VORICONAZOLE IBISQUS

4). It is recommended that Voriconazole is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours. Other brands of Voriconazole are available as 50 mg and 200 mg film-coated tablets and 40 mg/ml powder for oral suspension.

Treatment Adults Therapy must be initiated with the specified loading dose regimen of either intravenous or oral Voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. 2), switching between intravenous and oral administration is appropriate when clinically indicated.

Detailed information on dosage recommendations is provided in the following table:

Oral Intravenous Patients 40 kg and above* Patients less than 40 kg* Loading dose regimen (first 24 hours) 6 mg/kg every 12 hours 400 mg every 12 hours 200 mg every 12 hours Maintenance dose (after first 24 hours) 4 mg/kg twice daily 200 mg twice daily 100 mg twice daily * This also applies to patients aged 15 years and older Duration of treatment Treatment duration should be as short as possible depending on the patient's clinical and mycological response.

1). Dosage adjustment (Adults) If patient is unable to tolerate intravenous treatment at 4 mg/kg twice daily, reduce the dose to 3 mg/kg twice daily. If patient response to treatment is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration.

For patients less than 40 kg the oral dose may be increased to 150 mg twice daily. If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.

In case of use as prophylaxis, refer below. Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg) Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more similarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous Oral Loading Dose Regimen (first 24 hours) 9 mg/kg every 12 hours Not recommended Maintenance Dose (after first 24 hours) 8 mg/kg twice daily 9 mg/kg twice daily (a maximum dose of 350 mg twice daily) Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.

Summary of safety profile The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials.

This represents a heterogeneous population, containing patients with haematological malignancy, HIV- infected patients with oesophageal candidiasis and refractory fungal infections, non- neutropenic patients with candidaemia or aspergillosis and healthy volunteers.

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain. The severity of the adverse reactions was generally mild to moderate.

No clinically significant differences were seen when the safety data were analysed by age, race, or gender. Tabulated list of adverse reactions In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class and frequency, are listed.

Frequency categories are expressed as:

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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving voriconazole:

System Organ Class 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) Not known (cannot be estimated from the available data) Infections and infestations sinusitis pseudomembranous colitis Neoplasms benign, malignant and unspecified (including cysts and polyps) squamous cell carcinoma (including cutaneous SCC in situ, or Bowen’s disease)* Blood and lymphatic system disorders agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anaemia bone marrow failure, lymphadenopathy, eosinophilia disseminated intravascular coagulation Immune system disorders hypersensitivity anaphylactoid reaction Endocrine disorders adrenal insufficiency, hypothyroidism hyperthyroidism Metabolism and nutrition disorders oedema peripheral hypoglycaemia, hypokalemia, hyponatraemia Psychiatric disorders depression, hallucination, anxiety, insomnia, agitation, confusional state Nervous system disorders headache convulsion, syncope, tremor, hypertonia3, paraesthesia, somnolence, dizziness brain oedema, encephalopathy4, extrapyramidal disorder5, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia hepatic encephalopathy, Guillain-Barre syndrome, nystagmus Eye disorders visual impairment6 retinal haemorrhage optic nerve disorder7, papilloedema8, oculogyric crisis, diplopia, scleritis, blepharitis optic atrophy, corneal opacity Ear and labyrinth disorders hypoacusis, vertigo, tinnitus Cardiac disorders arrhythmia supraventricular, tachycardia, bradycardia ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, electrocardiogram QT prolonged, supraventricular tachycardia torsades de pointes, atrioventricular block complete, bundle branch block, nodal rhythm Vascular disorders hypotension, phlebitis thrombophlebitis, lymphangitis Respiratory, thoracic and mediastinal disorders respiratory distress9 acute respiratory distress syndrome, pulmonary oedema *ADR identified post-marketing 1 Includes febrile neutropenia and neutropenia.

8). 3). Cardiovascular Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medicinal products that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as: • congenital or acquired QTc-prolongation • cardiomyopathy, in particular when heart failure is present • sinus bradycardia • existing symptomatic arrhythmias • concomitant medicinal product that is known to prolong QTc interval.

2). A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. 1). Infusion-related reactions Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of voriconazole.

8). Hepatic toxicity In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy).

Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. 8). Monitoring of hepatic function Patients receiving Voriconazole must be carefully monitored for hepatic toxicity.

Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with Voriconazole and at least weekly for the first month of treatment. 2), monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.

1. 5). 5). Co-administration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses.

4). 4). 5). 5). 5). 5). 5). 5).