ketoconazole (systemic)

REMS

Treatment of:
- Chromomycosis,
- Coccidioidomycosis,
- Histoplasmosis,
- Paracoccidioidomycosis,
- Blastomycosis.
Because ketoconazole has been associated with serious adverse reactions, it is not indicated for treatment of onychomycosis, cutaneous dermatophyte infections, or Candida infections. Ketoconazole should only be used when other effective antifungal therapy is NOT available AND its potential benefits outweigh its potential risks.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Hepatic impairment;
Concurrent use of dofetilide, quinidine, pimozide, methadone, disopyramide, dronedarone, and lurasidone;
Concurrent use of irinotecan, alprazolam, triazolam, midzolam (PO), felodipine, nisoldipine, lovastatin, simvastatin, tolvaptan, eplerenone, colchicine, ergotamine, and dihydroergotamine;
Lactation: Lactation.

Use Cautiously in:

Achlorhydria or hypochlorhydria;
Alcoholism;
Rep: Agents other than ketoconazole are recommended for the treatment of systemic fungal infections in pregnancy;
Pedi: Children <2 yr (safety not established).

Adv. Reactions/Side Effects ⬆ ⬇

CV: QT interval prolongation, TORSADES DE POINTES

Derm: rash, urticaria

EENT: photophobia

Endo: adrenal insufficiency, gynecomastia

GI: nausea, vomiting, abdominal pain, constipation, diarrhea, flatulence, HEPATOTOXICITY

GU: ↓libido (men), azoospermia, menstrual irregularities, oligospermia

Neuro: dizziness, drowsiness

Misc: ANAPHYLAXIS

Interactions ⬆ ⬇

Drug-drug:

May significantly ↑ levels and risk of torsades de pointes with dofetilide, disopyramide, dronedarone, lurasidone, quinidine, pimozide, ranolazine, and methadone; concurrent use contraindicated.
May significantly ↑ levels and risk of sedation of alprazolam, midzolam (PO), and triazolam; concurrent use contraindicated.
May significantly ↑ levels and risk of myopathy of lovastatin and simvastatin; concurrent use contraindicated.
May significantly ↑ levels and risk of toxicity of nisoldipine, felodipine, eplerenone, irinotecan, colchicine, tolvaptan, ergotamine, and dihydroergotamine; concurrent use contraindicated.
May ↑ levels and risk of toxicity of cyclosporine, tacrolimus, amlodipine, nicardipine, nifedipine, verapamil, aliskiren, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, atorvastatin, bosentan, rifabutin, buspirone, cilostazol, digoxin, clarithromycin, erythromycin, haloperidol, midazolam (IV), quetiapine, ramelteon, risperidone, warfarin (↑ risk of bleeding), dabigatran, rivaroxaban, carbamazepine, fentanyl, sufentanil, aprepitant, cinacalcet, eletriptan (not to be used within 72 hr), bortezomib, busulfan, docetaxel, erlotinib, imatinib, paclitaxel, vincristine, vinblastine, maraviroc, fesoterodine, solifenacin, tolterodine, tadalafil, sildenafil and vardenafil; dosage adjustments may be necessary.
May ↑ levels and risk of toxicity of dasatinib, lapatinib, nilotinib, everolimus, sirolimus, and salmeterol; concurrent use not recommended.
May ↑ levels and risk of toxicity of aripiprazole; ↓ aripiprazole dose by 50%.
May alter the effectiveness of hormonal contraceptives; alternative method of contraception recommended.
Drugs that ↑ gastric pH, including antacids, histamine H2 antagonists, and proton pump inhibitors, ↓ absorption; wait 2 hr before administration of ketoconazole.
↑risk of hepatotoxicity with other hepatotoxic agents, including alcohol.
Disulfiram-like reaction may occur with alcohol.
Rifampin, rifabutin, carbamazepine, phenytoin, or isoniazid may ↓ levels and effectiveness.
Ritonavir may ↑ levels and risk of toxicity; ↓ ketoconazole dose.
May ↓ absorption and effectiveness of theophylline.

Availability ⬆ ⬇

(Generic available)

Tablets: 200 mg

Route/Dosage ⬆ ⬇

PO (Adults ): 200–400 mg once daily.
PO (Children >2 yr): 3.3–6.6 mg/kg once daily.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Disrupts fungal cell membrane.
Interferes with fungal metabolism.
Also inhibits the production of adrenal steroids.

Therapeutic effects:

Fungistatic or fungicidal action against susceptible organisms, depending on organism and site of infection.

Spectrum:

Active against many pathogenic fungi, including:
- Blastomyces,
- Coccidioides,
- Cryptococcus,
- Histoplasma,
- many dermatophytes.

Classifications ⬆ ⬇

Therapeutic Classification: antifungals (systemic)

Pharmacokinetics ⬆ ⬇

Absorption: Absorption from the GI tract is pH dependent; ↑ pH ↓ absorption.

Distribution: Widely distributed. CNS penetration is unpredictable and minimal.

Protein Binding: 99%.

Metabolism/Excretion: Partially metabolized by the liver. Excreted in feces via biliary excretion.

Half-Life: 8 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1–4 hr	24 hr

Patient/Family Teaching ⬆ ⬇

Instruct patient to take ketoconazole as directed, at the same time each day, even if feeling better. Take missed doses as soon as remembered; if almost time for next dose, space missed dose and next dose 10–12 hr apart.
- Advise patient to avoid concurrent use of alcohol while taking ketoconazole; may cause a disulfiram-like reaction (flushing, rash, peripheral edema, nausea, headache) and ↑ risk of hepatotoxicity.
- May cause dizziness or drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
- Advise patient to avoid taking OTC antacids within 2 hr of ketoconazole.
- Caution patient to wear sunglasses and to avoid prolonged exposure to bright light to prevent photophobic reactions.
- Instruct patient to notify health care provider if abdominal pain, fever, or diarrhea becomes pronounced or if signs and symptoms of liver dysfunction (unusual fatigue, anorexia, nausea, vomiting, jaundice, dark urine, pale stools) occur.
- Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding. Advise women of reproductive potential to use a nonhormonal form of contraception during ketoconazole therapy.

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Indications ⬇