RECOMMENDED DOSING SCHEDULE: Adults and a subgroup of adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight):
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. On the basis of the high oral bioavailability (96 %), switching between intravenous and oral administration is appropriate when clinically indicated.
: over 18 years, body weight over 40 kg, 400 mg every 12 hours for 2 doses then 200 mg every 12 hours, increased if necessary to 300 mg every 12 hours; body weight over 40 kg, 200 mg every 12 hours for 2 doses then 100 mg every 12 hours, increased if necessary to 150 mg every 12 hours.
Detailed information on dosage recommendations is provided in the following table: See Table 1.
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Dosage adjustment: Film-coated tablets:
If patient response 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 patients are unable to tolerate treatment at these higher doses 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.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg).
The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg).
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg):
The recommended dosing regimen is as follows: See Table 2.
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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.
These oral dose recommendations for children are based on studies in which Voriconazole was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatrics, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2-<12.
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied.
If patient response is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patients are unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).
Duration of treatment:
Treatment should be as short as possible depending on the patients' clinical and mycological response.
For long term treatment greater than 6 months. a careful assessment of the benefit-risk balance should be considered.
The duration of treatment with the intravenous formulation should be no longer than 6 months. For voriconazole in general, long term treatment greater than 6 months requires careful assessment of the benefit-risk balance.
No dose adjustment is necessary for elderly patients.
Film-coated tablets: The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing 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 a sufficient amount of voriconazole to warrant dose adjustment.
The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole.
Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
There is limited data on the safety of Voriconazole in patients with abnormal Liver Function Tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), or total bilirubin >5 times the upper limit of normal).
Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
The safety and efficacy of Voriconazole in children below 2 years has not been established.
Method of administration:
Voriconazole film-coated tablets are to be taken at least one hour before, or one hour following, a meal.