Applies to ketoconazole: compounding powder, oral tablet
Ketoconazole therapy has commonly been associated with transient elevations in liver enzymes, which have resolved despite continued therapy.
Serious hepatotoxicity has been reported with both high doses for short durations and low doses for long therapy durations. Hepatic injury has usually (but not always) been reversible with discontinuation of ketoconazole (the active ingredient contained in Nizoral) therapy. Hepatitis has been reported in children.
Hepatotoxicity has been reported with oral ketoconazole rechallenge.
Frequency not reported: Hepatitis, jaundice, abnormal hepatic function, hepatotoxicity, transient elevations of liver enzymes
Postmarketing reports: Serious hepatotoxicity including cholestatic hepatitis, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure (including cases resulting in death or requiring liver transplantation)
Frequency not reported: Orthostatic hypotension, QT interval prolongation (sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes)
Ketoconazole inhibits hydroxylation of deoxycortisol, which results in diminished cortisol production, especially when given in divided doses. In some patients, symptomatic adrenal insufficiency may occur, presenting with hyponatremia, hyperkalemia, hypotension, lethargy, depression, and malaise.
A 77-year-old male with prostate cancer experienced adrenal crisis coincident with ketoconazole (the active ingredient contained in Nizoral) therapy. He presented with progressive right lower extremity weakness, debilitating low back pain, and a serum prostate-specific antigen level of 78.8 ng/mL. He was given ketoconazole 200 mg orally four times daily to reduce serum testosterone levels. Nine days after initiating ketoconazole therapy, he experienced generalized weakness, abdominal pain, nausea with vomiting, and severely diminished mentation. The urology service was advised of the patient's admission and suggested that adrenal insufficiency related to high-dose ketoconazole therapy should be considered in the differential diagnosis. However, a serum cortisol level was not obtained prior to steroid treatment. An ACTH stimulation test performed 2 days later showed no evidence of underlying adrenal insufficiency when the patient was no longer being given ketoconazole.
Rare (less than 0.1%): Hypothyroidism, adrenal crisis (at least 1 case)
Frequency not reported: Inhibition of cortisol production (sometimes resulting in symptomatic adrenal insufficiency)
Postmarketing reports: Adrenocortical insufficiency
Rare (less than 0.1%): Dry skin (at least 5 cases), bruising (at least 1 case), loss of scalp hair (at least 6 cases), worsening loss of scalp hair (at least 5 cases), desquamation (at least 6 cases)
Frequency not reported: Erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia, xeroderma
Postmarketing reports: Acute generalized exanthematous pustulosis, photosensitivity
Rare (less than 0.1%): Stomatitis (at least 1 case)
Frequency not reported: Nausea, vomiting, diarrhea, constipation, abdominal pain, upper abdominal pain, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration
Gastrointestinal intolerance may resolve with continued therapy and may improve if ketoconazole is taken with food.
A 23-year-old female with vaginal discharge experienced fatal aplastic anemia coincident with ketoconazole (the active ingredient contained in Nizoral) therapy. She was admitted with widespread purpuric lesions on her face, arms, and legs. She had taken ketoconazole 200 mg twice daily for vaginal discharge for 4 days before admission. Ketoconazole was discontinued on admission. The patient was diagnosed with aplastic anemia based on clinical findings. The patient did not respond to therapy and died of disseminated candidiasis 2 months later.
Rare (less than 0.1%): Hemolytic anemia, fatal aplastic anemia (at least 1 case)
Frequency not reported: Platelet count decreased
Postmarketing reports: Thrombocytopenia
Frequency not reported: Anaphylactoid reaction, hypersensitivity reactions (including urticaria), anaphylaxis (sometimes after first dose), cross-sensitivity between imidazoles
Postmarketing reports: Allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema
A 72-year-old female with a Candida albicans infection experienced a severe reaction of refractory anaphylactic shock coincident with ketoconazole therapy. She was initially given oral ketoconazole 200 mg twice daily. She developed hypotension over the first 2 days of treatment (BP 136/82 mmHg at baseline; 90/50 mmHg on day 2). Severe hypotension (BP 90/49 mmHg) unresponsive to fluid therapy or high-dose dopamine developed on day 4 of treatment. When laboratory tests revealed a high level of plasma tryptase, anaphylactic redistribution shock was diagnosed. Her vital signs became more stable after therapy with hydrocortisone and epinephrine infusion.
Rare (less than 0.1%): Polymenorrhea anovulatory cycles (at least 13 cases), anovulatory oligomenorrhea (at least 14 cases)
Frequency not reported: Menstrual disorder, serum testosterone decreased, gynecomastia (in males), breast tenderness (in males), oligospermia
Postmarketing reports: Erectile dysfunction, azoospermia (with doses higher than recommended dose of 200 to 400 mg per day)
Gynecomastia and breast tenderness have been reported in male patients. Gynecomastia in males resulted from decreased steroidogenesis and testosterone production, which led to an increased estrogen to testosterone ratio.
Rare (less than 0.1%): Hypoglycemia
Frequency not reported: Alcohol intolerance, anorexia, hyperlipidemia, increased appetite, transient fall in serum cholesterol with an increase in triglycerides
Frequency not reported: Headache, somnolence, dizziness, paresthesia
Postmarketing reports: Reversible increased intracranial pressure (e.g., papilledema, fontanel bulging in infants)
Frequency not reported: Fatigue, asthenia, hot flush, malaise, peripheral edema, pyrexia, chills
Frequency not reported: Myalgia
Postmarketing reports: Arthralgia
Rare (less than 0.1%): Paranoid delusions (at least 1 case), confusion, suicidal tendencies
Frequency not reported: Insomnia, nervousness
Paranoid delusions have been reported in a patient treated with ketoconazole for cutaneous leishmaniasis.
Frequency not reported: Photophobia
Frequency not reported: Epistaxis