oral ketoconazole inhibits the metabolism of astemizole, resulting in
therapy with NIZORAL® Tablets has been discontinued, serum testosterone levels return to baseline
elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong
values. Testosterone levels are impaired with doses of 800 mg per day and abolished by 1600 mg per
QT intervals. Coadministration of astemizole with ketoconazole tablets is therefore contraindicated. See
day. NIZORAL® Tablets also decrease ACTH induced corticosteroid serum levels at similar high doses.
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.
The recommended dose of 200 mg - 400 mg daily should be followed closely.
Coadministration of cisapride with ketoconazole is contraindicated. Serious cardiovascular adverse
In four subjects with drug-induced achlorhydria, a marked reduction in ketoconazole absorption was
events including ventricular tachycardia, ventricular fibrillation and torsades de pointes have occurred in
observed. NIZORAL® Tablets require acidity for dissolution. If concomitant antacids, anticholinergics, and
patients taking ketoconazole concomitantly with cisapride. See CONTRAINDICATIONS, WARNINGS,
H -blockers are needed, they should be given at least two hours after administration of NIZORAL® 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
NIZORAL® (ketoconazole) is a synthetic broad-spectrum antifungal agent available in scored white tablets,
with the teeth. This administration should be followed with a cup of tap water.
each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon
Information for Patients: Patients should be instructed to report any signs and symptoms which
dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Ketoconazole
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
piperazine and has the following structural formula:
or pale stools (see WARNINGS section).
Drug Interactions: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system.
Coadministration of NIZORAL® Tablets and drugs primarily metabolized by the cytochrome P450 3A4
enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong
both therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjust-
ments may be necessary. The following drug interactions have been identified involving NIZORAL® Tablets
and other drugs metabolized by the cytochrome P450 3A4 enzyme system:
Ketoconazole tablets inhibit the metabolism of terfenadine, resulting in an increased plasma concentration
of terfenadine and a delay in the elimination of its acid metabolite. The increased plasma concentration of
Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44.
terfenadine or its metabolite may result in prolonged QT intervals. (See BOX WARNING, CONTRAINDI-CATIONS, and WARNINGS sections.)
Pharmacokinetic data indicate that oral ketoconazole inhibits the metabolism of astemizole, resulting in
Mean peak plasma levels of approximately 3.5 µg/mL are reached within 1 to 2 hours, following oral
elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT
administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with
intervals. Coadministration of astemizole with ketoconazole tablets is therefore contraindicated. (See BOX
a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the
WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
gastrointestinal tract, NIZORAL® (ketoconazole) is converted into several inactive metabolites. The majoridentified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative
Human pharmacokinetics data indicate that oral ketoconazole potently inhibits the metabolism of cisapride
O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, of which 2 to
resulting in a mean eight-fold increase in AUC of cisapride. Data suggest that coadministration of oral keto-
4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract. In vitro,
conazole and cisapride can result in prolongation of the QT interval on the ECG. Therefore concomitant
the plasma protein binding is about 99% mainly to the albumin fraction. Only a negligible proportion of
administration of ketoconazole tablets with cisapride is contraindicated. (See BOX WARNING,
ketoconazole reaches the cerebral-spinal fluid. Ketoconazole is a weak dibasic agent and thus requires
CONTRAINDICATIONS, and WARNINGS sections.)
acidity for dissolution and absorption.
Ketoconazole tablets may alter the metabolism of cyclosporine, tacrolimus, and methylprednisolone, resulting
NIZORAL® Tablets are active against clinical infections with Blastomyces dermatitidis, Candida spp.,
in elevated plasma concentrations of the latter drugs. Dosage adjustment may be required if cyclosporine,
Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp.
tacrolimus, or methylprednisolone are given concomitantly with NIZORAL® Tablets.
NIZORAL® Tablets are also active against Trichophyton spp., Epidermophyton spp., and Microsporum spp.
Coadministration of NIZORAL® Tablets with midazolam or triazolam has resulted in elevated plasma concen-
Ketoconazole is also active in vitro against a variety of fungi and yeast. In animal models, activity has been
trations of the latter two drugs. This may potentiate and prolong hypnotic and sedative effects, especially
demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur,
with repeated dosing or chronic administration of these agents. These agents should not be used in patients
Coccidioides immitis, and Cryptococcus neoformans.
treated with NIZORAL® Tablets. If midazolam is administered parenterally, special precaution is required
Mode of Action: In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a
since the sedative effect may be prolonged.
vital component of fungal cell membranes.
Rare cases of elevated plasma concentrations of digoxin have been reported. It is not clear whether this wasdue to the combination of therapy. It is, therefore, advisable to monitor digoxin concentrations in patients
INDICATIONS AND USAGE
NIZORAL® (ketoconazole) Tablets are indicated for the treatment of the following systemic fungal infections:
When taken orally, imidazole compounds like ketoconazole may enhance the anticoagulant effect of
candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis,
coumarin-like drugs. In simultaneous treatment with imidazole drugs and coumarin drugs, the anticoagulant
histoplasmosis, chromomycosis, and paracoccidioidomycosis. NIZORAL® Tablets should not be used for
effect should be carefully titrated and monitored.
fungal meningitis because it penetrates poorly into the cerebral-spinal fluid.
Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole (an
NIZORAL® Tablets are also indicated for the treatment of patients with severe recalcitrant cutaneous
imidazole) and oral hypoglycemic agents, such a potential interaction involving the latter agents when used
dermatophyte infections who have not responded to topical therapy or oral griseofulvin, or who are unable
concomitantly with ketoconazole tablets (an imidazole) can not be ruled out.
Concomitant administration of ketoconazole tablets with phenytoin may alter the metabolism of one or both
of the drugs. It is suggested to monitor both ketoconazole and phenytoin.
Coadministration of terfenadine or astemizole with ketoconazole tablets is contraindicated. (See BOX
Concomitant administration of rifampin with ketoconazole tablets reduces the blood levels of the latter. INH
WARNING, WARNINGS, and PRECAUTIONS sections.)
(Isoniazid) is also reported to affect ketoconazole concentrations adversely. These drugs should not be
Concomitant administration of NIZORAL® Tablets with cisapride is contraindicated. (See BOX WARNING,
After the coadministration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11
Concomitant administration of NIZORAL® Tablets with oral triazolam is contraindicated. (See PRECAUTIONS
of loratadine averaged 302% (± 142 S.D.) and 251% (± 68 S.D.), respectively, of
those obtained after co-treatment with placebo. The AUC and C
NIZORAL® is contraindicated in patients who have shown hypersensitivity to the drug.
metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively. However, no related changes
were noted in the QT 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
Hepatotoxicity, primarily of the hepatocellular type, has been associated with the use of NIZORAL
(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
Rare cases of a disulfiram-like reaction to alcohol have been reported. These experiences have been
is the case for most reported adverse reactions to drugs. The median duration of NIZORAL
characterized by flushing, rash, peripheral edema, nausea, and headache. Symptoms resolved within a
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
Carcinogenesis, Mutagenesis, Impairment of Fertility: The dominant lethal mutation test in male and female
upon discontinuation of NIZORAL
® Tablet treatment. Several cases of hepatitis have been reported
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
Prompt recognition of liver injury is essential. Liver function tests (such as SGGT, alkaline phosphatase,
long term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity.
SGPT, SGOT and bilirubin) should be measured before starting treatment and at frequent intervals during
Pregnancy: Teratogenic effects: Pregnancy Category C: Ketoconazole has been shown to be teratogenic
treatment. Patients receiving NIZORAL® Tablets concurrently with other potentially hepatotoxic drugs
(syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (10 times the maximum
should be carefully monitored, particularly those patients requiring prolonged therapy or those who have
recommended human dose). However, these effects may be related to maternal toxicity, evidence of which
also was seen at this and higher dose levels.
Most of the reported cases of hepatic toxicity have to date been in patients treated for onychomycosis. Of
There are no adequate and well controlled studies in pregnant women. NIZORAL® Tablets should be used
180 patients worldwide developing idiosyncratic liver dysfunction during NIZORAL® Tablet therapy, 61.3%
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
had onychomycosis and 16.8% had chronic recalcitrant dermatophytoses.
Nonteratogenic Effects: Ketoconazole has also been found to be embryotoxic in the rat when given in the
Transient minor elevations in liver enzymes have occurred during treatment with NIZORAL® Tablets. The
diet at doses higher than 80 mg/kg during the first trimester of gestation.
drug should be discontinued if these persist, if the abnormalities worsen, or if the abnormalities become
In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole during the third
accompanied by symptoms of possible liver injury.
trimester of gestation. This occurred when ketoconazole was administered at doses higher than 10 mg/kg
In rare cases anaphylaxis has been reported after the first dose.
Several cases of hypersensitivity
(higher than 1.25 times the maximum human dose).
reactions including urticaria have also been reported.
It is likely that both the malformations and the embryotoxicity resulting from the administration of oral keto-
Coadministration of ketoconazole tablets and terfenadine has led to elevated plasma concentrations of terfe-
conazole during gestation are a reflection of the particular sensitivity of the female rat to this drug. For
nadine which may prolong QT intervals, sometimes resulting in life-threatening cardiac dysrhythmias. Cases
example, the oral LD of ketoconazole given by gavage to the female rat is 166 mg/kg whereas in the male
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
Nursing Mothers: Since ketoconazole is probably excreted in the milk, mothers who are under treatment
ketoconazole tablets and terfenadine is contraindicated.
Coadministration of astemizole with ketoconazole tablets is contraindicated. (See BOX WARNING,
Pediatric Use: NIZORAL® (ketoconazole) Tablets have not been systematically studied in children of any
CONTRAINDICATIONS, and PRECAUTIONS sections.)
age, and essentially no information is available on children under 2 years. NIZORAL® Tablets should not be
Concomitant administration of NIZORAL® Tablets with cisapride is contraindicated because it has resulted
used in pediatric patients unless the potential benefit outweighs the risks.
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 NIZORAL® (ketoconazole) Tablets. In contrast, the rare
occurrences of hepatic dysfunction require special attention (see WARNINGS section).
In worldwide postmarketing experience with NIZORAL® Tablets there have been rare reports of alopecia,
paresthesia, and signs of increased intracranial pressure including bulging fontanelles and papilledema.
Hypertriglyceridemia has also been reported but a causal association with NIZORAL® Tablets is uncertain.
Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely
in patients using NIZORAL® Tablets.
Ventricular dysrhythmias (prolonged QT intervals) have occurred with the concomitant use of terfenadine
with ketoconazole tablets. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
Data suggest that coadministration of ketoconazole tablets and cisaspride can result in prolongation of the
QT interval and has rarely been associated with ventricular arrhythmias. (See CONTRAINDICATIONS,
WARNINGS, and PRECAUTIONS sections.)
In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate,
should be employed.
DOSAGE AND ADMINISTRATION
Adults: The recommended starting dose of NIZORAL® (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 NIZORAL® Tablets 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. NIZORAL® 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 poor 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.
NIZORAL® (ketoconazole) is available as white, scored tablets containing 200 mg of ketoconazole
debossed "JANSSEN" and on the reverse side debossed "NIZORAL". They are supplied in bottles of
100 tablets (NDC 50458-220-10).
Store at controlled room temperature 15°-25°C (59°-77°F).Protect from moisture.
7501310Rev. March 1997, July 1998U.S. Patent 4,335,125 Janssen Pharmaceutica Inc. 1998
This is not the original version of this decision. It is a revised version that has been edited for public disclosure to protect confidential and third party personal information. Dr. Frances Forrest-Richards, Member Counsel for Appellant Heard at Port Alberni, B.C. on July 9 & 10, 1990, in Vancouver, B.C. on January 14 & 15, 1991 and at Nanaimo, B.C. on April 12, 1991. Majority O
Contact: Leslie J. Yerman email@example.com Emily Berlanstein firstname.lastname@example.org JAMA Article Looks at Data-Sharing in Clinical Trials for Heart Disease Discussion of When and How to Share Data, and When to Suspend a Study Authored by Dr. Jeffrey Borer of NewYork-Presbyterian/Weill Cornell NEW YORK (April 9, 2008) — How and when to share clinical trial data fo