VORICONAZOLE

4). This medicine is also available as 200mg film-coated tablets, 200 mg powder for solution for infusion 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:

OralIntravenous 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 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 metabolise 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.

It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

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, 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 Freque ncy not known (cannot be estimate d from availabl e data) Infections and infestation s sinusitis pseudomembra nous colitis Neoplasms benign, malignant and unspecifie d (including cysts and polyps) squamous cell carcinoma (including cutaneous SCC in situ, or Bowen’s disease)*,** Blood and lymphatic system disorders agranulocytosis1 , pancytopenia, thrombocytopen ia2, leukopenia, anaemia bone marrow failure, lymphadenopat hy, eosinophilia disseminated intravascular coagulation Immune system disorders hypersensitivity anaphylactoi d reaction Endocrine disorders adrenal insufficiency, hypothyroidism hyperthyroi dism Metabolis m and nutrition disorders oedema peripheral hypoglycaemia, hypokalaemia, hyponatraemia Psychiatric disorders depression, hallucination, anxiety, insomnia, agitation, confusional state 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 Freque ncy not known (cannot be estimate d from availabl e data) Nervous system disorders headache convulsion, syncope, tremor, hypertonia3, paraesthesia, somnolence, dizziness brain oedema, encephalopathy4 , extrapyramidal disorder5, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia hepatic encephalopat hy, 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, electrocardiogra m QT prolonged, supraventricular tachycardia torsades de pointes, atrioventricul ar block complete, bundle branch block, nodal rhythm Vascular disorders hypotension, phlebitis thrombophlebiti s, lymphangitis Respirator y, thoracic and mediastina l disorders respiratory distress9 acute respiratory distress syndrome, pulmonary oedema 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 Freque ncy not known (cannot be estimate d from availabl e data) Gastrointe stinal disorders diarrhoea, vomiting, abdominal pain, nausea cheilitis, dyspepsia, constipation, gingivitis peritonitis, pancreatitis, swollen tongue, duodenitis, gastroenteritis, glossitis Hepatobili ary disorders liver function test abnormal jaundice, jaundice cholestatic, hepatitis10 hepatic failure, hepatomegaly, cholecystitis, cholelithiasis Skin and subcutaneo us tissue disorders rash dermatitis exfoliative, alopecia, rash maculo-papular, pruritus, erythema, phototoxicity** Stevens- Johnson syndrome8, purpura, urticaria, dermatitis allergic, rash papular, rash macular, eczema toxic epidermal necrolysis8, drug reaction with eosinophilia and systemic symptoms (DRESS)8, angioedema, actinic keratosis*, pseudoporph yria, erythema multiforme, psoriasis, drug eruption cutaneou s lupus erythema tosus*, ephelide s*, lentigo* Musculosk eletal and connective tissue disorders back pain arthritis, periostitis*,** Renal and urinary disorders renal failure acute, haematuria renal tubular necrosis, proteinuria, nephritis 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 Freque ncy not known (cannot be estimate d from availabl e data) General disorders and administrat ion site conditions pyrexia chest pain, face oedema11, asthenia, chills infusion site reaction, influenza like illness Investigati ons blood creatinine increased blood urea increased, blood cholesterol increased *ADR identified post-marketing **Frequency category is based on an observational study utilising real-world data from secondary data sources in Sweden 1 Includes febrile neutropenia and neutropenia.

8). 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, hypokalaemia 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). 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 this medicine 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.

If the liver function tests become markedly elevated, voriconazole should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use. Monitoring of hepatic function should be carried out in both children and adults.

1. 5 are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated. , ergotamine, dihydroergotamine) • Sirolimus • Naloxegol • Tolvaptan • Finerenone • Eplerenone • Voclosporin • Venetoclax: Coadministration contraindicated at initiation and during venetoclax dose titration phase.

, phenobarbital and St. 5). 5). 4. 5). 4.