Voriconazole 50 mg and 200 mg FC tablets

• Treatment of invasive aspergillosis.
• Treatment of serious invasive infections caused by Candida spp (including C. krusei ).
• Treatment of serious fungal infections caused by Scedosporium spp and Fusarium spp.
• Prevention of breakthrough of fungal infections in febrile high-risk patients (allogeneic bone marrow transplants, relapsed leukaemia patients) where liposomal amphotericin B cannot be used.

Posology

Adult dosage

Therapy should be initiated with the specified loading dose regimen of Vorispore to achieve plasma concentrations on day 1 that are close to steady-state (see Table 1 ). On the basis of the high oral bioavailability (96 %), switching between intravenous and oral administration is appropriate when clinically indicated. Detailed information on dosage recommendations for adults is provided in Table 1 and for children in Table 2 .

Table 1 Adult dosage recommendations

Patients 40 kg and above

Patients less than 40 kg

Loading dose regimen for all indications (first 24 hours)

400 mg every 12 hours (for the first 24 hours)

200 mg every 12 hours (for the first 24 hours)

Maintenance dose (after first 24 hours)

Prevention of breakthrough infections

200 mg every 12 hours

100 mg every 12 hours

Invasive aspergillosis, serious Candida infections, Scedosporium/Fusarium infections

200 mg every 12 hours

100 mg every 12 hours

Dosage adjustment: If patient response is inadequate, the maintenance dose may be increased to 300 mg every 12 hours for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily. If patients are unable to tolerate treatment at these higher doses, reduce the oral dose by 50 mg steps to the 200 mg every 12 hours (or 100 mg every 12 hours for patients less than 40 kg) maintenance dose. Phenytoin may be co-administered with Vorispore if the maintenance dose of Vorispore is increased from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg), see sections 4.4 and 4.5.

Efavirenz : When Vorispore is co-administered with adapted doses of efavirenz, the maintenance dose of Vorispore should be increased to 400 mg every 12 hours (see sections 4.4 and 4.5).

Duration of treatment: Treatment duration depends upon patientsu2019 clinical and mycological response.

Use in the elderly

No dose adjustment is necessary for elderly patients.

Use in patients with renal impairment

The pharmacokinetics of orally administered Vorispore are not affected by renal impairment. No adjustment in oral dosage is consequently required for patients with mild to severe renal impairment. Vorispore is haemodialysed with a clearance of 121 ml/min. A four-hour haemodialysis session does not remove enough Vorispore to warrant dose adjustment.

Use in patients with hepatic impairment

No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALT, AST), but continued monitoring of liver function tests for future elevations is recommended. It is recommended that the standard loading dose regimens of 400 mg every 12 hours (orally) and a maintenance dose of 100 mg every 12 hours (orally) be used in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) taking Vorispore. No data are available on the use of Vorispore in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

Vorispore has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice. Patients with hepatic impairment must be carefully monitored for medicine toxicity (see section 4.8).

Paediatric dosage

Safety and effectiveness in paediatric patients below the age of 2 years have not been established. Therefore, Vorispore is not recommended for children less than 2 years of age.

Children aged 2 to < 12 years

Limited data are available to determine the optimal posology. However, the regimen detailed in Table 2 has been used. If a child can swallow tablets, the dose should be administered to the nearest mg/kg dose possible using whole 50 mg tablets.

Table 2 Children dosage recommendations

Oral

Loading dose regimen (first 24 hours)

6 mg/kg every 12 hours (for the first 24 hours)

Maintenance dose (after first 24 hours)

4 mg/kg every 12 hours

The pharmacokinetics and tolerability of higher doses have not been studied in paediatric populations.

Adolescents (12 to 16 years of age): See adult dose.

Duration of treatment

Treatment duration depends on the patientu2019s clinical and mycological response. The duration of treatment ranges from 12 weeks to more than 6 months.

Method of administration

Vorispore should be taken at least one hour before, or one hour after a meal.

• Hypersensitivity to voriconazole or to any of the excipients of Vorispore listed in section 6.1.
• Patients with prolonged QT- syndrome.
• Severe impairment of hepatic function.
• Coadministration with the following medicines:
• CYP3A4 substrates, astemizole, cisapride, pimozide or quinidine, since increased plasma concentrations of these medicines can lead to QTc prolongation and rare occurrences of Torsades de Pointes ( see sections 4.4 and 4.5).
• CYP3A4 substrates such as ergot alkaloids, e.g. ergotamine, dihydroergotamine, since increased plasma concentrations of these drugs can lead to ergotism (see sections 4.4 and 4.5).
• Rifampicin, carbamazepine and phenobarbital, since these medicines are likely to decrease plasma voriconazole concentrations significantly (see sections 4.4 and 4.5).
• Rifabutin, since Vorispore is likely to increase plasma concentrations of rifabutin significantly (see sections 4.4 and 4.5).
• Ritonavir (high dose u2013 400 mg and above twice daily), because ritonavir significantly decreased plasma Vorispore concentrations in healthy subjects at this dose (see sections 4.4 and 4.5).
• Efavirenz (doses u2265 400 mg/day), because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see sections 4.4 and 4.5).
• Sirolimus, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see sections 4.4 and 4.5).
• St. Johnu2019s wort (see sections 4.4 and 4.5).

Women of childbearing potential

Women of childbearing potential must always use effective contraception during treatment.

Hypersensitivity

Caution should be used in prescribing Vorispore to patients with hypersensitivity to other azoles (see section 4.8).

Cardiovascular effects

Vorispore has been associated with QTc- interval prolongation. There have been cases of torsades de pointes in patients who had risk factors, such as a history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory (see section 4.5). Vorispore should be administered with caution to patients with potentially pro- dysrhythmic conditions, such as:

• Congenital or acquired QTc prolongation.
• Cardiomyopathy, in particular when heart failure is present.
• Sinus bradycardia.
• Existing symptomatic dysrhythmias.

Concomitant treatment with medicines known to prolong QTc interval (see u201cConcomitant administrationu201d below and section 4.5) . Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during Vorispore therapy (see section 4.2).

Hepatic toxicity

Serious hepatic reactions may occur during treatment with Vorispore (see section 4.8). These reactions include clinical hepatitis, cholestasis and fulminant hepatic failure including fatalities which mostly occurred 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. Liver dysfunction has usually been reversible on discontinuation of therapy.

Monitoring of hepatic function

Patients receiving Vorispore 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 Vorispore and at least weekly for the first month of treatment. Treatment duration should be as short as possible, however, if based on the benefit-risk assessment the treatment is continued (see section 4.2), 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, Vorispore 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.

Visual disturbances

Vorispore may cause prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8). There have been post-marketing reports of irreversible visual adverse events.

Renal toxicity

Acute renal failure has been reported in severely ill patients treated with voriconazole. Patients treated with Vorispore are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may contribute to decreased renal function (see section 4.8).

Monitoring of renal function

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Serious dermatological adverse reactions

u2022 Phototoxicity Vorispore has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during Vorispore treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

u2022 Squamous cell carcinoma of the skin (SCC) Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought, Vorispore discontinuation and use of alternative antifungal medicines should be considered and the patient should be referred to a dermatologist. If Vorispore is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Vorispore should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under u201c Long-term treatment u201d).

u2022 Exfoliative cutaneous reactions Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash, she/he should be monitored closely and Vorispore discontinued if lesions progress.

Monitoring of pancreatic function

Adults and children with risk factors for acute pancreatitis (e.g. recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored for the development of pancreatitis during Vorispore -treatment.

Long-term treatment

Long-term exposure (treatment or prophylaxis), exceeding 6 months, requires careful assessment of the benefit-risk balance. Doctors should therefore consider the need to limit the exposure to Vorispore (see section 4.2).

Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Vorispore treatment. Non-infectious periostitis, with elevated fluoride and alkaline phosphatase levels, has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis, multidisciplinary advice should be obtained and discontinuation of Vorispore considered.

Paediatric use

Safety and effectiveness in paediatric patients below the age of 2 years has not been established. Vorispore is indicated for children aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 to <12 years with malabsorption and very low body mass for age. Intravenous administration is recommended for these patients. There have been post-marketing reports of pancreatitis in paediatric patients.

Serious skin reactions (including squamous cell carcinoma): The frequency of phototoxicity reactions is higher in the paediatric population. As SCC has been reported, stringent measures for photoprotection are required in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended, even after discontinuation of treatment.

Prophylaxis

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of Vorispore and use of alternative antifungal medicines must be considered.

Concomitant administration of other medicines

The following medicines may only be given with extra caution or may be contraindicated. Refer to sections 4.5 and 4.3.

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes.

Vorispore should be administered with caution in patients taking concomitant medicines that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide), coadministration is contraindicated (see below and section 4.3).

Interaction table

Interactions between voriconazole (contained in Vorispore ) and other medicines are listed in the table below (u201cNDu201d is the abbreviation for u201c not determined u201d ). The direction of the arrow for each pharmacokinetic parameter is based on the 90 % confidence interval of the geometric mean ratio being within (u2194), below (u2193) or above (u2191) the 80 -125 % range. The asterisk (*) indicates a two-way interaction.

Pregnancy

Adequate information is not available on the use of Vorispore in pregnant women. Studies in animals have shown reproductive toxicity and teratogenicity. The potential risk to humans is unknown. Vorispore should not be used during pregnancy.

Lactation

The excretion of Vorispore into breastmilk has not been investigated. Breastfeeding must be stopped on initiation of treatment with Vorispore.

Vorispore may affect vision and dizziness has also been reported (see sections 4.4 and 4.8). Patients should be advised to avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.

Summary of the safety profile

The most frequently reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

Tabulated summary of adverse reactions

System Organ Class Frequent Less frequent Frequency not known (cannot be estimated from available data)

Infections and infestations sinusitis pseudomembranous colitis Neoplasms benign, malignant and unspecified (including cysts and polyps) squamous cell carcinoma* Blood and lymphatic system disorders agranulocytosis 1 , pancytopenia, thrombocytopenia 2 , 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, hypokalaemia, hyponatraemia

Psychiatric disorders depression, hallucination, anxiety, insomnia, agitation, confusional state Nervous system disorders headache, convulsion, syncope, tremor, hypertonia 3 , paraesthesia, somnolence, dizziness brain oedema, encephalopathy 4 , extrapyramidal disorder 5 , peripheral neuropathy, ataxia, hypoaesthesia, dysgeusia, hepatic encephalopathy, Guillain-Barre syndrome, nystagmus Eye disorders visual impairment, 6 retinal haemorrhage optic nerve disorder 7 , papilloedema 8 , oculogyric crisis, diplopia, scleritis, blepharitis, optic atrophy, corneal opacity Ear and labyrinth disorders hypoacusis, vertigo, tinnitus

Cardiac disorders dysrhythmia supraventricular, tachycardia, bradycardia ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, prolonged QT interval, supraventricular tachycardia, torsades de pointes, complete atrioventricular block, bundle branch block, nodal rhythm Vascular disorders hypotension, phlebitis thrombophlebitis, lymphangitis Respiratory, thoracic and mediastinal disorders respiratory distress, 9 acute respiratory distress syndrome, pulmonary oedema Gastrointestinal disorders diarrhoea, vomiting, abdominal pain, nausea, cheilitis, dyspepsia, constipation, gingivitis peritonitis, pancreatitis, swollen tongue, duodenitis, gastroenteritis, glossitis

Hepatobiliary disorders liver function test abnormal, jaundice, cholestatic jaundice, hepatitis 10 cholecystitis, cholelithiasis, hepatomegaly, hepatic failure Skin and subcutaneous tissue disorders rash, exfoliative dermatitis, alopecia, maculo-papular rash, pruritus, erythema, facial oedema 1 Stevens-Johnson syndrome 8 , phototoxicity, purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema, toxic epidermal necrolysis 8 , drug reaction with eosinophilia and systemic symptoms (DRESS) 8 , angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug eruption cutaneous lupus erythematosus*, ephelides*, lentigo* Musculoskeletal and connective tissue disorders back pain arthritis periostitis*

Renal and urinary disorders renal failure acute, haematuria renal tubular necrosis, proteinuria, nephritis General disorders and administration site conditions pyrexia, chest pain, face oedema, 11 asthenia, chills influenza like illness Investigations increased blood creatinine increased blood urea, increased blood cholesterol *ADR identified post-marketing 1 Includes febrile neutropenia and neutropenia. 2 Includes immune thrombocytopenic purpura. 3 Includes nuchal rigidity and tetany. 4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy. 5 Includes akathisia and parkinsonism. 6 See u201cVisual impairmentsu201d paragraph in section 4.8. 7 Prolonged optic neuritis has been reported post-marketing. See section 4.4. 8 See section 4.4. 9 Includes dyspnoea and exertional dyspnoea. 10 Includes medicine-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity. 11 Includes periorbital oedema, lip oedema, and oedema mouth.

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). There is no known antidote to Vorispore . Vorispore is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole from the body.