VFEND Powder for solution Ref.[8126] Active ingredients: Voriconazole

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 VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

VFEND is also available as 50 mg and 200 mg film-coated tablets and 40 mg/ml powder for oral suspension.

Treatment

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%; 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:

* 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).

Dosage adjustment (Adults)

If patient is unable to tolerate intravenous treatment at 4 mg/kg twice daily, reduce the dose to 3 mg/kg twice daily.

If patient response to treatment 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 patient is unable to tolerate treatment at a higher dose 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.

In case of use as prophylaxis, refer below.

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:

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.

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 patient response to treatment is inadequate, the intravenous dose may be increased by 1 mg/kg steps. If patient is unable to tolerate treatment, reduce the intravenous dose by 1 mg/kg steps.

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).

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 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 treatmentrelated 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)

Dosage adjustments in case of co-administration

Rifabutin or 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).

Elderly

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

Renal impairment

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).

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.

The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.

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 VFEND 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 severe hepatic impairment must be carefully monitored for drug toxicity (see section 4.8).

Paediatric population

The safety and efficacy of VFEND in children below 2 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Method of administration

VFEND requires reconstitution and dilution (see section 6.6) prior to administration as an intravenous infusion. Not for bolus injection.

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 voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole 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 voriconazole and SBECD from the body.

VFEND 200 mg powder for solution for infusion and VFEND 200 mg powder and solvent for solution for infusion: 3 years.

From a microbiological point of view, once reconstituted, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C (in a refrigerator), unless reconstitution has taken place in controlled and validated aseptic conditions.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.

Solvent for solution for infusion: VFEND solvent for solution for infusion is a sterile, single use polypropylene infusion bag. Therefore, from a microbiological point of view, once solvent has been removed from the bag to reconstitute the VFEND powder for solution for infusion and then reintroduced into the bag, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

VFEND 200 mg powder for solution for infusion: 30 ml clear Type I glass vial with rubber stopper and aluminium cap with plastic seal.

VFEND 200 mg powder and solvent for solution for infusion: VFEND powder and solvent for solution for infusion is available in a box containing: 1 single use 30 ml clear Type I glass vial with rubber stopper and aluminium cap with plastic seal of VFEND 200 mg, powder for solution.

1 sterile, single use, foil overwrapped, polypropylene bag containing VFEND solvent for solution for infusion in one compartment (50 ml).

1 sterile, single use vial adapter.

1 sterile, single use syringe.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

VFEND 200 mg powder for solution for infusion

The powder is reconstituted with either 19 ml of water for injections or 19 ml of 9 mg/ml (0.9%) Sodium Chloride for Infusion to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole. Discard the VFEND vial if vacuum does not pull the diluent into the vial. It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact amount (19.0 ml) of water for injections or (9 mg/ml [0.9%]) Sodium Chloride for Infusion is dispensed. This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.

For administration, the required volume of the reconstituted concentrate is added to a recommended compatible infusion solution (detailed in the table below) to obtain a final voriconazole solution containing 0.5-5 mg/ml.

The reconstituted solution can be diluted with:

• Sodium Chloride 9 mg/ml (0.9%) Solution for Injection
• Compound Sodium Lactate Intravenous Infusion
• 5% Glucose and Lactated Ringer’s Intravenous Infusion
• 5% Glucose and 0.45% Sodium Chloride Intravenous Infusion
• 5% Glucose Intravenous Infusion
• 5% Glucose in 20 mEq Potassium Chloride Intravenous Infusion
• 0.45% Sodium Chloride Intravenous Infusion
• 5% Glucose and 0.9% Sodium Chloride Intravenous Infusion

The compatibility of voriconazole with diluents other than described above or in section 6.2 is unknown.

VFEND 200 mg powder and solvent for solution for infusion

Use only items provided in the box with VFEND powder and solvent for solution for infusion in the preparation of the infusion.

Instructions for reconstitution and use:

• This medicinal product is for single use only and any unused solution should be discarded.
• To prepare the VFEND vial for reconstitution, remove the plastic cap from the vial and wipe the top with an antiseptic swab. Hold the vial adapter over the vial and press down firmly, until the vial locks into place. The spike in the vial adapter will penetrate the vial seal.
• Remove the bag of VFEND solvent for solution for infusion from the foil overwrap (do not use scissors or any other sharp tool). Snap open the blue port of the infusion bag.
• The VFEND powder is reconstituted by using the specially marked syringe provided to remove 19 ml of VFEND solvent for solution for infusion (Sodium Chloride (0.9%) from the blue port of the infusion bag.
• The VFEND solvent for solution for infusion is then added to the vial by unscrewing the syringe from the bag, connecting it to the vial adapter and then emptying the contents from the syringe into the vial.
• This will provide an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole. The connected syringe and vial are then gently swirled to ensure that the VFEND powder has completely dissolved and no particulates are visible (do not shake).
• For dilution, gently invert the vial, vial adapter and syringe assembly and withdraw the required volume of the reconstituted concentrate into the syringe (see table below). Only clear solutions without particulates should be used. Do not administer to the patient as a bolus injection.
• Once the syringe is reconnected to the blue port of the infusion bag, the contents are then emptied into the infusion bag from the syringe to provide a final voriconazole solution containing 0.5-5 mg/ml.
• The syringe may then be removed and the contents of the infusion bag mixed gently by inverting the bag several times. The bag should be carefully inspected to ensure that there are no particulates. The syringe, vial and vial adapter can then be discarded.

If the required volume of VFEND concentrate as described in the table below requires the use of multiple vials in order to provide the appropriate dose for a given body weight, then multiple infusion kits should be used. The instructions should be followed for reconstitution, dilution and administration of each kit. Each kit is for single use only.

If multiple vials are required, each individual vial used must be administered using a separate sterile sodium chloride bag.

For administration, the twist-off port at the bottom of the infusion bag should be opened and the infusion line connected and primed. The contents of the infusion bag are now ready for infusion to the patient.

The infusion bag should be checked to ensure that the entire contents of the bag have been infused, especially if the same intravenous line is to be used for sequential infusion of other drugs. Other additives should not be introduced into the infusion bag.

Required Volumes of 10 mg/ml VFEND Concentrate:

Further information is provided for medical or healthcare professionals at the end of the Package Leaflet.