Posology : מינונים

4.2      Posology and method of administration

Posology
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).

It is recommended that Vortimal is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

Treatment
Adults
Therapy must be initiated with the specified Intravenous loading dose regimen of Vortimal to achieve adequate plasma concentrations on Day 1. Intravenous treatment should be continued for at least 7 days before switching to oral treatment (see section 5.1). Once the patient is clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. On the basis of the high oral bioavailability (96 %; see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

Detailed information on dosage recommendations is provided in the following table: Intravenous                    Orala
Patients 40 kg and       Patients less than 40 kg* above*
Loading dose regimen        6 mg/kg every 12                   -----------------         ----------------- (first 24 hours)            hours
Maintenance dose            3-4 mg/kg every 12             200 mg (5 ml) every 12   100 mg (2.5ml) every 12 (after first 24 hours)      hours                          hours                    hours Prophylaxis of invasive fungal infections

Invasive Aspergillosis/     4 mg/kg every 12               200 mg (5 ml) every 12   100 mg (2.5ml) every 12 Scedosporium       and      hours                          hours                    hours Fusarium infections/
Other serious mould infectionsb
Candidemia in non-          3-4 mg/kg every 12             200 mg (5 ml) every 12   100 mg (2.5ml) every 12 neutropenic patients        hoursc                         hours                    hours 
 a
In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 3 mg/kg IV every 12 hours dose, the 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg IV every 12 hours dose (see section 5.2).
b
In the pivotal clinical study of invasive aspergillosis, the median duration of IV voriconazole therapy was 10 days (range 2-85 days). The median duration of oral voriconazole therapy was 76 days (range 2-    232 days) (see Section 5.1).
c
In clinical trials, patients with candidemia received 3 mg/kg every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg as salvage therapy. Appropriate dose should be based on severity and nature of the infection.

* 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. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

Dose adjustment (Adults)

Vortimal powder for solution for infusion:
If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose may be increased to 4 mg/kg every 12 hours.

If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous maintenance dose to a minimum of 3 mg/kg every 12 hours.

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily (see sections 4.4 and 4.5).

Efavirenz may be coadministered 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 (see sections 4.4 and 4.5).

Use in paediatrics

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 metabolize voriconazole more similarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous                  Oral
Loading Dose Regimen            9 mg/kg every 12 hours       Not recommended (first 24 hours)
Maintenance Dose                8 mg/kg twice daily          9 mg/kg twice daily (after first 24 hours)                                       (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. Safety and effectiveness in pediatric patients below the age of 2 years has not been established (see Section 5.1). Therefore, voriconazole is not recommended for children less than 2 years of age.

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight) voriconazole should be dosed as adults.

Dosage adjustment (Children [2 to<12 years]and young adolescents with low body weight [12 to 14 years and <50 kg])


If a patient response to treatment 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 patient is 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).

Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see sections 4.8 and 5.2).

Prophylaxis in Adults and Children
Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection (IFI) as defined by neutropenia or immunosuppression. 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).


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. On the basis of the high oral bioavailability (96%; see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

Detailed information on dosage recommendations is provided in the following table: 

Oral
Patients 40 kg and Patients less than 40
Intravenous above*              Kg *

Loading dose             6 mg/kg every 12 400 mg every 12 200 mg every 12 regimen                  hours            hours           hours
(first 24 hours)
Maintenance        dose 4 mg/kg twice daily        200 mg twice daily    100 mg twice daily (after first 24 hours)


* This also applies to patients aged 15 years and older


Children
The recommended dosing regimen for prophylaxis in children is the same as mentioned in the table located under the header: Use in paediatrics

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

Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

The following instructions apply to both treatment and prophylaxis

Dosage adjustment
For prophylaxis use, dose adjustments are not recommended in the case of lack of efficacy or treatment-related adverse events. In the case of treatment-related adverse events, discontinuation of voriconazole and use of alternative antifungal agents must be considered (see section 4.4 and 4.8).

Elderly
No dose adjustment is necessary for elderly patients (see section 5.2).

Renal impairment
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 voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see section 5.2).
The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.


Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4 hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Hepatic impairment
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 (see section 5.2).

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 (ALP), 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 (see section 4.8).


Method of administration
Voriconazole powder for solution for infusion requires reconstitution and dilution (see section 6.6) prior to administration as an intravenous infusion. Not for bolus injection.