VfendaFC Tablets & Powder For Solution For Infusion

• Treatment of invasive aspergillosis.
• Treatment of serious invasive infections caused by Candida spp (including C. krusei).
• VFEND has been used in the 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.
• Prophylaxis of invasive fungal infections in high risk allogeneic haematopoietic stem cell transplant (HSCT) recipients.

Posology

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation and during VFEND therapy (see section 4.4).

Adults

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral VFEND to achieve plasma concentrations on Day 1 that are close to steady state. 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 is provided in the following table:

Intravenous

Oral

Patients 40 kg and above

Patients less than 40 kg

Loading dose regimen for all indications (first 24 hours)

6 mg/kg every 12 hours (for the 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)

- Prophylaxis of invasive fungal infections

3 u2013 4 mg/kg every 12 hours

200 mg every 12 hours

100 mg every 12 hours

- Invasive aspergillosis, serious Candida infections, Scedosporium/ Fusarium infections

4 mg/kg every 12 hours

200 mg every 12 hours

100 mg every 12 hours

Dosage adjustment

Powder for solution for infusion

If patient response is inadequate, the maintenance dose may be increased to 4 mg/kg every 12 hours for intravenous administration. If patients are unable to tolerate treatment at these higher doses, reduce the intravenous dose to the original maintenance dose, 3 mg/kg every 12 hours.

Film-coated tablets

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.

Powder for solution for infusion

Phenytoin may be co-administered with VFEND if the maintenance dose of VFEND is increased to 5 mg/kg intravenously every 12 hours (see sections 4.4 and 4.5).

Film-coated tablets

Phenytoin may be co-administered with VFEND if the maintenance dose of VFEND 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).

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

Treatment duration depends upon patientsu2019 clinical and mycological response. Prophylaxis in adults and children should be initiated on the day of transplant and may be administered for up to 100 days. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section 5.1).

Dosage

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Please refer to the treatment tables above.

Duration of prophylaxis

The safety and efficacy of VFEND use for longer than 180 days has not been adequately studied in clinical trials.

Special populations

Elderly

No dose adjustment is necessary for elderly patients.

Renal impairment

Film-coated tablets

The pharmacokinetics of orally administered VFEND are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see section 5.2).

Powder for solution for infusion

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral VFEND should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous VFEND. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral VFEND therapy (see section 5.2).

Film-coated tablets and powder for solution for infusion

VFEND is haemodialysed with a clearance of 121 mL/min. A four-hour haemodialysis session does not remove a sufficient amount of VFEND to warrant dose adjustment. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 mL/min.

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) receiving VFEND. VFEND has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C). VFEND 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 population

Safety and effectiveness in paediatric subjects below the age of 2 years has not been established. Therefore, VFEND is not recommended for children less than 2 years of age.

Limited data are currently available to determine the optimal posology. However, the following regimen has been used in paediatric studies.

Children aged 2 to < 12 years

Intravenous

Oral

Loading dose regimen (first 24 hours)

6 mg/kg every 12 hours (for the 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

4 mg/kg every 12 hours

If a child is able to swallow tablets, the dose should be administered to the nearest mg/kg dose possible using whole 50 mg tablets. The pharmacokinetics and tolerability of higher doses have not been characterised in paediatric populations. Adolescents (12 to 16 years of age) should be dosed as adults.

Duration of treatment

Treatment duration depends on the patientu2019s clinical and mycological response. The duration of oral and intravenous VFEND treatment in the clinical studies ranged from 12 weeks to more than 6 months.

Method of administration

Film-coated tablets

For oral use. VFEND tablets are to be taken at least one hour before, or one hour following, a meal.

Powder for solution for infusion

VFEND requires reconstitution and dilution prior to administration as an intravenous infusion (see section 6.6). Not for bolus injection. It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

• Known hypersensitivity to voriconazole or to any of the excipients of VFEND (listed in section 6.1).
• Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine or ivabradine with VFEND is contraindicated since increased plasma concentrations of these medicines can lead to QTc prolongation and rare occurrences of Torsades de Pointes (see section 4.5).
• Co-administration of VFEND with rifampicin, carbamazepine, phenobarbital and St Johnu2019s Wort is contraindicated since these medicines are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).
• Co-administration of standard doses of VFEND with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma VFEND concentrations in healthy subjects at these doses. VFEND also significantly increases efavirenz plasma concentrations (see section 4.5, for lower doses see section 4.4).
• Co-administration of VFEND with high dose ritonavir (400 mg and above twice daily) is contraindicated because ritonavir significantly decreased plasma VFEND concentrations in healthy subjects at this dose (see section 4.5, for lower doses see section 4.4).
• Co-administration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated since increased plasma concentrations of these medicines can lead to ergotism (see section 4.5).
• Co-administration of VFEND and sirolimus is contraindicated, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5).
• Co-administration of VFEND and rifabutin is contraindicated since VFEND is likely to increase plasma concentrations of rifabutin significantly (see section 4.5).
• Co-administration of VFEND with naloxegol, a CYP3A4 substrate, is contraindicated since increased plasma concentrations of naloxegol can precipitate opioid withdrawal symptoms (see section 4.5).
• Co-administration of VFEND with tolvaptan is contraindicated since strong CYP3A4 inhibitors such as VFEND significantly increase plasma concentrations of tolvaptan (see section 4.5).
• Co-administration of VFEND with lurasidone is contraindicated since significant increases in lurasidone exposure have the potential for serious adverse reactions (see section 4.5).
• Co-administration with venetoclax at initiation and during the venetoclax dose titration phase is contraindicated since VFEND is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome (see section 4.5).
• Patients with prolonged QT syndrome.
• Pregnancy and lactation.
• Severe impairment of hepatic function (Child-Pugh Class C).

Hypersensitivity

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

Infusion-related reaction

Infusion-related reactions, predominantly flushing and nausea have been observed during administration of the intravenous formulation of VFEND. Depending on the severity of the symptoms, consideration should be given to stopping treatment (see section 4.8).

Cardiovascular

VFEND has been associated with QTc interval prolongation. There have been rare cases of Torsades de pointes in patients taking VFEND who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicines that may have been contributory. VFEND should be administered with caution to patients with potentially prodysrhythmic conditions, such as:

• Congenital or acquired QTc prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic dysrhythmias
• Concomitant medicines known to prolong QTc interval.

Electrolyte disturbances such as hypokalaemia, hypomagnesemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation of and during VFEND therapy (see section 4.2).

Hepatic toxicity

In clinical trials, there have been cases of serious hepatic reactions during treatment with VFEND (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. Liver dysfunction has usually been reversible on discontinuation of therapy (see section 4.8).

Monitoring of hepatic function

Patients receiving VFEND 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 VFEND and at least weekly for the first month of treatment. If treatment is continued, 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, VFEND should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use (see section 4.2).

Visual adverse events

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilloedema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medicines which may have caused or contributed to these events (see section 4.8).

Renal adverse events

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with VFEND are likely to be treated concomitantly with nephrotoxic medicines and have concurrent conditions that may result in 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.

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 development of pancreatitis during VFEND treatment.

Dermatological adverse events

During treatment with VFEND, patients have developed 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 (see section 4.8). If a patient develops a severe cutaneous adverse reaction VFEND should be discontinued. In addition, VFEND has been associated with photosensitivity skin reaction. It is recommended that patients, particularly children, avoid intense or prolonged exposure to direct sunlight during VFEND treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Adrenal events

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, including VFEND. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, VFEND associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression (see section 4.5). Cushingu2019s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving VFEND concomitantly with corticosteroids. Patients on long-term treatment with VFEND and corticosteroids (including inhaled corticosteroids e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when VFEND is discontinued (see section 4.5). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushingu2019s syndrome or adrenal insufficiency.

Long-term treatment

Squamous cell carcinoma of the skin (SCC) in patients with photosensitivity skin reactions and additional risk factors, squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowenu2019s disease) and melanoma have been reported during long-term therapy (see section 4.8). If phototoxic reactions occur multidisciplinary advice should be sought, VFEND discontinuation and use of alternative antifungal medicines should be considered and the patient should be referred to a dermatologist. If VFEND is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND discontinuation should be considered.

Non-infectious periostitis

Periostitis has been reported in transplant patients during long-term VFEND therapy. If a patient develops skeletal pain and radiologic findings compatible with periostitis, VFEND should be discontinued (see section 4.8).

Methadone (CYP3A4 substrate)

Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed (see section 4.5).

Short-acting opiates (CYP3A4 substrate)

Reduction in the dose of alfentanil, fentanyl and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil) should be considered when co-administered with VFEND (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is co-administered with VFEND, frequent monitoring for opiate-associated adverse events (including a longer respiratory monitoring period) may be necessary.

Long-acting opiates (CYP3A4 substrate)

Reduction in the dose of oxycodone and other long-acting opiates metabolised by CYP3A4 (e.g., hydrocodone) should be considered when co-administered with VFEND. Frequent monitoring for opiate-associated adverse events may be necessary (see section 4.5).

VFEND 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 VFEND plasma concentrations, respectively and there is potential for VFEND to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since VFEND is a strong CYP3A4 inhibitor though the increase in AUC is substrate dependent (see table below).

Unless otherwise specified, medicine interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral VFEND at 200 mg twice daily. These results are relevant to other populations and routes of administration.

VFEND may prolong the QT interval without a clear relationship to plasma concentration. VFEND should not be used concomitantly with other medicines which prolong the QT interval. When there is also a potential for VFEND to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (e.g. certain antihistamines, quinidine, cisapride, pimozide and ivabradine) co-administration is contraindicated (see below and section 4.3).

Interaction table

Interactions between VFEND and other medicines are listed in the table below (once daily as u201cQDu201d, twice daily as u201cBIDu201d, three times daily as u201cTIDu201d and not determined as u201cNDu201d). 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 u2013 125 % range. The asterisk (*) indicates a two-way interaction. AUC u03c4, AUC t and AUC 0- uf0a5 represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively. The interactions in the table are presented in the following order: contraindications, those requiring dosage adjustment and careful clinical and/or biological monitoring and finally those that have no significant pharmacokinetic interaction but that may be of clinical interest in this therapeutic field.

Women of child-bearing potential must always use effective contraception during treatment.

Pregnancy (see section 4.3)

No adequate information on the use of VFEND in pregnant women is available. Studies in animals have shown reproductive toxicity and teratogenicity. The potential risk to humans is unknown. VFEND must not be used during pregnancy.

Breastfeeding

The excretion of VFEND into breastmilk has not been investigated. Breastfeeding must be stopped on initiation of treatment with VFEND (see section 4.3).

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats.

VFEND may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception, and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery whilst experiencing these symptoms.

Summary of the safety profile

The safety profile of VFEND is based on an integrated safety database of patients who participated in clinical 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. Duration of treatment ranged from 12 weeks to more than 6 months.

In addition, the safety of VFEND was investigated in 279 patients (including 270 adults) who were treated with VFEND in prophylaxis studies. The adverse event profile in these prophylaxis studies was similar to the established safety profile from 2000 subjects in VFEND clinical trials.

Tabulated summary of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse events, by system organ class and frequency if possibly causally related are listed as very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100) and rare (u2265 1/10 000 to < 1/1 000). The most commonly reported adverse events were visual disturbances, fever, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema and abdominal pain. The severity of the adverse events was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Side effects reported in subjects receiving VFEND

MedDRA system organ class

Frequency

Adverse reaction

Infections and infestations

Common

Sinusitis

Uncommon

Pseudomembranous colitis

Blood and lymphatic system disorders

Common

Agranulocytosis a, pancytopenia, thrombocytopenia b, leukopenia, anaemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic)

Uncommon

Bone marrow failure, lymphadenopathy, eosinophilia, disseminated intravascular coagulation

Immune system disorders

Uncommon

Hypersensitivity, anaphylactoid reaction

Endocrine disorders

Uncommon

Adrenal cortex insufficiency, hypothyroidism

Rare

Hyperthyroidism

Metabolism and nutrition disorders

Very common

Peripheral oedema

Common

Hypoglycaemia, hypokalaemia

Psychiatric disorders

Common

Depression, hallucinations, anxiety, insomnia, agitation, confusional state

Nervous system disorders

Very common

Headache

Common

Syncope, tremor, hypertonia e, paraesthesia, somnolence, dizziness

Uncommon

Brain oedema, encephalopathy c, extrapyramidal disorder d, peripheral neuropathy, ataxia, hypoaesthesia, dysgeusia, nystagmus

Rare

Hepatic encephalopathy, Guillain-Barre syndrome

Eye disorders

Very common

Visual impairment h (including altered/enhanced visual perception, blurred vision, colour vision change, photophobia)

Common

Retinal haemorrhage

Uncommon

Optic nerve disorder f, papilloedema g, oculogyric crisis, diplopia, scleritis, blepharitis

Rare

Optic atrophy, corneal opacity

Ear and labyrinth disorders

Uncommon

Hypoacusis, vertigo, tinnitus

Cardiac disorders

Common

Supraventricular dysrhythmia, atrial dysrhythmia, tachycardia, bradycardia

Uncommon

Ventricular fibrillation, ventricular extrasystoles, ventricular dysrhythmia, ventricular tachycardia, prolonged QT interval, supraventricular tachycardia

Rare

Torsades de Pointes, atrioventricular (AV) complete block, bundle branch block, nodal rhythm

Vascular disorders

Common

Hypotension, phlebitis, thrombophlebitis

Uncommon

Lymphangitis

Respiratory, thoracic and mediastinal disorders

Common

Acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal disorders

Very common

Diarrhoea, vomiting, abdominal pain, nausea

Common

Cheilitis, dyspepsia, constipation, gingivitis, gastroenteritis

Uncommon

Peritonitis, pancreatitis, swollen tongue, duodenitis, glossitis

Hepato-biliary disorders

Very common

Abnormal liver function tests (including AST, ALT, alkaline phosphatase, GGT, LDH, bilirubin)

Common

Jaundice, cholestatic jaundice, hepatitis i

Uncommon

Hepatic failure, hepatomegaly, cholecystitis, cholelithiasis

Skin and subcutaneous tissue disorders

Very common

Rash

Common

Exfoliative dermatitis, alopecia, purpura, maculo-papular rash, pruritus, photosensitivity skin reaction

Uncommon

Stevens-Johnson syndrome, urticaria, eczema, psoriasis, drug eruption

Rare

Toxic epidermal necrolysis, angioedema, pseudoporphyria, erythema multiforme, discoid lupus erythematosus

Musculoskeletal and connective tissue disorders

Common

Back pain

Uncommon

Arthritis

Renal and urinary disorders

Common

Acute renal failure, haematuria

Uncommon

Renal tubular necrosis, proteinuria, nephritis

General disorders and administration site conditions

Very common

Pyrexia

Common

Chest pain, facial oedema j, asthenia, chills, injection site reaction, influenza like illness

Investigations

Common

Increased creatinine

Uncommon

Increased blood urea, hypercholesterolaemia

a Includes febrile neutropenia and neutropenia.

b Includes immune thrombocytopenic purpura.

c Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

d Includes akathisia and parkinsonism.

e Includes nuchal rigidity and tetany.

f Prolonged optic neuritis has been reported post-marketing. See section 4.4.

g See section 4.4.

h See u201cVisual impairmentsu201d paragraph in section 4.8.

i Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.

j Includes periorbital oedema, lip oedema, and mouth oedema.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of VFEND. A single adverse event of photophobia of 10 minutes duration was reported. There is no known antidote to VFEND.

Film-coated tablets

VFEND is haemodialysed with a clearance of 121 mL/min. In an overdose, haemodialysis may assist in the removal of voriconazole from the body.

Powder for solution for infusion

VFEND is haemodialysed with a clearance of 121 mL/min. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 mL/min. In an overdose, haemodialysis may assist in the removal of VFEND and SBECD from the body.