Itraconazole GPO

Itraconazole GPO

itraconazole

Manufacturer:

GPO

Distributor:

GPO
Full Prescribing Info
Contents
Itraconazole.
Description
Each capsule contains itraconazole 100 mg.
Action
Pharmacology: Pharmacodynamics: Itraconazole is a systemic triazole antifungal agent. Itraconazole interferes with cytochrome P450 (CYP450) activity, decreasing ergosterol synthesis (principal component of fungal cell membrane) and inhibiting cell membrane formation.
Pharmacokinetics: Absorption: Following oral administration, bioavailability of itraconazole varies depending on whether the drug is administered as capsules or the oral solution; these preparations are not bioequivalent. When administered under optimum conditions for gastrointestinal (GI) absorption (oral solution under fasting conditions or oral capsules with food), the oral solution is more bioavailable than capsule.
When a single 200-mg dose is given as capsules (with a meal), peak plasma concentrations usually attained within 5 hours and average 302 ng/mL. When itraconazole capsules are used, bioavailability is maximal when administered with food. Food decreases the rate of absorption, but increases peak plasma concentrations and area under the curve (AUC) of the oral capsules.
Distribution: The average volume of distribution (Vd) is 10 L/kg. Itraconazole is 99.8% and hydroxyitraconazole is 99.5% bound to plasma proteins. Itraconazole is highly lipophilic and is distributed into nail matrix, bed, and plate following oral administration, persisting in these tissues for several months after discontinuance of the drug. Tissue concentrations of the drugs are higher than plasma concentrations. Itraconazole is distributed into human milk.
Metabolism: Itraconazole is metabolized principally in the liver by CYP3A4 isoenzyme to several metabolites. Hydroxyitraconazole, the major metabolite, has antifungal activity.
Elimination: Approximately 40% of an itraconazole dose is eliminated in urine as inactive metabolites, less than 0.03% is eliminated in urine as unchanged drug, and 3-18% is eliminated in feces as unchanged drug. In adults receiving oral capsules (200 mg twice daily with a meal), the half-life of itraconazole is 64 hours and the half-life of hydroxyitraconazole is 56 hours at steady state. Itraconazole is not appreciably removed by hemodialysis or peritoneal dialysis.
Indications/Uses
Itraconazole, an azole antifungal agent, is used for treatment of susceptible fungal infections in immunocompromised and immunocompetent patients including blastomycosis and histoplasmosis; indicated for aspergillosis (in patients intolerant/refractory to amphotericin B), and onychomycosis of the toenail and fingernail (in nonimmunocompromised patients).
Dosage/Direction for Use
Oral: Usual dosage ranges: Children: Efficacy and safety have not been established; a small number of patients 3-16 years of age have been treated with 100 mg/day for systemic fungal infections with no serious adverse effects reported. A dose of 5 mg/kg once daily was used in a pharmacokinetic study using the oral solution in patients 6 months to 12 years; duration of study was 2 weeks.
Adults: 100-400 mg/day; doses >200 mg/day are given in 2 divided doses; length of therapy varies from 1 day to >6 months depending on the condition and mycological response.
Maximum dose: 400 mg/day, but this may differ depending on indication.
Indication-specific dosing: Adults: Aspergillosis, invasive (salvage therapy): Duration of therapy should be a minimum of 6-12 weeks or throughout period of immunosuppression: Oral: 200-400 mg/day; Note: 2008 IDSA guidelines recommend 600 mg/day for 3 days, followed by 400 mg/day.
Appropriate use: Itraconazole should NOT be used for voriconazole-refractory aspergillosis since the same antifungal and/or resistance mechanism(s) may be shared by both agents. Itraconazole oral solution and capsule formulations are not bioequivalent or interchangeable. Due to variable bioavailability of oral preparations, therapeutic drug monitoring advisable.
Aspergillosis, allergic (ABPA, sinusitis): 200 mg/day; may be used in conjunction with corticosteroids.
Blastomycosis: 200 mg 3 times/day for 3 days, then 200 mg twice daily for 6-12 months; in moderately-severe to severe infection, therapy should be initiated with ~2 weeks of amphotericin B.
Brain abscess: Cerebral phaeohyphomycosis (dematiaceous): 200 mg twice daily for at least 6 months with amphotericin.
Coccidioidomycosis: 200 mg twice daily.
Histoplasmosis: 200 mg 3 times/day for 3 days, then 200 mg twice daily (or once daily in mild-moderate disease) for 6-12 weeks in mild-moderate disease or ≥12 months in progressive disseminated or chronic cavitary pulmonary histoplasmosis; in moderately-severe to severe infection, therapy should be initiated with ~2 weeks of a lipid formation of amphotericin B. Long-term suppression therapy: 200 mg/day.
Meningitis: Coccidioides: 400-800 mg/day.
Appropriate use: Fluconazole is preferred for meningeal infections.
Onychomycosis: 200 mg once daily for 12 consecutive weeks; alternative "pulse-dosing" may be considering for fingernail involvement only: 200 mg twice daily for 1 week; repeat 1-week course after 3-week off-time.
Pneumonia: Coccidioides: Mild-to-moderate: 200 mg twice daily.
Coccidioides, HIV-positive (focal pneumonia): 200 mg 3 times/day for 3 days, then 200 mg twice daily.
Protothecal infection: 200 mg once daily for 2 months.
Sporotrichosis: Lymphocutaneous: 100-200 mg/day for 3-6 months.
Osteoarticular and pulmonary: 200 mg twice daily for 1-2 years (may use amphotericin B initially for stabilization).
Dosing adjustment in renal impairment: Use with caution in patients with renal impairment. The following guidelines have been used by some clinicians: Clcr >10 mL/minute: No adjustment recommended, Clcr <10 mL/minute: Administer 50% of normal dose.
Continuous renal replacement therapy (CRRT)/hemodialysis: 200 mg every 12 hours for 4 doses, then 200 mg every 24 hours.
Hemodialysis: Not dialyzable.
Dosing adjustment in hepatic impairment: Use caution in patients with hepatic impairment.
Mode of Administration: Administer orally. Doses >200 mg/day are given in 2 divided doses; do not administer with antacids. Capsule and oral solution formulations are not bioequivalent and thus are not interchangeable. Capsule absorption is best if taken with food, therefore, it is best to administer itraconazole after meals.
Overdosage
Manifestation: Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking itraconazole capsules up to 3,000 mg, the adverse event profile was similar to that observed at recommended doses.
Treatment: Itraconazole is not removed by dialysis. In the event of accidental overdosage, use supportive measures, including gastric lavage with sodium bicarbonate.
Contraindications
Itraconazole is contraindicated in patients with known hypersensitivity to itraconazole (use caution in patients with a history of hypersensitivity to other azoles), any component of the formulation; concurrent administration with cisapride, dofetilide, ergot derivatives, levomethadyl, lovastatin, midazolam (oral), nisoldipine, pimozide, quinidine, simvastatin, or triazolam; treatment of onychomycosis (or other non-life-threatening indications) in patients with evidence of ventricular dysfunction, heart failure (HF) or a history of HF; treatment of onychomycosis in patients who are pregnant or intend on becoming pregnant.
Special Precautions
Concerns related to adverse effects: Hearing loss: Transient or permanent hearing loss has been reported. Quinidine (a contraindicated drug) was used concurrently in several of these cases. Hearing loss usually resolves after discontinuation, but may persist in some patients.
Heart failure: Negative inotropic effects have been observed following intravenous administration. Discontinue or reassess use if signs or symptoms of heart failure (HF) occur during treatment. HF has been reported, particularly in patients receiving a total daily oral dose of 400 mg. Use with caution in patients with risk factors for HF (COPD, renal failure, edematous disorders, ischemic or valvular disease).
Hepatotoxicity: Rare cases of serious hepatotoxicity (including liver failure and death) have been reported (including some cases occurring within the first week of therapy); hepatotoxicity was reported in some patients without pre-existing liver disease or risk factors. Use with caution in patients with pre-existing hepatic impairment; monitor liver function closely and dosage adjustment may be warranted. Not recommended for use in patients with active liver disease, elevated liver enzymes, or prior hepatotoxic reactions to other drugs unless the expected benefit exceeds the risk of hepatotoxicity.
Neuropathy: Discontinue if signs or symptoms of neuropathy occurs during treatment.
Disease-related concerns: Cystic fibrosis: Large differences in itraconazole pharmacokinetic parameters have been observed in cystic fibrosis patients receiving the solution; if a patient with cystic fibrosis does not respond to therapy, alternate therapies should be considered.
Onychomycosis: Not recommended for treatment of onychomycosis in patients with ventricular dysfunction or a history of HF.
Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues: Calcium channel blockers (CCBs): May cause additive negative inotropic effects when used concurrently with itraconazole. Itraconazole may also inhibit the metabolism of CCBs. Therefore, use caution with concurrent use of itraconazole and CCBs due to an increased risk of heart failure. Concurrent use of itraconazole and nisoldipine is contraindicated.
High potential for interactions: Serious cardiovascular (CV) adverse events including, QT prolongation, ventricular tachycardia, torsade de pointes, cardiac arrest and/or sudden death have been observed due to increased cisapride, pimozide, quinidine, dofetilide or levomethadyl concentrations induced by itraconazole; concurrent use contraindicated. Additionally, the following drugs metabolized by the CYP 3A4 isoenzyme system are also contraindicated: Ergot derivatives, lovastatin, midazolam (oral), simvastatin, and triazolam.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy category C. Itraconazole should not be used to treat onychomycosis during pregnancy. Effective contraception should be used during treatment and for 2 months following treatment.
Lactation: Itraconazole enters breast milk. Use is not recommended.
Adverse Reactions
>10%: Gastrointestinal: Nausea (11%), diarrhea (3% to 11%).
1% to 10%: Cardiovascular: Edema (4%), hypertension (3%), chest pain (3%).
Central nervous system: Fever (3% to 7%), headache (4%), fatigue (2% to 3%), dizziness (2%), depression (2%).
Dermatologic: Rash (4% to 9%), pruritus (3%).
Endocrine & metabolic: Hypokalemia (2%).
Gastrointestinal: Vomiting (5% to 7%), abdominal pain (2% to 6%), constipation (2%).
Hepatic: Liver function tests abnormal (3%).
Respiratory: Rhinitis (5% to 9%), cough (4%), dyspnea (2%), pneumonia (2%), sinusitis (2%), sputum increased (2%).
Miscellaneous: Diaphoresis increased (3%).
<2%, postmarketing, and/or case reports: Adrenal insufficiency, albuminuria, allergic reactions, alopecia, anaphylactoid reactions, anaphylaxis, angioedema, anorexia, arrhythmia, arthralgia, asthenia, blurred vision, diplopia, dysgeusia, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, flatulence, gastritis, gynecomastia, hearing loss, heart failure, hematuria, hepatic failure, hepatitis, hepatotoxicity, hepatitis, hot flashes, hypertriglyceridemia, hypoesthesia, impotence, insomnia, leukocytoclastic dermatitis, leukopenia, libido decreased, malaise, menstrual disorders, myalgia, neutropenia, pancreatitis, paresthesia, peripheral neuropathy, photosensitivity, pollakiuria, pulmonary edema, pharyngitis, rigors, serum sickness, somnolence, Stevens-Johnson syndrome, stomatitis ulcerative, thrombocytopenia, taste perversion, tinnitus, toxic epidermal necrolysis, urinary incontinence, urticaria, vasculitis.
Drug Interactions
Cytochrome P450 Effects: Substrate of CYP3A4 (major).
Inhibits CYP3A4 (strong), P-glycoprotein.
Specific Drug Interaction: see Table.

Click on icon to see table/diagram/image

Ethanol/Nutrition/Herb Interactions: Food: Absorption enhanced by food and possibly by gastric acidity. Cola drinks have been shown to increase the absorption of the capsules in patients with achlorhydria or those taking H2-receptor antagonists or other gastric acid suppressors. Avoid grapefruit juice.
Herb/Nutraceutical: St John's wort may decrease itraconazole levels.
Storage
Store below 30°C. Protect from light and moisture.
MIMS Class
ATC Classification
J02AC02 - itraconazole ; Belongs to the class of triazole derivatives. Used in the systemic treatment of mycotic infections.
Presentation/Packing
Cap 100 mg (off white to cream spherical pellets in pink body and blue cap hard gelatin capsule no.0) 10 x 10's.
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