ketoconazole (systemic)

REMS

Treatment of:
- Candidiasis (disseminated and mucocutaneous),
- Chromomycosis,
- Coccidioidomycosis,
- Histoplasmosis,
- Paracoccidioidomycosis,
- Blastomycosis
Should only be used when other effective antifungal therapy is NOT available AND the potential benefits of oral ketoconazole outweigh its potential risks

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,
- Candida,
- Coccidioides,
- Cryptococcus,
- Histoplasma,
- many dermatophytes.

Pharmacokinetics ⬆ ⬇

Absorption: Absorption from the GI tract is pH dependent; increasing pH decreases absorption.

Distribution: Widely distributed. CNS penetration is unpredictable and minimal. Crosses the placenta; enters breast milk.

Protein Binding: 99%.

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

Half-Life: 8 hr.

Time/Action Profile ⬆ ⬇

(blood levels)

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

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Liver disease
Concurrent dofetilide, quinidine, pimozide, methadone, disopyramide, dronedarone, irinotecan, lurasidone, alprazolam, triazolam, midzolam (PO), felodipine, nisoldipine, lovastatin, simvastatin, ranolazine, tolvaptan, eplerenone, colchicine, ergotamine, and dihydroergotamine;
OB: Reported association with limb defects (1st trimester) and growth retardation (3rd trimester).

Use Cautiously in:

History of liver disease;
Achlorhydria or hypochlorhydria;
Alcoholism;
Lactation: Usually compatible with breastfeeding. Careful timing of dosage may infant exposure;
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: ↓male libido, azoospermia, menstrual irregularities, oligospermia

Neuro: dizziness, drowsiness

Misc: ANAPHYLAXIS

Interactions ⬆ ⬇

Drug-drug:

Ketoconazole is a strong inhibitor of the CYP3A4 isoenzyme
May significantly ↑ levels and risk of torsades de pointes with dofetilide, disopyramide, dronedarone, quinidine, pimozide, ranolazine, and methadone; concurrent use contraindicated
May significantly ↑ levels and risk of sedation with alprazolam, midzolam (PO), and triazolam; concurrent use contraindicated
May significantly ↑ levels and risk of myopathy with lovastatin and simvastatin; concurrent use contraindicated
May significantly ↑ levels and risk of toxicity with nisoldipine, felodipine, eplerenone, irinotecan, lurasidone, colchicine, tolvaptan, ergotamine, and dihydroergotamine; concurrent use contraindicated
May ↑ levels 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 with dasatinib, lapatinib, nilotinib, everolimus, sirolimus, and salmeterol; concurrent use not recommended
May ↑ levels 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; should ↓ ketoconazole dose
May ↓ absorption and effectiveness of theophylline.

Route/Dosage ⬆ ⬇

PO (Adults ): 200–400 mg/day, single dose.
PO (Children >2 yr): 3.3–6.6 mg/kg/day, single dose.

Availability ⬆ ⬇

(Generic available)

Tablets: 200 mg

Assessment ⬆ ⬇

Assess patient for symptoms of infection prior to and periodically during therapy.
Specimens for culture should be taken prior to instituting therapy. Therapy may be started before results are obtained.

Lab Test Considerations:

Monitor hepatic function tests (SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and testing for viral hepatitides) prior to therapy. Monitor ALT weekly during therapy; if ↑ above normal limits or >30% above baseline, or patient develops symptoms of liver injury, interrupt ketoconazole therapy and obtain full set of liver tests. Repeat tests to ensure normalization of values. If restarting therapy, monitor liver function frequently.
- May cause ↓ serum testosterone concentrations.

Implementation ⬆ ⬇

PO: Administer with meals or snacks to minimize nausea and vomiting.
- Do not administer histamine H₂ antagonists or antacids within 2 hr of ketoconazole.
- For patients with achlorhydria, dissolve each tablet in 4 mL of aqueous solution of 0.2 N hydrochloric acid. Use a glass or plastic straw to avoid contact with teeth and follow with a glass of water, swished in mouth and swallowed.

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 increase 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 professional if abdominal pain, fever, or diarrhea becomes pronounced or if signs and symptoms of liver dysfunction (unusual fatigue, anorexia, nausea, vomiting, jaundice, dark urine, or pale stools) occur.
- Advise patient to use a nonhormonal form of contraception during ketoconazole therapy.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇