Nizoral Information
Nizoral (Ketoconazole) Warning
When used orally, ketoconazole has been associated
with hepatic toxicity, including some fatalities. Patients receiving this
drug should be informed by the physician of the risk and should be closely
monitored. See and sections.
Coadministration
of terfenadine with ketoconazole tablets is contraindicated. Rare cases of
serious cardiovascular adverse events, including death, ventricular tachycardia
and tordades de pointes have been observed in patients taking ketoconazole
tablets concomitantly with terfenadine, due to increased terfenadine concentrations
induced by ketoconazole tablets. See , , and sections.
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 , , and sections.
Coadministration of cisapride with ketoconazole is contraindicated.
Serious cardiovascular adverse events including ventricular tachycardia, ventricular
fibrillation and torsades de pointes have occurred in patients taking ketoconazole
concomitantly with cisapride. See , , and sections.
Nizoral (Ketoconazole) Description
Nizoral (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. Ketoconazole is -1- acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl]
piperazine and has the following structural formula:
Ketoconazole is
a white to slightly beige, odorless powder, soluble in acids, with a molecular
weight of 531.44.
Nizoral (Ketoconazole) Clinical Pharmacology
Mean peak plasma levels of approximately 3.5 µg/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
a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following
absorption from the gastrointestinal tract, Nizoral (Ketoconazole) (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. , 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 a weak dibasic agent and thus requires acidity for
dissolution and absorption.
Nizoral (Ketoconazole) Tablets
are active against clinical infections with , and . Nizoral (Ketoconazole) Tablets
are also active against and .
Ketoconazole is also active against
a variety of fungi and yeast. In animal models, activity has been demonstrated
against ,
and .
Nizoral (Ketoconazole) Indications And Usage
Nizoral (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.
Nizoral (Ketoconazole) Tablets should not be used for fungal meningitis
because it penetrates poorly into the cerebral-spinal fluid.
Nizoral (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.
Nizoral (Ketoconazole) Contraindications
Coadministration of terfenadine or astemizole with
ketoconazole tablets is contraindicated. (See , , and sections.)
Concomitant
administration of Nizoral (Ketoconazole) Tablets with cisapride is contraindicated.
(See , ,
and sections.)
Concomitant administration of Nizoral (Ketoconazole) Tablets
with oral triazolam is contraindicated. (See section.)
Nizoral (Ketoconazole) is contraindicated in patients who
have shown hypersensitivity to the drug.
Nizoral (Ketoconazole) Warnings
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 Nizoral (Ketoconazole) Tablets 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
Nizoral (Ketoconazole) Tablet therapy, 61.3% had onychomycosis and 16.8%
had chronic recalcitrant dermatophytoses.
Transient
minor elevations in liver enzymes have occurred during treatment with Nizoral (Ketoconazole) Tablets.
The drug should be discontinued if these persist, if the abnormalities worsen,
or if the abnormalities become accompanied by symptoms of possible liver injury.
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 , , and sections.)
Concomitant administration of Nizoral (Ketoconazole) Tablets
with cisapride is contraindicated because it has resulted in markedly elevated
cisapride plasma concentrations and prolonged QT interval, and has rarely
been associated with ventricular arrhythmias and torsades de pointes. (See , ,
and sections.)
In European clinical trials involving 350 patients with metastatic
prostatic cancer, eleven deaths were reported within two weeks of starting
treatment with high doses of ketoconazole tablets (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 mechanism responsible for this
phenomenon is obscure. Limited studies in dogs failed to demonstrate such
an effect on the metacarpals and ribs.
Nizoral (Ketoconazole) Precautions
Nizoral (Ketoconazole) Tablets
have been demonstrated to lower serum testosterone. Once therapy with Nizoral (Ketoconazole) Tablets
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. Nizoral (Ketoconazole) Tablets 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. Nizoral (Ketoconazole) Tablets
require acidity for dissolution. If concomitant antacids, anticholinergics,
and H-blockers are needed, they should be given at least two hours
after administration of Nizoral (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.
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 section).
Ketoconazole is a potent inhibitor of the cytochrome
P450 3A4 enzyme system. Coadministration of Nizoral (Ketoconazole) 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 adjustments may be necessary. The following
drug interactions have been identified involving Nizoral (Ketoconazole) 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 terfenadine or its metabolite may result in prolonged QT intervals. (See , ,
and sections.)
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 , ,
and sections.)
Human pharmacokinetics data indicate that oral ketoconazole
potently inhibits the metabolism of cisapride resulting in a mean eight-fold
increase in AUC of cisapride. Data suggest that coadministration of oral ketoconazole
and cisapride can result in prolongation of the QT interval on the ECG. Therefore
concomitant administration of ketoconazole tablets with cisapride is contraindicated.
(See , ,
and sections.)
Ketoconazole tablets may alter the metabolism of cyclosporine,
tacrolimus, and methylprednisolone, resulting in elevated plasma concentrations
of the latter drugs. Dosage adjustment may be required if cyclosporine, tacrolimus,
or methylprednisolone are given concomitantly with Nizoral (Ketoconazole) Tablets.
Coadministration of Nizoral (Ketoconazole) Tablets with
midazolam or triazolam has resulted in elevated plasma concentrations of the
latter two drugs. This may potentiate and prolong hypnotic and sedative effects,
especially with repeated dosing or chronic administration of these agents.
These agents should not be used in patients treated with Nizoral (Ketoconazole) Tablets.
If midazolam is administered parenterally, special precaution is required
since the sedative effect may be prolonged.
Rare
cases of elevated plasma concentrations of digoxin have been reported. It
is not clear whether this was due to the combination of therapy. It is, therefore,
advisable to monitor digoxin concentrations in patients receiving ketoconazole.
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.
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
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.
Concomitant administration of
rifampin with ketoconazole tablets reduces the blood levels of the latter.
INH (Isoniazid) is also reported to affect ketoconazole concentrations adversely.
These drugs should not be given concomitantly.
After
the coadministration of 200 mg oral ketoconazole twice daily and one 20 mg
dose of loratadine to 11 subjects, the AUC and C 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 of
descarboethoxyloratadine, an active 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 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.
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 LD of ketoconazole given
by gavage to the female rat is 166 mg/kg whereas in the male rat the oral
LD is 287 mg/kg.
Nizoral (Ketoconazole) Adverse Reactions
In
worldwide postmarketing experience with Nizoral (Ketoconazole) 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 (Ketoconazole) Tablets
is uncertain.
Neuropsychiatric disturbances,
including suicidal tendencies and severe depression, have occurred rarely
in patients using Nizoral (Ketoconazole) Tablets.
Ventricular
dysrhythmias (prolonged QT intervals) have occurred with the concomitant use
of terfenadine with ketoconazole tablets. (See , ,
and sections.) Data suggest
that coadministration of ketoconazole tablets and cisapride can result in
prolongation of the QT interval and has rarely been associated with ventricular
arrhythmias. (See , , and sections.)
Nizoral (Ketoconazole) Overdosage
In the event of accidental overdosage, supportive
measures, including gastric lavage with sodium bicarbonate, should be employed.
Nizoral (Ketoconazole) Dosage And Administration
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 (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 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) How Supplied
Nizoral (Ketoconazole) is available
as white, scored tablets containing 200 mg of ketoconazole debossed "JANSSEN"
and on the reverse side debossed "Nizoral (Ketoconazole) ". 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.
Keep out
of reach of children.
Nizoral (Ketoconazole)
