Voriconazol Hexal

Voriconazol Hexal is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows:

- Treatment of invasive aspergillosis.

- Treatment of candidaemia in non-neutropenic patients.

- Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).

- Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.

Voriconazol Hexal should be administered primarily to patients with progressive, possibly life-threatening infections.

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Voriconazol Hexal, is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows:

- Treatment of invasive aspergillosis.

- Treatment of candidaemia in non-neutropenic patients.

- Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei). Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.

Voriconazol Hexal should be administered primarily to patients with progressive, possibly life-threatening infections.

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Posology

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy.

Powder for solution for infusion:

It is recommended that Voriconazol Hexal 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 loading dose regimen of either intravenous or oral Voriconazol Hexal to achieve plasma concentrations on Day 1 that are close to steady state.), 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.

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.

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 paediatric patients, 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 to <12.

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 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.

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).

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.

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

Dosage adjustments in case of co-administration

The combination of voriconazole with rifabutin should, if possible be avoided.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.

Elderly

No dose adjustment is necessary for elderly patients.

Renal impairment

Film-coated tablets & Powder for oral suspension:

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 4- hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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.

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.

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

There is limited data on the safety of Voriconazol Hexal 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.

Paediatric population

The safety and efficacy of Voriconazol Hexal in children below 2 years has not been established.1 but no recommendation on a posology can be made.

Method of administration

Voriconazol Hexal film-coated tablets are to be taken at least one hour before, or one hour following, a meal.

Voriconazol Hexal powder for solution for infusion requires reconstitution and dilution prior to administration as an intravenous infusion. Not for bolus injection.

Voriconazol Hexal oral suspension is to be taken at least one hour before, or two hours following, a meal.

Posology

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during Voriconazol Hexal therapy.

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

Voriconazol Hexal is also available as 50 mg and 200 mg film-coated tablets, 200 mg powder and solvent for solution for infusion.

Treatment

Adults

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral Voriconazol Hexal to achieve plasma concentrations on Day 1 that are close to steady state.), 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 Voriconazol Hexal greater than 180 days (6 months) requires careful assessment of the benefit-risk balance. Clinical data to establish the safety of intravenously administered Hydroxypropil-β-cyclodextrin (HPBCD) in long term treatment are limited.

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) Voriconazol Hexal should be dosed as children as these young adolescents may metabolize Voriconazol Hexal 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 Voriconazol Hexal 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)

Voriconazol Hexal should be dosed as adults.

Dosage adjustment (Children [2 to <12years] and young adolescents with low body weight [12 to14years and<50kg])

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.

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).

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 Voriconazol Hexal use for longer than 180 days has not been adequately studied in clinical trials.

Use of Voriconazol Hexal in prophylaxis for greater than 180 days (6 months) requires careful assessment of the benefit-risk balance. Clinical data to establish the safety of intravenously administered Hydroxypropil-β-cyclodextrin (HPBCD) in long term treatment are limited.

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 Voriconazol Hexal and use of alternative antifungal agents must be considered

Dosage adjustments in case of co-administration

Efavirenz may be coadministered with Voriconazol Hexal if the maintenance dose of Voriconazol Hexal 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 Voriconazol Hexal is stopped, the initial dosage of efavirenz should be restored.

Specific patient groups

Elderly patients

No dose adjustment is necessary for elderly patients.

Patients with renal impairment

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation of the intravenous vehicle, hydroxypropylbetadex, occurs. Oral Voriconazol Hexal should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous Voriconazol Hexal. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral Voriconazol Hexal therapy. Use in patients who are not undergoing haemodialysis is not recommended.

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

The intravenous vehicle, hydroxypropilbetadex, is haemodialysed with a clearance of 37.5 ± 24 ml/min.

Patients with 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 Voriconazol Hexal.

Voriconazol Hexal has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

There is limited data on the safety of Voriconazol Hexal 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).

Voriconazol Hexal 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.

Paediatric population

The safety and efficacy of Voriconazol Hexal in children below 2 years has not been established.1 but no recommendation on a posology can be made.

Clinical data to establish the safety of intravenously administered HPBCD in the paediatric population are limited.

Method of administration

Voriconazol Hexal 200 mg powder for solution for infusion requires reconstitution and dilution prior to administration as an intravenous infusion. Not for bolus injection.

Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes.

Coadministration with rifampicin, carbamazepine and phenobarbital since these medicinal products are likely to decrease plasma voriconazole concentrations significantly.

Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations.

Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose.

Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism.

Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimus significantly.

Coadministration with St. John's Wort.

Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes.

Coadministration with rifampicin, carbamazepine and phenobarbital since these medicinal products are likely to decrease plasma Voriconazol Hexal concentrations significantly.

Coadministration of standard doses of Voriconazol Hexal with efavirenz doses of 400 mg once daily or higher is contraindicated because efavirenz significantly decreases plasma Voriconazol Hexal concentrations in healthy subjects at these doses. Voriconazol Hexal also significantly increases efavirenz plasma concentrations.

Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma Voriconazol Hexal concentrations in healthy subjects at this dose.

Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism.

Coadministration with sirolimus since Voriconazol Hexal is likely to increase plasma concentrations of sirolimus significantly.

Coadministration with St. John's Wort.

Hypersensitivity

Duration of IV treatment

The duration of treatment with the intravenous formulation should be no longer than 6 months.

Cardiovascular

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

- Congenital or acquired QTc-prolongation.

- Cardiomyopathy, in particular when heart failure is present.

- Sinus bradycardia.

- Existing symptomatic arrhythmias.

- Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy. A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.

Infusion-related reactions

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

Hepatic toxicity

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (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.

Monitoring of hepatic function

Patients receiving Voriconazol Hexal 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 Voriconazol Hexal 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 , 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, Voriconazol Hexal should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.

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

Serious dermatological adverse reactions

- Phototoxicity

In addition Voriconazol Hexal 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 Voriconazol Hexal 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, Voriconazol Hexal discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Voriconazol Hexal is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazol Hexal should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under Long-term treatment).

- Exfoliative cutaneous reactions

Reactions such as Stevens-Johnson syndrome developed during treatment with Voriconazol Hexal. If a patient develops a rash he should be monitored closely and Voriconazol Hexal discontinued if lesions progress.

Long-term treatment

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to Voriconazol Hexal.

Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Voriconazol Hexal treatment.

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 Voriconazol Hexal discontinuation should be considered after multidisciplinary advice.

Visual adverse reactions

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema.

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with Voriconazol Hexal. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function.

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

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazol Hexal treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established. Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population. 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 weight for age. In that case, intravenous voriconazole administration is recommended.

- Serious dermatological adverse reactions (including SCC)

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted 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 treatment discontinuation.

Prophylaxis

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours.

Rifabutin (Potent CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk.

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Everolimus (CYP3A4 substrate, P-gp substrate)

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation.

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. Dose reduction of methadone may be needed.

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 coadministered with voriconazole. As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with voriconazole, and in an independent published study concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC_0-∞ of fentanyl, frequent monitoring for opiate-associated adverse reactions (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 metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse reactions may be necessary.

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in C_max and AUC of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole - associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.

Voriconazol Hexal tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Voriconazol Hexal oral suspension contains sucrose and should not be given to patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.

Sodium content: Each vial of Voriconazol Hexal powder for solution for infusion contains 217.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.

Hypersensitivity

Duration of treatment

The duration of treatment with the intravenous formulation should be no longer than 6 months.

Cardiovascular

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

- Congenital or acquired QTc-prolongation.

- Cardiomyopathy, in particular when heart failure is present.

- Sinus bradycardia.

- Existing symptomatic arrhythmias.

- Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during Voriconazol Hexal therapy. A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of Voriconazol Hexal up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentiall clinically-relevant threshold of 500 msec.

Infusion-related reactions

Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of Voriconazol Hexal. Depending on the severity of symptoms, consideration should be given to stopping treatment.

Hepatic toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Voriconazol Hexal (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.

Monitoring of hepatic function

Patients receiving Voriconazol Hexal 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 Voriconazol Hexal 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 , 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, Voriconazol Hexal should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.

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

Visual adverse reactions

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema.

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with Voriconazol Hexal. Patients being treated with Voriconazol Hexal are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function.

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

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazol Hexal treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Dermatological adverse reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with Voriconazol Hexal. If a patient develops a rash he should be monitored closely and Voriconazol Hexal discontinued if lesions progress.

In addition Voriconazol Hexal has been associated with phototoxicity and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during Voriconazol Hexal treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Long-term treatment

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to Voriconazol Hexal. The following severe adverse events have been reported in relation with long-term Voriconazol Hexal treatment:

Squamous cell carcinoma of the skin (SCC) has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazol Hexal discontinuation and use of alternative antifungal agents should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever Voriconazol Hexal is continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions. Voriconazol Hexal should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.

Non-infectious periostitis with elevated fluoride and alkaline phosphatese levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis Voriconazol Hexal discontinuation should be considered after multidisciplinary advice.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established. Voriconazol Hexal is indicated for paediatric patients aged two years or older. 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 weight for age. In that case, intravenous Voriconazol Hexal administration is recommended.

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted 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 treatment discontinuation.

Prophylaxis

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of Voriconazol Hexal and use of alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with Voriconazol Hexal. Concomitant use of Voriconazol Hexal and phenytoin should be avoided unless the benefit outweighs the risk.

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

When Voriconazol Hexal is coadministered with efavirenz the dose of Voriconazol Hexal should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours.

Rifabutin (Potent CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended when rifabutin is coadministered with Voriconazol Hexal. Concomitant use of Voriconazol Hexal and rifabutin should be avoided unless the benefit outweighs the risk.

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

Coadministration of Voriconazol Hexal and low-dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of Voriconazol Hexal.

Everolimus (CYP3A4 substrate, P-gpsubstrate)

Coadministration of Voriconazol Hexal with everolimus is not recommended because Voriconazol Hexal is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation.

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with Voriconazol Hexal since methadone levels increased following coadministration of Voriconazol Hexal. Dose reduction of methadone may be needed.

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 coadministered with Voriconazol Hexal. As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with Voriconazol Hexal, and in an independent published study, concomitant use of Voriconazol Hexal with fentanyl resulted in an increase in the mean AUC_0-∞ of fentanyl, frequent monitoring for opiate- associated adverse reactions (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 metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with Voriconazol Hexal. Frequent monitoring for opiate-associated adverse reactions may be necessary.

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral Voriconazol Hexal and oral fluconazole resulted in a significant increase in C_max and AUC of Voriconazol Hexal in healthy subjects. The reduced dose and/or frequency of Voriconazol Hexal and fluconazole that would eliminate this effect have not been established. Monitoring for Voriconazol Hexal- associated adverse reactions is recommended if Voriconazol Hexal is used sequentially after fluconazole.

Sodium content

This medical product contains 1.54 mmol (35.38 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Summary of safety profile

The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis 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.

The most commonly 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 reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, are listed.

Frequency categories are expressed as: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving voriconazole:

*ADR identified post-marketing

¹ Includes febrile neutropenia and neutropenia.

² Includes immune thrombocytopenic purpura.

³ Includes nuchal rigidity and tetany.

⁴ Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

⁵ Includes akathisia and parkinsonism.

⁷ Prolonged optic neuritis has been reported post-marketing.

⁹ Includes dyspnoea and dyspnoea exertional.

¹⁰ Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.

¹¹ Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Altered taste perception

In the combined data from three bioequivalence studies using the powder for oral suspension formulation, treatment-related taste perversion was recorded in 12 (14%) of subjects.

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments 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. In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.

There have been post-marketing reports of prolonged visual adverse events.

Dermatological reactions

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed serious cutaneous reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with Voriconazol Hexal.

If a patient develops a rash they should be monitored closely and Voriconazol Hexal discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy.

There have been reports of squamous cell carcinoma of the skin in patients treated with Voriconazol Hexal for long periods of time; the mechanism has not been established.

Liver function tests

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0 % (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death.

Infusion-related reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion.

Prophylaxis

In an open-label, comparative, multicentre study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in paediatric populationwas similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

United Kingdom

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected].

Summary of safety profile

The safety profile of Voriconazol Hexal is based on an integrated safety database of more than 2,000 subjects (including 1,655 patients in therapeutic trials and 279 in prophylaxis 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. Seven hundred and five (705) patients had a duration of Voriconazol Hexal therapy of greater than 12 weeks, with 164 patients receiving Voriconazol Hexal for over 6 months.

The most commonly reported adverse reactions were visual disturbances, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions, by system organ class and frequency, are listed.

Frequency categories are expressed as: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving Voriconazol Hexal:

*Undesirable events identified during post-approval use

Description of selected adverse reactions

Visual disturbances

In clinical trials, visual impairments with Voriconazol Hexal were very common. In therapeutic studies, Voriconazol Hexal treatment-related visual disturbances were very common. In these studies, short-term as well as long-term treatment, approximately 21% of subjects 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 and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of Voriconazol Hexal. The 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. In a study in healthy volunteers investigating the impact of Voriconazol Hexal on retinal function, Voriconazol Hexal caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of Voriconazol Hexal.

There have been post-marketing reports of prolonged visual adverse events.

Dermatological reactions

Dermatological reactions were common in patients treated with Voriconazol Hexal in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with Voriconazol Hexal.

If a patient develops a rash they should be monitored closely and Voriconazol Hexal discontinued if lesions progress. Photosensitivity reactions have been reported, especially during long-term therapy.

There have been reports of squamous cell carcinoma of the skin in patients treated with Voriconazol Hexal for long periods of time; the mechanism has not been established.

Liver function tests

The overall incidence of clinically significant transaminase abnormalities in the Voriconazol Hexal clinical programme was 13.5 % (258/1918) of subjects treated with Voriconazol Hexal. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy. Voriconazol Hexal has been infrequently associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and hepatic failure leading to death.

Infusion-related reactions

During infusion of the intravenous formulation of Voriconazol Hexal in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion.

Prophylaxis

In an open-label, comparative, multicenter study comparing Voriconazol Hexal and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable invasive fungal infections (IFI), permanent discontinuation of Voriconazol Hexal due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with Voriconazol Hexal and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of Voriconazol Hexal was investigated in 285 paediatric patients aged 2 to <12 years who were treated with Voriconazol Hexal in pharmacokinetic studies (127 paediatric patients) and in compassionate use programmes (158 paediatric patients). The adverse reaction profile of these 285 paediatric patients was similar to that in adults. Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received Voriconazol Hexal in a compassionate use programme, the following adverse reactions (for which a relationship to Voriconazol Hexal could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

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.

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

There is no known antidote to Voriconazol Hexal.

Voriconazol Hexal is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle hydroxypropylbetadex is haemodialysed with a clearance of 37.5 ± 24 ml/min. In an overdose, haemodyalisis may assist in the removal of Voriconazol Hexal and hydroxypropylbetadex from the body.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02 AC03

Mode of action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Pharmacokinetic/pharmacodynamic relationship

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found and this relationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances. Dose adjustments in prophylaxis studies have not been explored.

Clinical efficacy and safety

In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole- resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.

Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C. inconspicua and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans; and Fusarium spp.

Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 μg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/L for voriconazole.

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Clinical experience

Successful outcome in this section is defined as complete or partial response.

Aspergillus infections - efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days). After IV voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2-232 days).

A satisfactory global response (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-treated patients compared to 31% of patients treated with comparator. The 84-day survival rate for voriconazole was statistically significantly higher than that for the comparator and a clinically and statistically significant benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to toxicity.

This study confirmed findings from an earlier, prospectively designed study where there was a positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, in particular, cerebral infections (normally associated with almost 100 % mortality).

The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.

Candidaemia in non-neutropenic patients

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41% of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively. The Investigator's assessment of successful outcome at each of these time points is shown in the following table.

Serious refractory Candida infections

The study comprised 55 patients with serious refractory systemic Candida infections (including candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non-albicans species, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility data.

Scedosporium and Fusarium infections

Voriconazole was shown to be effective against the following rare fungal pathogens:

Scedosporium spp.: Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partial responses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more than one organism including Scedosporium spp.

Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; 2 of them had a successful outcome.

The majority of patients receiving voriconazole treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.

Primary Prophylaxis of Invasive Fungal Infections - Efficacy in HSCT recipients without prior proven or probable IFI

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of patients having AML. From all patients 58% were subject to myeloablative conditions regimens. Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITT group.

Success rates and other secondary endpoints are presented in the table below:

* Primary endpoint of the study

** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 180, for patients with AML and myeloablative conditioning regimens respectively, is presented in the table below:

AML

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

***Difference in proportions, 95% CI obtained after adjustment for randomization

Myeloablative conditioning regimens

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

*** Difference in proportions, 95% CI obtained after adjustment for randomization

Secondary Prophylaxis of IFI - Efficacy in HSCT recipients with prior proven or probable IFI

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Duration of treatment

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.

Paediatric population

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, open-label, non-comparative, multi-centre clinical trials. One study enrolled 31 patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and oesophageal candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA the overall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC the global response rate at EOT was 85.7% (6/7) and for patients with EC the global response rate at EOT was 70% (7/10). The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to <12 years old and 62.5% (5/8) for 12 to <18 years old.

Clinical studies examining QTc interval

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of > 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives,

ATC code: J02A C03

Mode of Action

Voriconazol Hexal is a triazole antifungal agent. The primary mode of action of Voriconazol Hexal is the inhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of Voriconazol Hexal. Voriconazol Hexal has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Pharmacokinetic/pharmacodynamics Relationship

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter- quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma Voriconazol Hexal concentration and efficacy in therapeutic studies was not found and this relationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma Voriconazol Hexal concentrations and both liver function test abnormalities and visual disturbances. Dose adjustments in prophylaxis studies have not been explored.

Clinical efficacy and safety

In vitro, Voriconazol Hexal displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition Voriconazol Hexal shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.

Clinical efficacy defined as partial or complete response has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans; and Fusarium spp.

Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp.,Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of Voriconazol Hexal in the range 0.05 to 2 µg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/L for Voriconazol Hexal.

However, the in vitro activity of Voriconazol Hexal against Candida species is not uniform. Specifically, for C. glabrata, the MICs of Voriconazol Hexal for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Clinical experience

Successful outcome in this section is defined as complete or partial response.

Aspergillus infections-efficacy in aspergillosis patients with poor prognosis

Voriconazol Hexal has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of Voriconazol Hexal versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. Voriconazol Hexal was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV Voriconazol Hexal therapy was 10 days (range 2-85 days). After IV Voriconazol Hexal therapy, the median duration of oral Voriconazol Hexal therapy was 76 days (range 2-232 days).

A satisfactory global response (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of Voriconazol Hexal-treated patients compared to 31% of patients treated with comparator. The 84-day survival rate for Voriconazol Hexal was statistically significantly higher than that for the comparator and a clinically and statistically significant benefit was shown in favour of Voriconazol Hexal for both time to death and time to discontinuation due to toxicity.

This study confirmed findings from an earlier, prospectively designed study where there was a positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, in particular, cerebral infections (normally associated with almost 100% mortality).

The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.

Candidaemia in non-neutropenic patients

The efficacy of Voriconazol Hexal compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with Voriconazol Hexal. Nine subjects in the Voriconazol Hexal group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41% of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) Voriconazol Hexal and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively.

The Investigator's assessment of successful outcome at each of these time points is shown in the following table.

Serious refractory Candida infections

The study comprised 55 patients with serious refractory systemic Candida infections (including candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non-albicans species, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility data.

Scedosporium and Fusarium infections

Voriconazol Hexal was shown to be effective against the following rare fungal pathogens:

Scedosporium spp.: Successful response to Voriconazol Hexal therapy was seen in 16 (6 complete, 10 partial responses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more than one organism including Scedosporium spp.

Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with Voriconazol Hexal. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; 2 of them had a successful outcome.

The majority of patients receiving Voriconazol Hexal treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.

Primary Prophylaxis of Invasive Fungal Infections-Efficacy in HSCT recipients without prior proven or probable IFI

Voriconazol Hexal was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of patients having AML.

From all patients 58% were subject to myeloablative conditions regimens. Prophylaxis with study drug was started immediately after HSCT: 224 received Voriconazol Hexal and 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for Voriconazol Hexal and 68 days for itraconazole in the MITT group.

Success rates and other secondary endpoints are presented in the table below:

* Primary endpoint of the study

** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 180, for patients with AML and myeloablative conditioning regimens respectively, is presented in the table below:

AML

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

***Difference in proportions, 95% CI obtained after adjustment for randomization

Myeloablative conditioning regimens

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

*** Difference in proportions, 95% CI obtained after adjustment for randomization

Secondary Prophylaxis of IFI-Efficacy in HSCT recipients with prior proven or probable IFI

Voriconazol Hexal was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidaemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Duration of treatment

In clinical trials, 705 patients received Voriconazol Hexal therapy for greater than 12 weeks, with 164 patients receiving Voriconazol Hexal for over 6 months.

Paediatric population

Sixty-one paediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections were treated with Voriconazol Hexal. This population included 34 patients 2 to <12 years old and 20 patients 12-15 years of age.

The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients aged 12-15 years, the remaining patients received Voriconazol Hexal in the compassionate use programmes. Underlying diseases in these patients included haematological malignancies (27 patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal infection was aspergillosis (43/61; 70%).

Clinical studies examining QTc interval

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval of healthy volunteers was conducted with three oral doses of Voriconazol Hexal and ketoconazole. The placebo- adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of Voriconazol Hexal were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of > 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.

General pharmacokinetic characteristics

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of subjects.

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%. When multiple doses of voriconazole are administered with high fat meals, C_max and AUC are reduced by 34% and 24%, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Powder for oral suspension

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%.

Bioequivalence was established between the 200 mg tablet and the 40mg/ml oral suspension when administered as a 200 mg dose. When multiple doses of voriconazole are administered with high fat meals, C_max and AUC are reduced by 58% and 37%, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Distribution

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.

Biotransformation

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of voriconazole pharmacokinetics is high.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUC) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Elimination

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (> 94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups

Gender

In an oral multiple-dose study, C_max and AUC for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in C_max and AUC were observed between healthy elderly males and healthy elderly females (> 65 years).

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.

Elderly

In an oral multiple-dose study C_max and AUC in healthy elderly males (> 65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUC were observed between healthy elderly females (> 65 years) and healthy young females (18-45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.

Paediatric population

The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses.

Renal impairment

Film-coated tablets:

In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment..

Powder for solution for infusion:

In patients with moderate to severe renal dysfunction (serum creatinine levels >2.5 mg /dl), accumulation of the intravenous vehicle, SBECD, occurs..

Hepatic impairment

After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.

In an oral multiple-dose study, AUC was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C).

General pharmacokinetic characteristics

The pharmacokinetics of Voriconazol Hexal have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.

The pharmacokinetics of Voriconazol Hexal are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a Voriconazol Hexal exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma Voriconazol Hexal concentrations being achieved by Day 6 in the majority of subjects.

Long term safety of HPBCD in humans is limited to 21 days (250 mg/kg/day).

Absorption

Voriconazol Hexal is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of Voriconazol Hexal after oral administration is estimated to be 96%. When multiple doses of Voriconazol Hexal are administered with high fat meals, C_max and AUC are reduced by 34% and 24%, respectively. The absorption of Voriconazol Hexal is not affected by changes in gastric pH.

Distribution

The volume of distribution at steady state for Voriconazol Hexal is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.

Cerebrospinal fluid samples from eight patients in a compassionate program showed detectable Voriconazol Hexal concentrations in all patients.

Biotransformation

In vitro studies showed that Voriconazol Hexal is metabolised by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of Voriconazol Hexal pharmacokinetics is high.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of Voriconazol Hexal. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher Voriconazol Hexal exposure (AUC) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher Voriconazol Hexal exposure than their homozygous extensive metaboliser counterparts.

The major metabolite of Voriconazol Hexal is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of Voriconazol Hexal.

Elimination

Voriconazol Hexal is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

After administration of a radiolabelled dose of Voriconazol Hexal, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half-life of Voriconazol Hexal depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of Voriconazol Hexal.

In relation to the excipient, Hydroxypropyl-β-cyclodextrin (HPBCD), IV-administered CDs (cyclodextrins) disappear rapidly from systemic circulation and are renally excreted intact. The steady-state volume of distribution (Vdss) for β-CD and most of its chemically modified derivatives in all animal species tested corresponds well with the respective extracellular fluid volume. This indicates that systemically absorbed CDs distribute mainly in the extracellular compartments, and no deep compartments or storage pools are involved. The total plasma clearance for HP-β-CD and SBE-β-CD in all species tested is similar to the glomerular filtration rate of individual species, and essentially 100% of a given dose is recovered in the urine within 6 to 12 hours following IV administration.

Pharmacokinetics in special patient groups

Gender

In an oral multiple-dose study, C_max and AUC for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in C_max and AUC were observed between healthy elderly males and healthy elderly females (>65 years).

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.

Elderly

In an oral multiple-dose study C_max and AUC in healthy elderly males (>65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUC were observed between healthy elderly females (>65 years) and healthy young females (18-45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of Voriconazol Hexal in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.

Paediatric population

The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide Voriconazol Hexal exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous Voriconazol Hexal administration is recommended.

Voriconazol Hexal exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower Voriconazol Hexal exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize Voriconazol Hexal more similarly to children than to adolescents/adults. Based on the population pharmacokinetic analysis, 12- to 14- year-old adolescents weighing less than 50 kg should receive children's doses.

Renal impairment

In patients with normal renal function, the pharmacokinetic profile of hydroxypropyl- ß-cyclodextrin, an ingredient of Voriconazol Hexal 200 mg intravenous formulation, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority (>85%)of an 8 g dose of hydroxypropyl-ß-cyclodextrin is eliminated in the urine.

In subjects with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-ß-cyclodextrin until steady state is reached. Hydroxypropyl- ßcyclodextrin is removed by hemodialysis, with a clearance of 37.5 ± 24 ml/min.

Hepatic impairment

After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of Voriconazol Hexal was not affected by impaired hepatic function.

In an oral multiple-dose study, AUC was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C).

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.

In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-natal development study in rats at exposures lower than those obtained in humans with therapeutic doses, voriconazole prolonged the duration of gestation and labour and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazole administration induced no impairment of male or female fertility in rats at exposures similar to those obtained in humans at therapeutic doses.

Powder for solution for infusion:

Preclinical data on the intravenous vehicle SBECD indicated that the main effects were vacuolation of urinary tract epithelium and activation of macrophages in the liver and lungs in the repeated-dose toxicity studies. As GPMT (guinea pig maximisation test) result was positive, prescribers should be aware of the hypersensitivity potential of the intravenous formulation. Standard genotoxicity and reproduction studies with the excipient SBECD reveal no special hazard for humans. Carcinogenicity studies were not performed with SBECD. An impurity present in SBECD has been shown to be an alkylating mutagenic agent with evidence for carcinogenicity in rodents. This impurity should be considered a substance with carcinogenic potential in humans. In light of these data the duration of treatment with the intravenous formulation should be no longer than 6 months.

Repeated-dose toxicity studies with Voriconazol Hexal indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, Voriconazol Hexal also induced minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.

In reproduction studies, Voriconazol Hexal was shown to be teratogenic in rats and embryotoxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-natal development study in rats at exposures lower than those obtained in humans with therapeutic doses, Voriconazol Hexal prolonged the duration of gestation and labour and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazol Hexal administration induced no impairment of male or female fertility in rats at exposures similar to those obtained in humans at therapeutic doses.

Hydroxypropyl-β-cyclodextrin

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. In a rat carcinogenicity study hydroxypropyl-β-cyclodextrin produced adenocarcinoma in the large intestine and exocrine pancreatic adenocarcinomas. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of the large intestine adenocarcinoma is low and the mechanism of exocrine pancreatic adenocarcinomas induction not considered relevant to humans.

Film-coated tablets:

Not applicable

Powder for solution for infusion:

Voriconazol Hexal must not be infused into the same line or cannula concomitantly with other intravenous products. The bag should be checked to ensure that the infusion is complete. When the Voriconazol Hexal infusion is complete, the line may be used for administration of other intravenous products.

Powder and solvent for solution for infusion:

Voriconazol Hexal must not be infused into the same line or cannula concomitantly with other intravenous products. The bag should be checked to ensure that the infusion is complete. When the Voriconazol Hexal infusion is complete, the line may be used for administration of other intravenous products.

Powder for solution for infusion & Powder and solvent for solution for infusion:

Blood products and short-term infusion of concentrated solutions of electrolytes:

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy. Voriconazol Hexal must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines.

Total parenteral nutrition:

Total parenteral nutrition (TPN) need not be discontinued when prescribed with Voriconazol Hexal, but does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for Voriconazol Hexal. Voriconazol Hexal must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.

Powder for oral suspension:

Voriconazol Hexal must not be infused into the same line or cannula concomitantly with other intravenous products. When the Voriconazol Hexal infusion is complete, the line may be used for administration of other intravenous products.

Blood products and short-term infusion of concentrated solutions of electrolytes: Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation of Voriconazol Hexal therapy. Voriconazol Hexal must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines.

Total parenteral nutrition: Total parenteral nutrition (TPN) need not be discontinued when prescribed with Voriconazol Hexal, but does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for Voriconazol Hexal. Voriconazol Hexal must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.

Film-coated tablets:

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

Powder for solution for infusion:

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

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 Voriconazol Hexal 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

Powder and solvent for solution for infusion:

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

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

Instructions for reconstitution and use:

- This medicinal product is for single use only and any unused solution should be discarded.

- To prepare the Voriconazol Hexal 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 Voriconazol Hexal 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 Voriconazol Hexal powder is reconstituted by using the specially marked syringe provided to remove 19 ml of Voriconazol Hexal solvent for solution for infusion (Sodium Chloride (0.9%)) from the blue port of the infusion bag.

- The Voriconazol Hexal 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 Voriconazol Hexal 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 Voriconazol Hexal 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 Voriconazol Hexal Concentrate

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

Powder for oral suspension:

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

Constitution instructions:

1. Tap the bottle to release the powder.

2. Add 2 measuring cups of water, providing a total volume of 46 ml.

3. Shake the closed bottle vigorously for about 1 minute.

4. Remove child-resistant cap. Press bottle adaptor into the neck of the bottle.

5. Replace the cap.

6. Write the date of expiration of the constituted suspension on the bottle label (the shelf-life of the constituted suspension is 14 days).

Following constitution, the volume of the suspension is 75 ml, providing a usable volume of 70 ml.

Instructions for use:

Shake the closed bottle of constituted suspension for approximately 10 seconds before each use.

Once constituted, Voriconazol Hexal oral suspension should only be administered using the oral syringe supplied with each pack. Refer to the patient leaflet for more detailed instructions for use.

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

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 Voriconazol Hexal. Discard the Voriconazol Hexal 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 below) to obtain a final Voriconazol Hexal solution containing 0.5- 5 mg/ml.

Required Volumes of 10 mg/ml Voriconazol Hexal Concentrate

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