Ketoconazole is a synthetic, broad-spectrum imidazole antifungal agent. It is primarily used for the systemic treatment of serious fungal infections when other antifungal therapies are ineffective or contraindicated. Its use is now largely restricted due to significant hepatotoxicity and multiple drug interactions, particularly its potent inhibition of CYP3A4. In India, it is a critical drug for specific endemic mycoses but requires stringent monitoring.
Adult: 200 mg once daily (range: 200-400 mg daily). For life-threatening infections, a loading dose of 400 mg on first day may be used. Must be taken with food to improve tolerance and with an acidic beverage (e.g., cola) if patient is on acid-reducing therapy.
Note: Take with food to minimize gastrointestinal upset and enhance absorption. Tablets should be swallowed whole with a full glass of water. For patients with reduced gastric acidity, administer with an acidic beverage (e.g., non-diet cola). Do not administer concurrently with antacids, H2-receptor antagonists, or proton pump inhibitors; separate by at least 2 hours.
Ketoconazole inhibits the synthesis of ergosterol, a critical component of fungal cell membranes. It acts by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-α-demethylase. This inhibition leads to accumulation of 14-α-methyl sterols (like lanosterol) and depletion of ergosterol, disrupting membrane structure and function, increasing permeability, and inhibiting fungal growth.
Pregnancy: Category C (US FDA). Animal studies show teratogenicity. Adequate human data lacking. Should be used ONLY if the potential benefit justifies the potential risk to the fetus. Topical therapy is preferred for localized infections.
Driving: May cause dizziness, vertigo, or somnolence. Patients should be cautioned about operating machinery or driving until they are certain ketoconazole does not affect them adversely.
| Rifampicin, Rifabutin, Phenytoin, Carbamazepine | Markedly reduce ketoconazole plasma levels via CYP450 induction, leading to therapeutic failure. | Major |
| H2 Blockers (Ranitidine), PPIs (Omeprazole), Antacids | Reduce gastric acidity, severely impairing ketoconazole absorption. | Major |
| Statins (Simvastatin, Lovastatin, Atorvastatin) | Increased statin levels (CYP3A4 inhibition), dramatically raising risk of myopathy/rhabdomyolysis. | Contraindicated/ Major |
| Benzodiazepines (Midazolam, Triazolam) | Increased sedation and prolonged effect due to reduced metabolism. | Major |
| Warfarin | Potentiated anticoagulant effect, increased risk of bleeding. | Major |
| Cyclosporine, Tacrolimus, Sirolimus | Markedly increased immunosuppressant levels, leading to nephrotoxicity and other toxicities. | Major |
| Digoxin | Increased digoxin levels (P-glycoprotein inhibition), risk of toxicity. | Major |
| Oral Hypoglycemics (Sulfonylureas) | Enhanced hypoglycemic effect. | Moderate |
| Quinidine, Disopyramide | Increased antiarrhythmic levels, high risk of QTc prolongation and Torsades de Pointes. | Contraindicated |