Vcide 20mg / 200mg 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 VCIDE to achieve voriconazole 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 voriconazole 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.

Dosage adjustments in case of co-administration: Phenytoin may be co-administered with VCIDE if the maintenance dose of VCIDE 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 VCIDE is co-administered with adjusted doses of efavirenz, the maintenance dose of VCIDE 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.

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.

Special populations

Use in the elderly: No dose adjustment is necessary for elderly patients.

Use in patients with renal impairment: The pharmacokinetics of orally administered VCIDE are not affected by renal impairment. No adjustment in oral dosage is consequently required for patients with mild to severe renal impairment. Voriconazole is haemodialysed with a clearance of 121 mL/min. A four-hour haemodialysis session does not remove enough VCIDE 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 VCIDE. No data are available on the use of voriconazole (as contained in VCIDE) in patients with severe chronic hepatic cirrhosis (Child-Pugh C). VCIDE 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, VCIDE is not recommended for children less than 2 years of age.

Method of administration: VCIDE should be taken at least one hour before, or one hour after a meal.

• Hypersensitivity to voriconazole or to any of the excipients of VCIDE listed in section 6.1.
• Patients with prolonged QT-syndrome.
• Severe impairment of hepatic function.
• Pregnancy and lactation.
• Coadministration with the following medicines:
• CYP3A4 substrates, astemizole, terfenadine, 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 medicines can lead to ergotism (see sections 4.4 and 4.5).
• Rifampicin, carbamazepine and phenobarbital (phenobarbitone), since these medicines are likely to decrease plasma voriconazole concentrations significantly (see sections 4.4 and 4.5).
• Rifabutin, since VCIDE 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 VCIDE concentrations in healthy subjects at this dose (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 must always use effective contraception during treatment.

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

Cardiovascular effects: Voriconazole (as in VCIDE) 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 cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory (see section 4.5). VCIDE should be administered with caution to patients with potentially pro-dysrhythmic conditions, such as:

• 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 VCIDE therapy.

Hepatic toxicity: Serious hepatic reactions may occur during treatment with VCIDE (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 VCIDE 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 VCIDE 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, VCIDE should be discontinued.

Monitoring of hepatic function should be carried out in both children and adults.

Visual disturbances: VCIDE 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. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events.

In clinical trials, subjects frequently experienced altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual disturbances were transient and fully reversible, with the majority spontaneously resolving within 60 minutes. There was evidence of attenuation with repeated doses of voriconazole. These visual disturbances were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances may be associated with higher plasma concentrations and/or doses. The mechanism of action is unknown, although the site of action is most likely to be within the retina.

Renal toxicity: Acute renal failure has been reported in severely ill patients treated with voriconazole. Patients treated with VCIDE 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:

• Phototoxicity: VCIDE 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 VCIDE treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).
• 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, VCIDE discontinuation and use of alternative antifungal medicines should be considered, and the patient should be referred to a dermatologist. If VCIDE is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. VCIDE should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under u201cLong-term treatmentu201d).
• Periostitis: 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 VCIDE considered.
• 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 VCIDE 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 VCIDE-treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric use: Safety and effectiveness in paediatric patients below the age of 2 years have not been established. VCIDE 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.

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.

VCIDE 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 VCIDE) and other medicines are listed in the table below (u201cNDu201d is the abbreviation for u201cnot determinedu201d). 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. AUC u03c4 , AUC t and AUC 0- u221e 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 dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

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

Pregnancy: Adequate information is not available on the use of VCIDE in pregnant women. Studies in animals have shown reproductive toxicity and teratogenicity. The potential risk to humans is unknown. VCIDE should not be used during pregnancy (see section 4.3).

Lactation: The excretion of voriconazole (as contained in VCIDE) into breastmilk has not been investigated. Breastfeeding must be stopped on initiation of treatment with VCIDE (see section 4.3).

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

VCIDE has moderate influence on the ability to drive and use machines. It 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. 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.

Tabulated summary of adverse reactions: In the table below, causality adverse reactions and their frequency categories are listed by system organ class. Frequency categories are expressed as: Frequent, Less frequent and Frequency unknown (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Frequent

Less frequent

Frequency not known

Infections and infestations

sinusitis

pseudomembranous colitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

squamous cell carcinoma*

Blood and lymphatic system disorders

agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anaemia

bone marrow failure, lymphadenopathy, eosinophilia, disseminated intravascular coagulation

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