Ketoconazole is a synthetic derivative of phenylpiperazine with broad antifungal properties and potential antineoplastic activity. Ketoconazole inhibits sterol 14-a-dimethylase, a microsomal cytochrome P450-dependent enzyme, thereby disrupting the synthesis of ergosterol, an important component of the fungal cell wall. (NCI04)
Mechanism of Action of Ketoconazole
Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.
Indications of Ketoconazole
- Blastomycosis
- Candidiasis, Cutaneous
- Candiduria
- Chromomycosis
- Coccidioidomycosis
- Dandruff
- Histoplasmosis
- Oral candida
- Paracoccidioidomycosis
- Pityriasis Versicolor
- Seborrheic dermatitis
- Tinea corporis
- Tinea cruris
- Tinea pedis
- Recalcitrant cutaneous dermatophyte infection
- Severe cutaneous dermatophyte infection
- Chronic mucocutaneous candidiasis
- Dermatophytosis
- Esophageal candidiasis
- Onychomycosis, Fingernail
- Onychomycosis, toenail
- Oral thrush
- Paracoccidioidomycosis
- Tinea corporis
- Tinea versicolor
- Vaginal yeast infection
Therapeutic Indications
- For the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.
- Treatment of Cushing’s syndrome
- Treatment of granulosa cell tumors
- Ketoconazole HRA is indicated for the treatment of endogenous Cushing’s syndrome in adults and adolescents above the age of 12 years.
Contraindications of Ketoconazole
- Have known hypersensitivity to other azole medicines such as ketoconazole;
- Are taking terfenadine, if 400 mg per day multidose of fluconazole is administered;
- Concomitant administration of ketoconazole and quinidine, especially when ketoconazole is administered in high dosages;
- Take SSRIs such as fluoxetine or sertraline.
Dosage of Ketoconazole
Strengths:
Tablets: 200 mg; Shampoo: 1% and 2%; Cream: 2%, Gel: 2%, Foam: 2%
Blastomycosis
- Initial dose: 200 mg orally once a day
- If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
- Duration of therapy: 6 months (usual duration for systemic infection)
Chromomycosis
- Initial dose: 200 mg orally once a day
- If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
Coccidioidomycosis
- Initial dose: 200 mg orally once a day
- If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
- Duration of therapy: 6 months (usual duration for systemic infection)
Histoplasmosis
- Initial dose: 200 mg orally once a day
- If clinical responsiveness insufficient within expected time: Dose may be increased to 400 mg orally once a day.
- Duration of therapy: 6 months (usual duration for systemic infection)
Blastomycosis
- 2 years or older: 3.3 to 6.6 mg/kg orally once a day
- Duration of therapy: 6 months (usual duration for systemic infection)
Chromomycosis
- 2 years or older: 3.3 to 6.6 mg/kg orally once a day
- Duration of therapy: 6 months (usual duration for systemic infection)
Coccidioidomycosis
- 2 years or older: 3.3 to 6.6 mg/kg orally once a day
- Duration of therapy: 6 months (usual duration for systemic infection)
Paracoccidioidomycosis
- 2 years or older: 3.3 to 6.6 mg/kg orally once a day
- Duration of therapy: 6 months (usual duration for systemic infection)
Side Effects of Ketoconazole
The most common
- Abdominal or stomach pain
- feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
- sudden tingling or coldness in an arm or leg
- Nausea
- liver problems,
- stomach pain,
- vomiting,
- Dizziness
- Burning, itching, stinging, redness, or other sign of irritation at the application site, rash
- a headache,
- increased intracranial pressure,
- meningeal signs,
- reversible hair loss or thinning, and
- fever.
Common
- chills or fever
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- discomfort in arms, shoulders, neck or upper back
- excessive sweating
- sudden slow or difficult speech
- sudden drowsiness or need to sleep
- fast breathing
- sharp pain when taking a deep breath
- fast or slow heartbeat
- coughing up blood
- rust colored urine
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- fainting
- hallucinations
- headache
- irritability
- lightheadedness
- mood or mental changes
- muscle pain or cramps
- muscle spasm or jerking of all extremities
- burning,
- stinging,
- severe pain in your upper stomach spreading to your back, nausea and vomiting;
- signs of congestive heart failure–shortness of breath (even with mild exertion), cough with mucus, fast heartbeats, swelling, rapid weight gain, sleep problems; or.
Interactions of Ketoconazole
Kitoconazole may interact with following drugs ,supplyments & may change the efficacy of drugs
- medications that use the enzyme such as budesonide , cyclosporine , darifenacin , dihydroergotamine , fentanyl pimozide , quinidine , sirolimus , tacrolimus , terfenadine , fluticasone , eletriptan , lovastatin quetiapine, sildenafil , and simvastatin
- medications that block the enzyme CYP3A4 such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan, delavirdine, and nefazodone
- medications that increase the activity of the enzyme CYP3A4 such as carbamazepine , phenobarbital, phenytoin , rifampin and nimodipine
- methylprednisolone
- midazolam
- triazolam
- digoxin
- warfarin
- phenytoin
- rifampin
- alcohol
Interactions that can make your drugs less effective
When ketoconazole is less effective: When ketoconazole is used with certain drugs, it may not work as well to treat your condition. This is because the amount of ketoconazole in your body may be decreased. Examples of these drugs include:
- Ranitidine, famotidine, cimetidine, pantoprazole, omeprazole, and rabeprazole. You should take ketoconazole with an acidic beverage, such as a non-diet soda, if you take these drugs together.
- Aluminum hydroxide. You should take this drug 1 hour before or 2 hours after taking ketoconazole.
- Antibiotics, such as isoniazid and rifabutin
- Anticonvulsants, such as carbamazepine and phenytoin
- Antivirals, such as efavirenz and nevirapine
- Carbamazepine. Your doctor may monitor your carbamazepine levels.
Pregnancy & Lactation
FDA Pregnancy category C
Ketoconazole falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. There are no well-controlled studies that have been done in humans with ketoconazole, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
Lactation
It is not known if ketoconazole crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using ketoconazole.
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