ACCORD HEALTHCARE LIMITED ITRACONAZOLE

Method of administration Itraconazole capsules is for oral administration and must be taken immediately after a meal for maximal absorption. Capsules must be swallowed whole with a small amount of water.

Posology Treatment schedules in adults for each indication are as follows:

INDICATIONS DOSE REMARKS - Vulvovaginal candidosis 200 mg twice daily for 1 day - Pityriasis versicolor 200 mg once daily for 7 days - Tinea corporis, tinea cruris 100 mg once daily for 15 days or 200 mg once daily for 7 days - Tinea pedis, tinea manuum 100 mg once daily for 30 days - Oropharyngeal candidosis 100 mg once daily for 15 days Increase dose to 200 mg once daily for 15 days in AIDS or neutropenic patients because of impaired absorption in these groups - Onychomycosis (toenails with or without fingernail involvement) 200 mg once daily for 3 months For skin, vulvovaginal and oropharyngeal infections, optimal clinical and mycological effects are reached 1 - 4 weeks after cessation of treatment and for nail infections, 6 – 9 months after the cessation of treatment.

This is because elimination of itraconazole from skin, nails and mucous membranes is slower than from plasma. The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy: INDICATIONS DOSE1 REMARKS Aspergillosis 200 mg once daily Candidiasis 100-200 mg once daily Increase dose to 200 mg twice daily in case of invasive or disseminated disease Non-meningeal cryptococcosis 200 mg once daily Cryptococcal meningitis 200 mg once daily Histoplasmosis 200 mg once daily 200 mg twice daily Maintenance therapy for penicilliosis and histoplasmosis only in AIDS patients 200 mg once or 200 mg twice daily until immune recovery The duration of treatment should be based upon the status of the immune recovery Maintenance therapy of cryptococcal meningitis only in AIDS patients 200 mg twice daily until immune recovery The duration of treatment should be based upon the status of the immune recovery Prophylaxis of fungal infections in immunocompromised patients with severe neutropenia 200 mg twice daily until immune recovery The duration of treatment should be based upon the status of the immune recovery.

4). Special populations Paediatric population Clinical data on the use of Itraconazole capsules in paediatric patients are limited. The use of itraconazole capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.

Summary of the safety profile The most frequently reported adverse drug reactions (ADRs) with itraconazole capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea.

The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), and serious skin reactions.

Refer to the tabulated list of adverse reactions for the frequencies and for other observed ADRs. 4 for additional information on other serious effects. Tabulated list of adverse reactions The ADRs in the table below were derived from open-label and double-blind clinical trials with itraconazole capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, and from spontaneous reporting.

The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

4. , excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration. 4), Hepatitis, Jaundice Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia Renal and urinary disorders: Renal impairment, Urinary incontinence General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pyrexia, Pain, Fatigue, Chills Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal Paediatric population The safety of itraconazole capsules was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a doubleblind phase).

Elderly Clinical data on the use of itraconazole capsules in elderly patients are limited. It is advised to use itraconazole capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

4 Special warnings and precautions for use. 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.

2 Pharmacokinetic properties – Special Populations, Hepatic impairment). Renal impairment Limited data are available on the use of oral itraconazole in renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency.

Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered. 1 • Co-administration of a number of CYP3A4 substrates is contraindicated with itraconazole capsules. Increased plasma concentrations of these drugs, caused by coadministration with itraconazole, may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur.

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. 4). • Itraconazole capsules must not be used during pregnancy except for life-threatening cases.

6. • Women of childbearing potential taking itraconazole should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of itraconazole therapy. 4 Special warnings and precautions for use Cross-hypersensitivity There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents.

1 • Co-administration of a number of CYP3A4 substrates is contraindicated with itraconazole capsules. Increased plasma concentrations of these drugs, caused by coadministration with itraconazole, may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur.

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. 4). • Itraconazole capsules must not be used during pregnancy except for life-threatening cases.

6. • Women of childbearing potential taking itraconazole should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of itraconazole therapy.