Clinical medicine profile
Itraconazole
Azole Antifungal [EPC]
- Route
- ORAL / TOPICAL / IV
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
BOXED WARNING Congestive Heart Failure, Cardiac Effects and Drug Interactions Congestive Heart Failure and Cardiac Effects: • Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of itraconazole capsules, discontinue administration. • When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Postmarketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions: • Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole capsules. Some examples of drugs that are contraindicated for coadministration with itraconazole capsules are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. • Coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. • Coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. • Coadministration with venetoclax is contraindicated in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose initiation and ramp-up phase of venetoclax. See PRECAUTIONS: Drug Interactions Section for specific examples. • Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples.
Contraindications
- CONTRAINDICATIONS Congestive Heart Failure: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
- (See BOXED WARNINGS, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Postmarketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.) Drug Interactions: Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole.
- Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride,naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
- In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
- (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs.
- For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes , a potentially fatal arrhythmia.
- Some specific examples are listed in PRECAUTIONS: Drug Interactions.
- Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome.
- Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.
- Itraconazole are contraindicated for patients who have shown hypersensitivity to itraconazole.
- There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents.
- Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.
Precautions
- WARNINGS Hepatic Effects: Itraconazole have been associated with rare cases of serious hepatotoxicity, including liver failure and death.
- Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.
- If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.
- Continued itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
- (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors.
- Concomitant administration of these drugs with itraconazole is contraindicated.
- (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
- Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
- For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy.
- These risk factors include cardiac disease such as ischemic and valvular disease
- significant pulmonary disease such as chronic obstructive pulmonary disease
- and renal failure and other edematous disorders.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
DOSAGE AND ADMINISTRATION Itraconazole capsules should be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole. Itraconazole capsule is a different preparation than itraconazole Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Itraconazole capsules and itraconazole Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without itraconazole. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)
Pediatric Use: The efficacy and safety of itraconazole have not been established in pediatric patients. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (0.5 times the MRHD of 400 mg based on body surface area comparisons). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (2 times the MRHD based on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.
Fluconazole dose-adjust in CKD; amphotericin nephrotoxicity high-alert.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Monitor LFTs for courses >14 days or higher-risk patients.
Use, effects & interactions
Indications
- INDICATIONS AND USAGE Itraconazole capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1.
- Blastomycosis, pulmonary and extrapulmonary 2.
- Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and 3.
- Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
- Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.
- Therapy may be instituted before the results of the cultures and other laboratory studies are known
- however, once these results become available, antiinfective therapy should be adjusted accordingly.
- Itraconazole capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1.
- Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2.
- Onychomycosis of the fingernail due to dermatophytes (tinea unguium).
- Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
- (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Postmarketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.
Adverse effects
- ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death.
- Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition.
- If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.
- The risks and benefits of itraconazole use should be reassessed.
- (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications.
- Treatment was discontinued in 10.5% of patients due to adverse events.
- The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days).
- The table lists adverse events reported by at least 1% of patients.
- Table 3: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia 11 5 3 2 1 Body as a Whole Edema Fatigue Fever Malaise 4 3 3 1 Skin and Appendages Rash* Pruritus 9 3 Central/Peripheral Nervous System Headache Dizziness 4 2 Psychiatric Libido Decreased Somnolence 1 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 * Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.
- Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.
- Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks.
- The following adverse events led to temporary or permanent discontinuation of therapy.
- Table 4: Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%
Drug interactions
Open multi-drug checker ↗- Match agent to site and species.
- For tinea, continue topical beyond clearance.
- Invasive fungal disease needs ID/specialist input and source control.
Mechanism & disposition
Imidazole- and triazole-class antifungals inhibit the fungal cytochrome P-450 3-A dependent enzyme, 14-alpha demethylase interrupting synthesis of ergosterol and resulting in increased cellular permeability and loss of cell contents.
Read complete mechanism
Imidazole- and triazole-class antifungals inhibit the fungal cytochrome P-450 3-A dependent enzyme, 14-alpha demethylase interrupting synthesis of ergosterol and resulting in increased cellular permeability and loss of cell contents.
Days for clinical response (varies)
Days–weeks per indication
ORAL / TOPICAL / IV
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. The oral bioavailability of itraconazole...
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed...
General Pharmacokinetic Characteristics Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentration...
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral rad...
of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose a...
Pregnancy, lactation & diet
Pregnancy: Teratogenic Effects: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40 to 160 mg/kg/day (1 to 4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Highly effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment. During postmarketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Postmarketing Experience.)
Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of itraconazole therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| CANDIFORCE-100 | MANKIND PHARMA LTD. | Capsule, Hard | Unavailable |
| CANDITRAL CAPS 12`S | Not recorded | — | KES 1,956.34Daima Chemist price-list reference ↗ Source date not recorded · verify current price |
| ETRACO CAPSULES | Win- Pharma Limited | Capsule | Unavailable |
| FUNGICOS 100MG CAPSULES | COSMOS LIMITED | Capsule 100MG | Unavailable |
| FUNGTRA | SIMBA PHARMACEUTICALS LTD | Capsule | Unavailable |
| ICON | DAIMA BIASHARA / Wholesale Import | 100MG 4*S | KES 212.20daima_biashara_price_list |
| ITACON | DAIMA BIASHARA / Wholesale Import | 100MG TABS 10`S | KES 354.75daima_biashara_price_list |
| ITACON 200 | NATIONAL PHARMACY LTD | Capsule, Hard | Unavailable |
| Itramet | distributed byMetro | tabs 4's | Unavailable |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.