|blackBoxWarningTitle=
Hepatotoxicity and QT prolongation
|blackBoxWarningBody=
Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.
Hepatotoxicity: Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored.
QT Prolongation and Drug Interactions Leading to QT Prolongation: Coadministration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as Torsades de pointes.
Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.
There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole tablet therapy. The usual duration of therapy for systemic infection is 6 months. Treatment should be continued until active fungal infection has subsided.
The recommended starting dose of ketoconazole tablets is a single daily administration of 200 mg (one tablet). If clinical responsiveness is insufficient within the expected time, the dose of ketoconazole tablets may be increased to 400 mg (two tablets) once daily.
|offLabelAdultGuideSupport=
There is limited information regarding Off-Label Guideline-Supported Use of Ketoconazole (oral) in adult patients.
|offLabelAdultNoGuideSupport=
Atopic dermatitis
Dosing Information
Ketoconazole (200 mg orally once daily for 30 days).
Carcinoma of prostate
Dosing Information
Ketoconazole 400 mg every 8 hours.
|fdaLIADPed=
Systemic Fungal Infections
Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.
There should be laboratory as well as clinical documentation of infection prior to starting ketoconazole tablet therapy. The usual duration of therapy for systemic infection is 6 months. Treatment should be continued until active fungal infection has subsided.
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. Ketoconazole tablets have not been studied in children under 2 years of age.
|offLabelPedGuideSupport=
There is limited information regarding Off-Label Guideline-Supported Use of Ketoconazole (oral) in pediatric patients.
|offLabelPedNoGuideSupport=
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketoconazole (oral) in pediatric patients.
|contraindications=
Drug Interactions
Coadministration of a number of CYP3A4 substrates such as dofetilide, quinidine, cisapride and pimozide is contraindicated with ketoconazole tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious adverse reaction may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and sometimes resulting in life-threatening ventricular tachyarrhythmias including occurrences of Torsades de pointes, a potentially fatal arrhythmia.
Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam, or alprazolam is contraindicated.
The use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease.
Hypersensitivity
Ketoconazole is contraindicated in patients who have shown hypersensitivity to the drug.
|warnings=
Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.
Hepatotoxicity
Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity was reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations.
The hepatic injury has usually, but not always, been reversible upon discontinuation of ketoconazole tablets treatment. Cases of hepatitis have been reported in children.
Prompt recognition of liver injury is essential. During the course of treatment, serum ALT should be monitored weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30% above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Liver tests should be repeated to ensure normalization of values. Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring liver injury from the drug.
Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. This effect is not shared with other azoles. The recommended dose of 200 mg to 400 mg daily should not be exceeded.
Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.).
Adverse Reactions Associated with Unapproved Uses
Ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for Cushing’s syndrome when other treatment options have failed. The safety and effectiveness of ketoconazole have not been established in these settings and the use of ketoconazole for these indications is not approved by FDA.
In a clinical trial involving 350 patients with metastatic prostatic cancer, 11 deaths were reported within 2 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 or adrenal insufficiency in these patients with serious underlying disease.
Ketoconazole tablets have been demonstrated to lower serum testosterone. Once therapy with 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. Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia.
|clinicalTrials=
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 trials:
The following adverse reactions have been identified during post-approval use of ketoconazole 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 post-marketing experience:
Ketoconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of ketoconazole. Similarly, ketoconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Ketoconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosages.
Interaction studies have only been performed in adults. The relevance of the results from these studies in pediatric patients is unknown.
Drugs that May Decrease Ketoconazole Plasma Concentrations
Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of ketoconazole from ketoconazole tablets. These drugs should be used with caution when coadministered with ketoconazole tablets:
Ketoconazole tablets should be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
Acid neutralizing medicines (e.g. aluminum hydroxide) should be administered at least 1 hour before or 2 hours after the intake of ketoconazole tablets.
Upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary.
Coadministration of ketoconazole tablets with potent enzyme inducers of CYP3A4 may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. Examples include:
Therefore, administration of potent enzyme inducers of CYP3A4 with ketoconazole tablets is not recommended. The use of these drugs should be avoided from 2 weeks before and during treatment with ketoconazole tablets, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. Upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary.
Drugs that May Increase Ketoconazole Plasma Concentrations
Potent inhibitors of CYP3A4 (e.g. antivirals such as ritonavir, ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir) may increase the bioavailability of ketoconazole. These drugs should be used with caution when coadministered with ketoconazole tablets. Patients who must take ketoconazole tablets concomitantly with potent inhibitors of CYP3A4 should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ketoconazole, and the ketoconazole tablets dose should be decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations should be measured.
Drugs that May Have Their Plasma Concentrations Increased by Ketoconazole
Ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of Torsades de pointes, a potentially fatal arrhythmia.
Examples of drugs that may have their plasma concentrations increased by ketoconazole presented by drug class with advice regarding coadministration with ketoconazole tablets:
Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (2 times the maximum recommended human dose, based on body surface area comparisons). 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 tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
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 (about one fourth the maximum human dose, based on body surface area comparison).
|useInPregnancyAUS=
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketoconazole (oral) in women who are pregnant.
|useInLaborDelivery=
There is no FDA guidance on use of Ketoconazole (oral) during labor and delivery.
|useInNursing=
Ketoconazole has been shown to be excreted in the milk. Mothers who are under treatment with ketoconazole tablets should not breast-feed.
|useInPed=
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.
|useInGeri=
There is no FDA guidance on the use of Ketoconazole (oral) with respect to geriatric patients.
|useInGender=
There is no FDA guidance on the use of Ketoconazole (oral) with respect to specific gender populations.
|useInRace=
There is no FDA guidance on the use of Ketoconazole (oral) with respect to specific racial populations.
|useInRenalImpair=
There is no FDA guidance on the use of Ketoconazole (oral) in patients with renal impairment.
|useInHepaticImpair=
There is no FDA guidance on the use of Ketoconazole (oral) in patients with hepatic impairment.
|useInReproPotential=
There is no FDA guidance on the use of Ketoconazole (oral) in women of reproductive potentials and males.
|useInImmunocomp=
There is no FDA guidance one the use of Ketoconazole (oral) in patients who are immunocompromised.
|administration=
Oral
|monitoring=
During the course of treatment, serum ALT should be monitored weekly for the duration of treatment.
|IVCompat=
There is limited information regarding IV Compatibility of Ketoconazole (oral) in the drug label.
|overdose=
Acute Overdose
In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered.
Chronic Overdose
There is limited information regarding Chronic Overdose of Ketoconazole (oral) in the drug label.
Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane.
|structure=
Ketoconazole tablets, USP are a synthetic broad spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. In addition, each tablet also contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Ketoconazole is cis-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 and molecular formula:
Ketoconazole, USP is a white to slightly beige, odorless powder, soluble in acids, with a molecular weight of 531.44.
|PD=
There is limited information regarding Pharmacodynamics of Ketoconazole (oral) in the drug label.
|PK=
Absorption
Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.
Mean peak plasma concentrations of approximately 3.5 mcg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Oral bioavailability is maximal when the tablets are taken with a meal.
Absorption of ketoconazole is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as acid neutralizing medicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors (e.g. H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. Absorption of ketoconazole under fasted conditions in these subjects is increased when ketoconazole tablets are administered with an acidic beverage (such as non-diet cola). After pretreatment with omeprazole, a proton pump inhibitor, the bioavailability of a single 200 mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone. When ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone.
Distribution
In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion reaches the cerebrospinal fluid.
Metabolism
Following absorption from the gastrointestinal tract, ketoconazole is converted into several inactive metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of ketoconazole. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, by hepatic microsomal enzymes. In addition, oxidative O-dealkylation and aromatic hydroxylation does occur. Ketoconazole has not been demonstrated to induce its own metabolism.
Elimination
Elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter.
Approximately 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 with about 57% being excreted in the feces.
Special Populations
Patients with Hepatic or Renal Impairment
In patients with hepatic or renal impairment, the overall pharmacokinetics of ketoconazole was not significantly different when compared with healthy subjects.
Pediatric Patients
Limited pharmacokinetic data are available on the use of ketoconazole tablets in the pediatric population.
Measurable ketoconazole plasma concentrations have been observed in pre-term infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension, tablet or crushed tablet. Limited data suggest that absorption may be greater when the drug is administered as a suspension compared to a crushed tablet. Conditions that raise gastric pH may lower or prevent absorption. Maximum plasma concentrations occurred 1 to 2 hours after dosing and were in the same general range as those seen in adults who received a 200 mg to 400 mg dose.
Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QTc interval. Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3 to 7 days can result in an increase of the QTc interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma concentrations about 1 to 4 hours after ketoconazole administration.
|nonClinToxic=
Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a 24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80 mg/kg/day. The high dose in these studies was approximately 1 time (mouse) or 2 times (rat) the clinical dose in humans based on a mg/m2 comparison.
|clinicalStudies=
There is limited information regarding Clinical Studies of Ketoconazole (oral) in the drug label.
|howSupplied=
Ketoconazole Tablets, USP are available containing 200 mg of ketoconazole, USP.
The 200 mg tablet is a white to off-white round, scored tablet debossed with M above the score and 261 below the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0261-01
bottles of 100 tablets
Store at 20° to 25°C (68° to 77°F).
Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Keep out of reach of children.
|fdaPatientInfo=
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, abdominal pain, jaundice, dark urine or pale stools.
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