Chemical formula: C₂₆H₂₈Cl₂N₄O₄ Molecular mass: 531.431 g/mol PubChem compound: 3823
Ketoconazole interacts in the following cases:
Expected effect on drug levels: Potential ↑ in plasma concentrations of these drugs.
Recommendation for co-administration: Careful monitoring. Dose adjustment of dihydropyridines and verapamil may be required.
Ketoconazole is a potent inhibitor of CYP3A4: inhibition of CYP3A4 by ketoconazole can increase patients' exposure to a number of medicinal products which are metabolised through this enzymatic system.
Exceptional cases of a disulfiram-like reaction have been reported when ketoconazole was co-administered with alcohol, characterised by flushing, rash, peripheral oedema, nausea and headache, have been reported. All symptoms resolved completely within a few hours.
Ketoconazole is a potent inhibitor of P-gp: inhibition of P-gp by ketoconazole can increase patients' exposure to medicinal products which are P-gp substrates.
Ketoconazole is mainly metabolised through CYP3A4. Coadministration of potent enzyme inducers of CYP3A4 may decrease the bioavailibity of Ketoconazole.
Absorption of ketoconazole is impaired when gastric acidity is decreased. Acid-neutralising medicines (e.g. aluminium hydroxide) should not be administered for at least 2 hours after the intake of ketoconazole. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists, proton pump inhibitors), it is advised to administer ketoconazole with an acidic beverage eg cola beverage, orange juice.
If acid secretion suppressors are added to or removed from the concomitant medication then ketoconazole dose should be adjusted according to cortisol levels.
Expected effect on drug levels: Potential ↑ in plasma concentrations of warfarin.
Recommendation for co-administration: Careful monitoring. INR (international normalised ratio) monitoring recommended.
Studies in animals have shown effects on male and female reproductive parameters.
Expected effect on drug levels: Potential ↑in plasma concentrations of alfentanil and fentanyl.
Recommendation for co-administration: Careful monitoring of adverse effects (respiratory depression, sedation) is recommended. It may be necessary to lower the dose of alfentanil and fentanyl.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Dose adjustment of aliskiren may be required.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended due to an increased bleeding risk.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Dose adjustment of aprepitant may be required.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Aripiprazole dose should be reduced to approximatively one-half of its prescribed dose.
Expected effect on drug levels:
| AUC | Cmax | |
| Bortezomib | ↑1.4-fold | - |
| Imatinib | ↑1.4-fold | ↑1.3-fold |
| Cabazitaxel | ↑1.3-fold | - |
Docetaxel: ↑ in plasma concentrations of docetaxel have been observed.
Busulfan: Potential ↑ in plasma concentrations of busulfan.
Recommendation for co-administration: Careful monitoring. Dose adjustment of each drug may be required.
Expected effect on drug levels:
Recommendation for co-administration: Co-administration is not recommended due to the potential for hepatic toxicity.
Expected effect on drug levels:
Buprenorphine IV and sublingual:
Recommendation for co-administration: Careful monitoring. The buprenorphine dose should be adjusted.
Expected effect on drug levels: Potential ↑ in plasma concentrations of buspirone.
Recommendation for co-administration: Careful monitoring. Dose adjustement of buspirone may be required.
Expected effect on drug levels:
Potential ↑ in plasma concentrations of carbamazepine and phenytoin.
Potential ↓ in plasma concentrations of ketoconazole are expected.
(CYP3A enzyme induction)
Recommendation for co-administration: Not recommended.
Expected effect on drug levels:
The overall pharmacological activity of cilostazol increases 35% when coadministered with ketoconazole.
Recommendation for co-administration: Careful monitoring. A cilostazol dosage of 50 mg twice daily is recommended in combination with Ketoconazole.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Dose adjustment of cinacalcet may be required.
Expected effect on drug levels: ↑ in plasma concentrations of colchicine have been observed.
Recommendation for co-administration: Co-administration is not recommended due to a potential increase in colchicine-related toxicity. Contraindicated in patients with renal impairment.
Expected effect on drug levels:
Recommendation for co-administration: Co-administration not recommended due to the risk of QT interval prolongation and serious hepatic adverse reactions. Monitoring of QT-prolongation if used concomitantly.
Expected effect on drug levels: Potential ↑ in plasma concentrations of these drugs.
Recommendation for co-administration: Careful monitoring. Dose adjustment of these drugs (dexamethasone, fluticasone, methylprednisolone) may be required.
Expected effect on drug levels: Potential ↑ in plasma concentrations of digoxin.
Recommendation for co-administration: Careful monitoring of digoxin levels is recommended.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended due to an increased risk in QT prolongation.
Expected effect on drug levels: ↑ in plasma concentrations of ebastine have been observed.
Recommendation for co-administration: Co-administration is not recommended due to an increased risk in QT prolongation.
Expected effect on drug levels:
Recommendation for co-administration: Dose of edoxaban needs to be reduced when used concomitantly.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended.
Expected effect on drug levels:
| AUC | Cmax | |
| Fesoterodine active metabolite | ↑2.3-fold | ↑2.0-fold |
| Solifenacin | ↑3.0-fold | - |
Tolterodine: ↑ in plasma concentrations of tolterodine have been observed.
Recommendation for co-administration: Not recommended due to an increased risk of QT prolongation.
Expected effect on drug levels: Potential ↑ in plasma concentrations of haloperidol.
Recommendation for co-administration: Not recommended due to the increased risk of QT prolongation and extrapyramidal symptoms. It may be necessary to reduce haloperidol dosage.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended as it may increase ibrutinib-related toxicity.
Expected effect on drug levels:
(Relative to Indinavir 800 mg TID alone)
Recommendation for co-administration: Careful monitoring. Dose reduction of Indinavir to 600 mg every 8 hours should be considered.
Expected effect on drug levels:
Recommendation for co-administration: Co-administration not recommended due to increased risk of isavuconazole adverse reactions.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Maraviroc dose should be decreased to 150 mg twice daily.
Expected effect on drug levels: ↑ in plasma concentrations of nadolol have been observed.
Recommendation for co-administration: Careful monitoring. Dose adjustment of nadolol may be required.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended.
Expected effect on drug levels:
(CYP3A enzyme induction)
Recommendation for co-administration: Co-administration is not recommended.
Expected effect on drug levels: ↑ in plasma concentrations of oxycodone have been observed.
Recommendation for co-administration: Careful monitoring. The oxycodone dose may be adjusted.
Expected effect on drug levels:
Paclitaxel: No change in plasma concentration were shown with paclitaxel concentrate. No studies were performed with albumin bound nanoparticules.
Recommendation for co-administration: Careful monitoring. Dose adjustment of paclitaxel may be required.
Co-administration of ketoconazole and pasireotide is not recommended since the combination can lead to a QT prolongation in patients with known cardiac rhythm disorders.
Expected effect on drug levels: ↑ in plasma concentrations of praziquantel have been observed.
Recommendation for co-administration: Careful monitoring. Dose adjustment of praziquantel may be required.
Expected effect on drug levels:
Recommendation for co-administration: Co-administration is not recommended because of reboxetine narrow’s therapeutic margin.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Dose adjustement of repaglinide may be required.
Expected effect on drug levels:
Potential ↑ in plasma concentrations of rifabutine.
Potencial ↓ in plasma concentrations of ketoconazole are expected.
(CYP3A4 enzyme induction)
Recommendation for co-administration: Co-administration not recommended.
Expected effect on drug levels: Potential ↑ in AUC of risperidone.
Recommendation for co-administration: Careful monitoring. Dose adjustment of risperidone may be required.
Expected effect on drug levels:
(CYP3A enzyme inhibition)
Recommendation for co-administration: A dose reduction of ketoconazole should be considered when co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended due to an increased bleeding risk.
Expected effect on drug levels:
Recommendation for co-administration: Not recommended due to an increased risk in QT prolongation.
Expected effect on drug levels:
Associated with a decrease in corresponding values for the active metabolite.
Recommendation for co-administration: Careful monitoring. Dose adjustment of saxagliptin may be required.
Expected effect on drug levels:
| AUC | Cmax | |
| Sunitinib | ↑1.5-fold | ↑1.5-fold |
| Lapatinib | ↑3.6-fold | - |
| Nilotinib | ↑3.0-fold | - |
| Erlotinib | ↑1.9-fold | ↑1.7-fold |
| Dabrafenib | ↑1.7-fold | ↑1.3-fold |
| Cabozantinib | ↑1.4-fold | ↔ |
Dasatinib: ↑ in plasma concentrations of dasatinib have been observed.
Recommendation for co-administration: Not recommended due to the risk of increased exposure to these drugs and QT prolongation.
Expected effect on drug levels:
Potential ↑ in plasma concentrations of clarithromycin.
Recommendation for co-administration: Co-administration not recommended.
Expected effect on drug levels:
| AUC | Cmax | |
| Temsirolimus | ↔ | ↔ |
| Ciclesonide active metabolite | ↑3.5-fold | - |
Tacrolimus, ciclosporin, budesonide: ↑ in plasma concentrations of these drugs have been observed
Recommendation for co-administration: Co-administration is not recommended unless necessary. Careful monitoring and dose adjustment of these drugs may be required.
Expected effect on drug levels:
Recommendation for co-administration: Careful monitoring. Dose adjustment of tolbutamide may be required.
Expected effect on drug levels: Potential ↑ in plasma concentrations of vinca alkaloids.
Recommendation for co-administration: Careful monitoring as it may cause an earlier onset and/or an increased severity of side-effects.
Adrenal function should be monitored at regular intervals since adrenal insufficiency can occur during the treatment under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. in case of stress, surgery, or infection); and/or in case of ketoconazole overtreatment (for the patients treated with a block-only regimen); or if there is insufficient glucocorticoid replacement therapy (for the patients treated with a block-and-replace regimen). Serum or plasma and/or salivary cortisol and/or urinary free cortisol levels should be monitored, within one week following ketoconazole initiation as a minimum, and then periodically thereafter. When urinary free/serum/ plasma cortisol levels are normalised or close to target and the effective dose of ketoconazole is established, monitoring can be undertaken every 3 to 6 months.
All patients should be monitored and informed about the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, weight-loss, hypotension, hyponatraemia, hyperkalaemia and/or hypoglycaemia).
If clinical symptoms are suggestive of adrenal insufficiency, cortisol levels should be measured and ketoconazole should be temporarily discontinued or the dose reduced and if necessary corticosteroid substitution should be initiated. Ketoconazole can be resumed thereafter at a lower dose.
There are no adequate and well-controlled studies in pregnant women. To date, no other relevant epidemiological data are available. Data on a limited number of exposed pregnancies indicate no adverse effects of topical ketoconazole on pregnancy. Animal studies have shown reproductive toxicity at doses that are not relevant to the topical administration of ketoconazole.
Plasma concentrations of ketoconazole are not detectable after topical application of ketoconazole cream to the skin of non-pregnant humans. There are no known risks associated with the use of ketoconazole cream in pregnancy.
There are insufficient clinical data regarding the oral use of ketoconazole in pregnant women. Preclinical data show that ketoconazole crosses the placenta and is teratogenic. Ketoconazole is contraindicated during pregnancy and it should not be used in women of childbearing potential not using an effective method of contraception.
There are no adequate and well-controlled studies in lactating women. To date, no other relevant epidemiological data are available. Data on a limited number of exposed pregnancies indicate no adverse effects of topical ketoconazole on the health of the foetus/newborn child.
Plasma concentrations of ketoconazole are not detectable after topical application of ketoconazole cream to the skin of non-pregnant humans. There are no known risks associated with the use of ketoconazole cream in lactation.
Since ketoconazole is excreted in the milk, mothers who are under treatment must not breast-feed whilst being treated with ketoconazole tablets.
Studies in animals have shown effects on male and female reproductive parameters.
No specific studies have been conducted to assess the effect of ketoconazole on the ability to drive or use machines. Patients should be warned about the potential for dizziness and somnolence and should be advised not to drive or operate machines if any of these symptoms occur.
The safety of ketoconazole 2% shampoo was evaluated in 2890 subjects who participated in 22 clinical trials. Ketoconazole 2% shampoo was administered topically to the scalp and/or skin. Based on pooled safety data from these clinical trials, there were no ADRs reported with an incidence ≥1%.
The following table displays ADRs that have been reported with the use of Ketoconazole 2% Shampoo from either clinical trial or postmarketing experiences.
The displayed frequency categories use the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated form the available clinical trial data).
Rare: Hypersensitvity
Rare: Dysgeusia
Uncommon: Folliculitis
Uncommon: Increased lacrimation
Rare: Eye irritation
Uncommon: Alopecia, Dry skin, Hair texture abnormal, Rash, Skin burning sensation
Rare: Acne, Dermatitis contact, Skin disorder, Skin exfoliation
Not Known: Angioedema, Urticaria, Hair colour changes
Uncommon: Application site erythema, Application site irritation, Application site pruritus, Application site reaction
Rare: Application site hypersensitivity, Application site pustules
The safety of ketoconazole cream was evaluated in 1079 subjects who participated in 30 clinical trials. Ketoconazole cream was applied topically to the skin.
Based on pooled safety data from these clinical trials, the most commonly reported (≥1% incidence) ADRs were (with % incidence): application site pruritus (2%), skin burning sensation (1.9%), and application site erythema (1%). Including the above-mentioned adverse drug reactions (ADRs), the following table displays ADRs that have been reported with the use of ketoconazole cream from either clinical trial or postmarketing experiences.
The displayed frequency categories use the following convention: Very Common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not Known (cannot be estimated from the available clinical trial data).
Uncommon: Hypersensitivity
Common: Skin burning sensation
Uncommon: Bullous eruption, Dermatitis contact, Rash, Skin exfoliation, Sticky skin
Not Known: Urticaria
Common: Application site erythema, Application site pruritus
Uncommon: Application site bleeding, Application site discomfort, Application site dryness, Application site inflammation, Application site irritation, Application site paraesthesia, Application site reaction
The most frequent adverse reactions are adrenal insufficiency, nausea, vomiting, abdominal pain, diarrhoea, pruritus, rash and the hepatic enzymes increased.
The most serious adverse reaction is hepatotoxicity, primarily as acute hepatocellular toxicity but may also result in cholestatic injury or a mixed pattern of toxicity. ASAT, ALAT, gammaGT, bilirubin and alkaline phosphatase should be monitored at frequent intervals during treatment.
The safety of ketoconazole HRA has been evaluated based on published literature and use of ketoconazole as an antifungal treatment.
The adverse reactions listed below are classified according to System Organ Class. Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon: (≥1/1,000 to <1/100), rare: (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known: cannot be estimated from the available data.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Incidence of adverse reactions and marked laboratory abnormalities reported in the literature in adults and adolescents patients:
Uncommon: Thrombocytopenia
Uncommon: Allergic conditions including anaphylactic shock, anaphylactoid reaction and anaphylactic reaction and angioedema
Common: Adrenal insufficiency
Not Known: Insomnia, nervousness
Not known: Alcohol intolerance, anorexia, increased appetite
Uncommon: Headache, dizziness, somnolence
Not known: Intracranial pressure increased (papilloedema, fontanelle bulging), paraesthesia
Not known: Photophobia
Not known: Epistaxis
Common: Nausea, abdominal pain, vomiting, diarrhoea
Not known: Dyspepsia, flatulence, tongue discoloration, dry mouth, dysgeusia
Very common: Liver function tests abnormal
Rare: Serious hepatotoxicity, including jaundice, hepatitis, hepatic necrosis, hepatic cirrhosis, hepatic failure including cases necessitating transplantation or resulting in death
Common: Pruritus, rash
Uncommon: Urticaria, alopecia
Not known: Photosensitivity, erythema multiforme, dermatitis, erythema, xeroderma
Not known: Myalgia, arthralgia
Not known: Menstrual disorder, azoospermia, erectile dysfunction, gynaecomastia
Uncommon: Asthenia
Very rare: Pyrexia
Not known: Oedema peripheral, malaise, hot flush
Very common: Hepatic enzyme increased
Uncommon: Platelet count decreased
Not known: Transient decrease of testosterone concentrations
Serious hepatic toxicity caused by ketoconazole treatment is rare (1/15000). Acute hepatocellular injury has been primarily observed as has cholestatic injury or a mixed pattern of toxicity. Fatal cases have been reported particularly when treatment is continued despite liver enzyme elevation. Increases in liver enzymes (≤5N and >5N) were observed in ~13.5% and ~2.5% of patients respectively occurring mostly within the first 6 months of treatment. Liver enzyme levels returned to normal within 2-12 weeks after a dose decrease or withdrawal of ketoconazole. Hepatotoxicity does not appear to be dose dependent. All potential associated factors of hepatotoxicity, and abnormal liver enzyme levels detected before ketoconazole HRA initiation, should be taken into account before considering ketoconazole HRA treatment. Ketoconazole HRA should not be administered when liver enzymes are greater than 2 times the upper limit of normal or in association with other hepatotoxic drugs. Liver enzyme monitoring should be performed once weekly during the first month of treatment and then monthly for 6 months. In the case an increase of liver enzymes is detected which is less than 3 times the upper limit of normal, closer monitoring of liver function should be performed and the daily dose should be decreased by at least 200 mg. In the case of increase of liver enzymes levels above 3 times the upper limit of normal, ketoconazole HRA should be stopped immediately and should not be reintroduced because of the risk of serious hepatic toxicity.
Adrenal insufficiency may occur in patients on ketoconazole without corticosteroid substitution (block-only regimen) or if there is an insufficient glucocorticoid replacement therapy (for the patients treated with a block-and-replace regimen). Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalemia, hyponatraemia, hyperkalaemia or hypoglycaemia). Adrenal insufficiency may be detected by periodic clinical assessment and monitoring of plasma/serum or salivary cortisol levels. In case of adrenal insufficiency, ketoconazole HRA treatment should be temporarily discontinued or the dose reduced and, if needed, a corticosteroid substitution therapy added.
Frequency of hepatotoxicity could be higher in adolescents than in adults. In the literature, among 24 paediatric patients treated with ketoconazole, two developed severe hepatoxicity. A 14 year-old girl who was treated for Cushing’s disease with ketoconazole 200 mg twice daily presented one month later with jaundice, fever anorexia, nausea and vomiting. Ketoconazole was stopped but she deteriorated rapidly and died. A 17 years old girl was treated on ketoconazole 1200 mg/day for an adrenal carcinoma with liver metastasis and had altered liver function tests at 22 days. After ketoconazole withdrawal, liver enzymes returned to normal levels within 3 weeks.
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