Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
The following adverse reactions were reported in clinical
Immune System Disorders: anaphylactoid reaction
Endocrine Disorders: gynecomastia
Metabolism and Nutrition Disorders: alcohol
intolerance, anorexia, hyperlipidemia, increased appetite
Psychiatric Disorders: insomnia, nervousness
Nervous System Disorders: headache, dizziness,
Eye Disorders: photophobia
Vascular Disorders: orthostatic hypotension
Respiratory, Thoracic and Mediastinal Disorders: epistaxis
Gastrointestinal Disorders: vomiting, diarrhea,
nausea, constipation, abdominal pain, abdominal pain upper, dry mouth,
dysgeusia, dyspepsia, flatulence, tongue discoloration
Hepatobiliary Disorders: hepatitis, jaundice,
hepatic function abnormal
Skin and Subcutaneous Tissues Disorders: erythema
multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia,
Musculoskeletal and Connective Tissue Disorders: myalgia
Reproductive System and Breast Disorders: menstrual
General Disorders and Administration Site Conditions:
asthenia, fatigue, hot flush, malaise, edema peripheral, pyrexia, chills Investigations:
platelet count decreased.
The following adverse reactions have been identified
during postapproval use of Nizoral tablets. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
The following adverse reactions were reported during
Blood and Lymphatic System Disorders: thrombocytopenia
Immune System Disorders: allergic conditions
including anaphylactic shock, anaphylactic reaction, angioneurotic edema
Endocrine Disorders: adrenocortical insufficiency
Nervous System Disorders: reversible intracranial
pressure increased (e.g. papilloedema, fontanelle bulging in infants)
Hepatobiliary Disorders: serious hepatotoxicity
including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis,
hepatic failure including cases resulting in transplantation or death
Skin and Subcutaneous Tissue Disorders: acute
generalized exanthematous pustulosis, photosensitivity
Musculoskeletal and Connective Tissue Disorders: arthralgia
Reproductive System and Breast Disorders: erectile
dysfunction; with doses higher than the recommended therapeutic dose of 200 or
400mg daily, azoospermia.
Drugs that affect the absorption, distribution,
metabolism, and excretion of ketoconazole may alter the plasma concentrations
of ketoconazole. For example, gastric acid suppressants (e.g., antacids,
histamine H2-blockers, proton pump inhibitors) have been shown to reduce plasma
concentrations of ketoconazole.
Ketoconazole is a substrate and potent inhibitor of
CYP3A4. Therefore, the following drug interactions may occur when NIZORAL® is co-administered with other drugs that interact with CYP3A4. (See Table
1 and Table 2 for an overview of these drug interactions; details are provided
in the text that follows these tables.)
NIZORAL® may decrease the elimination of drugs
metabolized by CYP3A4, thereby increasing their plasma concentrations.
Increased exposure to these drugs may cause an increase or prolongation of
their therapeutic and/or adverse effects. Concomitant use with NIZORAL® Tablets
is contraindicated for drugs known to present a risk of serious side effects
with increased exposure (see BOXED WARNING, CONTRAINDICATIONS
section, and, Table 1). For
others, monitoring of plasma concentrations is advised when possible. Clinical
signs and symptoms associated with these drugs should be monitored, with dosage
adjusted as needed.
Inducers of CYP3A4 may decrease the plasma concentrations
of ketoconazole (see Table 2). NIZORAL® may not be effective in
patients concomitantly taking one of these drugs. Therefore, administration of
these drugs with NIZORAL® is not recommended.
Other inhibitors of CYP3A4 may increase the plasma
concentrations of ketoconazole (see Table 2). Patients who must take NIZORAL® concomitantly with one of these drugs should be monitored closely for
signs or symptoms of increased or prolonged pharmacologic effects of NIZORAL® .
Table 1: Selected Drugs That Have Been Shown To or Are Predicted To
Have Their Plasma Concentrations Altered By NIZORAL®*
|Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated.
|Alprazolam, midazolam, triazolam
||HMG-CoA reductase inhibitors (lovastatin, simvastatin)
|Ergot alkaloids (ergotamine, dihydroergotamine)
|Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended.
|Alfentanil, fentanyl, sulfentanil
|Amlodipine, felodipine, nicardipine, nifedipine
||Sirolimus (co-administration not recommended)
||Vinca alkaloids (vincristine, - vinblastine, vinorelbine)
|* This list is not
Table 2: Selected Drugs That Have Been Shown To or Are Predicted To
Alter The Plasma Concentration Of NIZORAL®
|Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.
|Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate)
||Rifampin, rifabutin, isoniazid
|Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered
|* This list is not
Effects of ketoconazole on
Systemic exposure to the
following drugs is significantly increased by coÂadministration of ketoconazole. Concomitant use of
these drugs with NIZORAL® Tablets is contraindicated:
Co-administration of NIZORAL® Tablets with alprazolam, midazolam, or triazolam has resulted in elevated
plasma concentrations of these drugs. This may potentiate and prolong hypnotic
and sedative effects, especially with repeated or chronic administration of
these agents. Concomitant administration of NIZORAL® Tablets with
alprazolam, oral midazolam, and oral triazolam is contraindicated. (See CONTRAINDICATIONS
and WARNINGS sections.) Special precaution and patient monitoring are
required with concomitant parenteral midazolam, because the sedative effect may
Oral ketoconazole potently
inhibits the metabolism of cisapride resulting in a mean eight-fold increase in
AUC of cisapride, which can lead to prolongation of QT interval. Therefore
concomitant administration of NIZORAL® Tablets with cisapride
is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS
The class III antiarrhythmic dofetilide is known to
prolong the QT interval. The potential increase in dofetilide plasma
concentrations when administered concomitantly with ketoconazole could result
in serious cardiovascular events including QTc prolongation and rare
occurrences of torsades de pointes. Therefore, concomitant administration of
NIZORAL® Tablets with dofetilide is contraindicated. (See BOXED
WARNING, CONTRAINDICATIONS, and WARNINGS sections.)
Ketoconazole increases the eplerenone AUC by roughly
5-fold, thereby increasing the risk for hyperkalemia and hypotension.
Co-administration of NIZORAL® and eplerenone is contraindicated.
(See CONTRAINDICATIONS section.)
Elevated concentrations of ergot alkaloids can cause
ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia
and/or ischemia of the extremities. Concomitant administration of ergot
alkaloids such as dihydroergotamine and ergotamine with NIZORAL® Tablets
is contraindicated. (See CONTRAINDICATIONS section.)
HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin)
Co-administration of ketoconazole with CYP3A4-metabolized
HMG-CoA reductase inhibitors such as simvastatin, and lovastatin, may increase
the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant
administration of NIZORAL® Tablets with these HMG-CoA reductase inhibitors
is contraindicated. (See CONTRAINDICATIONS and WARNINGS
Pre-treatment with and concomitant administration of
ketoconazole resulted in a 24-fold and 11-fold increase in mean AUC and Cmax of
nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone.
Concomitant administration of ketoconazole with nisoldipine is contraindicated.
(See CONTRAINDICATIONS section.)
Pimozide is known to prolong the QT interval and is
partially metabolized by CYP3A4. Co-administration of NIZORAL® and
pimozide could result in serious cardiovascular events including QTc prolongation
and rare occurrences of torsades de pointes, and is therefore contraindicated.
(See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS
The class IA antiarhythmic quinidine is known to prolong
the QT interval. The potential increase in quinidine plasma concentrations when
administered concomitantly with ketoconazole could result in serious
cardiovascular events including QTc prolongation and rare occurrences of
torsades de pointes. Therefore, concomitant administration of NIZORAL® Tablets
with quinidine is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS,
and WARNINGS sections.)
Co-administration of ketoconazole with the following
agents was shown or is expected to result in increased exposure to these drugs.
Therefore, careful monitoring of plasma concentrations or adverse events of
these drugs is recommended. Adjustment of dosage of these drugs may be needed.
Alfentanil, sufentanil, fentanyl
In vitro data suggest that alfentanil, sufentanil and
fentanyl are metabolized by CYP3A4. Concomitant administration of NIZORAL® Tablets and alfentanil, sufentanil, or fentanyl may increase plasma
concentrations of the latter drugs.
Amlodipine, felodipine, nicardipine, nifedipine
CYP3A4 metabolized calcium channel blockers such as
amlodipine, felodipine, nicardipine, and nifedipine should be used cautiously
with NIZORAL® Tablets as ketoconazole may cause several-fold increases
in plasma concentrations of these calcium channel blockers.
Concomitant administration of ketoconazole increased the
Cmax and AUC of bosentan 2.1- and 2.3 – fold, respectively. No dosage
adjustment of bosentan is needed but close monitoring for increased
bosentan-associated adverse effects is recommended.
Concomitant administration of buspirone with ketoconazole
may result in significant increases in plasma concentrations of buspirone. When
administered with NIZORAL® Tablets, a low initial dose of buspirone
with subsequent dosage adjustment based on clinical assessment is recommended.
NIZORAL® Tablets may decrease the clearance
and thus increase the systemic exposure to busulfan.
In vivo studies have demonstrated an increase in
plasma carbamazepine concentrations in subjects concomitantly receiving
ketoconazole. Close monitoring of plasma carbamazepine concentrations is
recommended whenever ketoconazole is given to patients stabilized on
Cilostazol Ketoconazole had been shown to increase both
cilostazol AUC and Cmax by about two-fold when administered concurrently.
Co-administration of ketoconazole with cilostazol resulted in increased
incidences of adverse effects, such as headache. When NIZORAL® Tablets
is administered concomitantly with cilostazol, the prescriber should consider
up to a 50% reduction in cilostazol dosage.
Ketoconazole tablets may alter the metabolism of
cyclosporine, thereby resulting in elevated cyclosporine plasma concentrations.
Dosage adjustment may be required if cyclosporine or tacrolimus is given
concomitantly with NIZORAL® Tablets.
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.
In the presence of ketoconazole, the clearance of
docetaxel in cancer patients was shown to decrease by 50%. When docetaxel and
NIZORAL® are administered together, dosage reduction in docetaxel
may be necessary in order to minimize the incidence of toxicities associated
Concomitant administration of NIZORAL® and
protease inhibitors metabolized by CYP3A4, such as indinavir and saquinavir,
may increase plasma concentrations of these protease inhibitors. Dosage
reduction of indinavir is recommended when administering ketoconazole
concomitantly. No dosage adjustments are recommended when saquinavir and
ketoconazole are coadministered for a short period of time.
NIZORAL® Tablets may alter the metabolism of
methylprednisolone, resulting in elevated plasma concentrations of
methylprednisolone. Dose adjustments may be required if methylprednisolone is
given concomitantly with NIZORAL® Tablets.
Oral imidazole compounds such as ketoconazole may enhance
the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect
should be carefully titrated and monitored.
Oral hypoglycemic agents
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) cannot be ruled out.
Ketoconazole was shown to inhibit the CYP-mediated
metabolism of rifabutin in vitro. Co-administration with NIZORAL® Tablets
may result in elevated plasma concentrations of rifabutin.
Ketoconazole had been shown to increase sildenafil plasma
concentrations. When used concomitantly with NIZORAL® Tablets, a 50%
reduction in sildenafil starting dose should be considered.
Multiple-dose ketoconazole had been shown to increase
sirolimus Cmax and AUC by 4.3-fold and 10.9-fold, respectively. The concomitant
use of NIZORAL® Tablets and sirolimus is not recommended.
Ketoconazole had been shown to decrease the oral
clearance of tacrolimus thereby leading to a 2-fold increase in tacrolimus oral
bioavailability. Adjustment in tacrolimus dosage may be required if tacrolimus
is given concomitantly with NIZORAL® Tablets.
Ketoconazole increased the AUC of telithromycin by 1.5 to
2-fold. Use caution when administering telithromycin concurrently with NIZORAL® Tablets since this may result in an increased risk for telithromycin
associated adverse events.
In the presence of ketoconazole, the apparent oral
clearance of tolterodine decreased resulting in at least a two-fold increase in
tolterodine. For patients receiving ketoconazole, a 50% reduction in the
initial tolterodine dosage is recommended.
In vitro data suggest that trimetrexate is
extensively metabolized by CYP3A4. In vitro animal models have demonstrated
that ketoconazole potently inhibits the metabolism of trimetrexate. Patients
treated concomitantly with trimetrexate and NIZORAL® Tablets should
be carefully monitored for trimetrexate-associated toxicities.
Findings of in vitro metabolic studies indicate that verapamil
is metabolized by enzymes including CYP3A4. Ketoconazole may increase verapamil
serum concentrations. Caution should be taken when co-administering verapamil
with NIZORAL® Tablets.
Vinca Alkaloids (vincristine, vinblastine, vinorelbine)
NIZORAL® may inhibit the metabolism of vinca
alkaloids metabolized by CYP3A4. Close monitoring for toxicities associated
with vincristine, vinblastine, or vinorelbine is recommended when
co-administered with NIZORAL® Tablets.
Effects of other drugs on ketoconazole
Drugs affecting the absorption of ketoconazole
Gastric Acid Suppressors/Neutralizers
Studies have shown that absorption of ketoconazole is
impaired when gastric acid production is decreased. Reduced plasma
concentrations of ketoconazole were reported when NIZORAL® Tablets
were administered with antacids, antimuscarinics, histamine H2-blockers, proton
pump inhibitors (omeprazole, lansoprazole) and sucralfate. (See
DRUG INTERACTIONS (General) section.)
Drugs that were shown or are expected to significantly
reduce the systemic exposure to ketoconazole
Co-administration of ketoconazole with potent CYP3A4
enzyme inducers is not recommended.
Concomitant administration of ketoconazole tablets with
carbamazepine may alter the metabolism of one or both of the drugs. Close
monitoring for both plasma concentrations of carbamazepine and reduced
ketoconazole efficacy is recommended.
Ketoconazole AUC and Cmax decreased by a median of 63%
and 40%, respectively, in HIV-infected patients who were given nevirapine 200
mg once daily for two weeks along with ketoconazole 400 mg daily. Concomitant
administration of NIZORAL® Tablets and nevirapine is not
Concomitant administration of ketoconazole with phenytoin
may alter the metabolism of one or both of the drugs. Close monitoring for both
plasma concentrations of phenytoin and reduced efficacy of NIZORAL® Tablets
Rifampin, rifabutin, isoniazid
Concomitant administration of rifampin and rifabutin with
ketoconazole tablets reduces the blood concentrations of the latter. INH
(Isoniazid) was also reported to affect ketoconazole concentrations adversely.
These antitubercular drugs should not be given concomitantly with NIZORAL® Tablets.
Drugs that significantly increase the systemic exposure
Concomitant administration of ritonavir with ketoconazole
tablets increases was shown to increase the oral bioavailability of
ketoconazole. Therefore, when ritonavir is to be given concomitantly, higher
doses ( > 200 mg/day) of NIZORAL® Tablets should not be used.
Other drug interactions
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.
After the co-administration 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 cotreatment 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 QTc 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.