Tirbas

Tirbas Beacon is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.

Tirbas Beacon is indicated as adjunctive therapy

- in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.

- in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

- in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

Tirbas Beacon concentrate is an alternative for patients when oral administration is temporarily not feasible.

Tirbas is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.

Tirbas is indicated as adjunctive therapy

- in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.

- in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

- in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

Tirbas concentrate is an alternative for patients when oral administration is temporarily not feasible.

Posology

Tirbas Beacon therapy can be initiated with either intravenous or oral administration. Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.

Monotherapy for adults and adolescents from 16 years of age

The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy for Adults (>18 years) and adolescents (12 to 17 years) weighing 50 kg or more

The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.

Duration of treatment

There is no experience with administration of intravenous Tirbas for longer period than 4 days.

Discontinuation

If Tirbas has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).

Special populations

Elderly (65 years and older)

Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).

Renal impairment

The daily dose must be individualised according to renal function.

For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function:

⁽¹⁾ A 750 mg loading dose is recommended on the first day of treatment with Tirbas.

⁽²⁾ Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For children with renal impairment, Tirbas dose needs to be adjusted based on the renal function as Tirbas clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

The CLcr in ml/min/1.73 m² may be estimated from serum creatinine (mg/dl) determination, for young adolescents and children, using the following formula (Schwartz formula):

ks=0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male

Dosing adjustment for children and adolescents patients weighing less than 50 kg with impaired renal function:

⁽¹⁾ A 15mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with Tirbas.

⁽²⁾ Following dialysis, a 5 to 10 mg (0.05 to 0.1 ml/kg) supplemental dose is recommended.

Hepatic impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73m².

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.

Monotherapy

The safety and efficacy of Tirbas in children and adolescents below 16 years as monotherapy treatment have not been established.

No data are available.

Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg

The initial therapeutic dose is 10 mg/kg twice daily.

Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.

Dose in children 50 kg or greater is the same as in adults.

Dose recommendations for children and adolescents:

⁽¹⁾ Children 25 kg or less should preferably start the treatment with Tirbas 100 mg/ml oral solution.

⁽²⁾ Dose in children and adolescents 50 kg or more is the same as in adults.

Add-on therapy for infants and children less than 4 years.

The safety and efficacy of Tirbas concentrate for solution for infusion in infants and children less than 4 years have not been established.

Method of administration

Tirbas Beacon concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion.

Posology

Tirbas therapy can be initiated with either intravenous or oral administration.

Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.

Monotherapy for adults and adolescents from 16 years of age

The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy for adults (>18 years) and adolescents (12 to 17 years) weighing 50 kg or more

The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.

Duration of treatment

There is no experience with administration of intravenous levetiracetam for longer period than 4 days.

Discontinuation

If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).

Special populations

Elderly (65 years and older)

Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).

Renal impairment

The daily dose must be individualised according to renal function.

For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function:

⁽¹⁾ A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.

⁽²⁾ Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination, for young adolescents and children using the following formula (Schwartz formula):

ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male

Dosing adjustment for children and adolescents patients weighing less than 50 kg with impaired renal function:

⁽¹⁾ A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.

⁽²⁾ Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.

Hepatic impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73 m².

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.

Monotherapy

The safety and efficacy of Tirbas in children below and adolescents 16 years as monotherapy treatment have not been established.

No data are available.

Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg

The initial therapeutic dose is 10 mg/kg twice daily.

Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.

Dose in children 50 kg or greater is the same as in adults.

Dose recommendations for children and adolescents:

⁽¹⁾ Children 25 kg or less should preferably start the treatment with Tirbas 100 mg/ml oral solution.

⁽²⁾ Dose in children and adolescents 50 kg or more is the same as in adults.

Add-on therapy for infants and children less than 4 years

The safety and efficacy of Tirbas concentrate for solution for infusion in infants and children less than 4 years have not been established.

Method of administration

Tirbas concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion.

Renal impairment

The administration of Tirbas to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute Kidney injury

The use of Tirbas has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.

Blood cell counts

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with Tirbas administration, generally at the beginning of the treatment.)

Suicide

Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including Tirbas). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.

Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population

Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Excipients

Tirbas Beacon contains 2.6 mmol (or 59.82 mg) sodium per maximum single dose [or 0.867 mmol (or 19.94 mg) per vial]. To be taken into consideration by patients on a controlled sodium diet.

Renal impairment

The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.

Acute Kidney injury

The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.

Blood cell counts

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment.).

Suicide

Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam. A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.

Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population

Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Excipients

This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose (0.8 mmol (or 19 mg) per vial). To be taken into consideration by patients on a controlled sodium diet.

Tirbas has minor or moderate influence on the ability to drive and use machines. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.

Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.

Summary of the safety profile

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with Tirbas. These data are supplemented with the use of Tirbas in corresponding open-label extension studies, as well as post-marketing experience. The safety profile of Tirbas is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications. Since there was limited exposure for Tirbas intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Tirbas intravenous will rely on Tirbas oral use.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: 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) and very rare (<1/10,000).

* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Cases of encephalopathy have been rarely observed after Tirbas administration. These undesirable effects generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

Description of selected adverse reactions

The risk of anorexia is higher when Tirbas is co-administered with topiramate.

In several cases of alopecia, recovery was observed when Tirbas was discontinued.

Bone marrow suppression was identified in some of the cases of pancytopenia.

Paediatric population

In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with Tirbas in placebo-controlled and open label extension studies. Sixty of these patients were treated with Tirbas in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with Tirbas in placebo-controlled and open label extension studies. 233 of these patients were treated with Tirbas in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of Tirbas.

In addition, 101 infants aged less than 12 months have been exposed in a post authorization safety study. No new safety concerns for Tirbas were identified for infants less than 12 months of age with epilepsy.

The adverse reaction profile of Tirbas is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of Tirbas in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.

A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of Tirbas in children 4 to 16 years of age with partial onset seizures. It was concluded that Tirbas was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in Tirbas treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL - Achenbach Child Behavior Checklist). However subjects, who took Tirbas in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.

Reporting of suspected adverse reactions

Reporting of 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 (www.mhra.gov.uk/yellowcard).

Summary of the safety profile

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness.The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications. Since there was limited exposure for Tirbas intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Tirbas intravenous will rely on Tirbas oral use.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: 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) and very rare (<1/10,000).

* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Cases of encephalopathy have been rarely observed after levetiracetam administration. These undesirable effects generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

Description of selected adverse reactions

The risk of anorexia is higher when levetiracetam is coadministered with topiramate.

In several cases of alopecia, recovery was observed when levetiracetam was discontinued.

Bone marrow suppression was identified in some of the cases of pancytopenia.

Paediatric population

In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.

In addition, 101 infants aged less than 12 months have been exposed in a post authorization safety study. No new safety concerns for levetiracetam were identified for infants less than 12 months of age with epilepsy.

The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.

A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that Tirbas was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetamtreated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL - Achenbach Child Behavior Checklist). However subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.

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 national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Symptoms

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Tirbas overdoses.

Management of overdose

There is no specific antidote for Tirbas. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for Tirbas and 74 % for the primary metabolite.

Symptoms

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Tirbas overdoses.

Management of overdose

There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.

The active substance, Tirbas, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.

Mechanism of action

The mechanism of action of Tirbas still remains to be fully elucidated. In vitro and in vivo experiments suggest that Tirbas does not alter basic cell characteristics and normal neurotransmission.

In vitro studies show that Tirbas affects intraneuronal Ca²⁺ levels by partial inhibition of N-type Ca²⁺ currents and by reducing the release of Ca²⁺ from intraneuronal stores. In addition it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, Tirbas has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Tirbas and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between Tirbas and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.

Pharmacodynamic effects

Tirbas induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.

In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of Tirbas.

Clinical efficacy and safety

Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy:

In adults, Tirbas efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50% or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7%, 31.6% and 41.3% for patients on 1000, 2000 or 3000 mg Tirbas respectively and of 12.6% for patients on placebo.

Paediatric population

In paediatric patients (4 to 16 years of age), Tirbas efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received Tirbas as a fixed dose of 60 mg/kg/day (with twice a day dosing).

44.6% of the Tirbas treated patients and 19.6% of the patients on placebo had a 50% or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4% of the patients were seizure-free for at least 6 months and 7.2% were seizure-free for at least 1 year.

35 infants aged less than 1 year with partial onset seizures have been exposed in placebo-control clinical studies of which only 13 were aged < 6 months.

Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.

Efficacy of Tirbas as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 - 1200 mg/day or Tirbas 1000 - 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response.

Six-month seizure freedom was achieved in 73.0% of Tirbas-treated patients and 72.8% of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95% CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6% and 58.5% of subjects on Tirbas and on carbamazepine CR respectively).

In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to Tirbas adjunctive therapy (36 adult patients out of 69).

Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

Tirbas efficacy was established in a double-blind, placebo-controlled study of 16 weeks duration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy with myoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonic epilepsy.

In this study, Tirbas, dose was 3000 mg/day given in 2 divided doses.

58.3% of the Tirbas treated patients and 23.3% of the patients on placebo had at least a 50% reduction in myoclonic seizure days per week. With continued long-term treatment, 28.6% of the patients were free of myoclonic seizures for at least 6 months and 21.0% were free of myoclonic seizures for at least 1 year.

Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy.

Tirbas efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, Tirbas dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.

72.2% of the Tirbas treated patients and 45.2% of the patients on placebo had a 50% or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4% of the patients were free of tonic-clonic seizures for at least 6 months and 31.5% were free of tonic-clonic seizures for at least 1 year.

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.

The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.

Mechanism of action

The mechanism of action of levetiracetam still remains to be fully elucidated. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.

In vitro studies show that levetiracetam affects intraneuronal Ca²⁺ levels by partial inhibition of N-type Ca²⁺ currents and by reducing the release of Ca²⁺ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.

Pharmacodynamic effects

Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.

In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.

Clinical efficacy and safety

Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 4 years of age with epilepsy.

In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6 % for patients on placebo.

Paediatric population

In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).

44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4 % of the patients were seizure-free for at least 6 months and 7.2 % were seizure-free for at least 1 year.

35 infants aged less than 1 year with partial onset seizures have been exposed in placebo-control clinical studies of which only 13 were aged < 6 months.

Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.

Efficacy of levetiracetam as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 - 1200 mg/day or levetiracetam 1000 - 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response.

Six-month seizure freedom was achieved in 73.0 % of levetiracetam-treated patients and 72.8 % of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95 % CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6 % and 58.5 % of subjects on levetiracetam and on carbamazepine CR respectively).

In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients out of 69).

Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

Levetiracetam efficacy was established in a double-blind, placebo-controlled study of 16 weeks duration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy with myoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonic epilepsy.

In this study, levetiracetam, dose was 3000 mg/day given in 2 divided doses.

58.3 % of the levetiracetam treated patients and 23.3 % of the patients on placebo had at least a 50 % reduction in myoclonic seizure days per week. With continued long-term treatment, 28.6 % of the patients were free of myoclonic seizures for at least 6 months and 21.0 % were free of myoclonic seizures for at least 1 year.

Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy.

Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, levetiracetam dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.

72.2 % of the levetiracetam treated patients and 45.2 % of the patients on placebo had a 50 % or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4 % of the patients were free of tonic-clonic seizures for at least 6 months and 31.5 % were free of tonic-clonic seizures for at least 1 year.

The pharmacokinetic profile has been characterized following oral administration. A single dose of 1500 mg Tirbas diluted in 100 ml of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg Tirbas oral intake, given as three 500 mg tablets.

The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9% sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9% sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns.

Tirbas is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. The time independent pharmacokinetic profile of Tirbas was also confirmed following 1500 mg intravenous infusion for 4 days with twice daily dosing.

There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.

Adults and adolescents

Distribution

Peak plasma concentration (C_max) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 μg/ml (arithmetic average ± standard deviation).

No tissue distribution data are available in humans.

Neither Tirbas nor its primary metabolite are significantly bound to plasma proteins (< 10 %). The volume of distribution of Tirbas is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.

Biotransformation

Tirbas is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P₄₅₀ isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose). Other unidentified components accounted only for 0.6 % of the dose.

No enantiomeric interconversion was evidenced in vivo for either Tirbas or its primary metabolite.

In vitro, Tirbas and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 AND UGT1A6) and epoxide hydroxylase activities. In addition, Tirbas does not affect the in vitro glucuronidation of valproic acid.

In human hepatocytes in culture, Tirbas had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Tirbas caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of Tirbas with other substances, or vice versa, is unlikely.

Elimination

The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.

The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.

The cumulative urinary excretion of Tirbas and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.

The renal clearance of Tirbas and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that Tirbas is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Tirbas elimination is correlated to creatinine clearance.

Elderly

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population.

Renal impairment

The apparent body clearance of both Tirbas and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Tirbas, based on creatinine clearance in patients with moderate and severe renal impairment.

In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.

The fractional removal of Tirbas was 51 % during a typical 4-hour dialysis session.

Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of Tirbas. In most subjects with severe hepatic impairment, the clearance of Tirbas was reduced by more than 50 % due to a concomitant renal impairment.

Paediatric population

Children (4 to 12 years)

The pharmacokinetics in paediatric patients has not been investigated after intravenous administration. However, based on the pharmacokinetic characteristics of Tirbas, the pharmacokinetics in adults after intravenous administration and the pharmacokinetics in children after oral administration, the exposure (AUC) of Tirbas is expected to be similar in paediatric patients aged 4 to 12 years after intravenous and oral administration.

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of Tirbas was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), Tirbas was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

The pharmacokinetic profile has been characterized following oral administration. A single dose of 1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as three 500 mg tablets.

The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9 % sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9 % sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns.

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. The time independent pharmacokinetic profile of levetiracetam was also confirmed following 1500 mg intravenous infusion for 4 days with twice daily dosing.

There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.

Adults and adolescents

Distribution

Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 µg/ml (arithmetic average ± standard deviation).

No tissue distribution data are available in humans.

Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).

The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.

Biotransformation

Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P₄₅₀ isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose).

Other unidentified components accounted only for 0.6 % of the dose.

No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.

In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P₄₅₀ isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of Tirbas with other substances, or vice versa, is unlikely.

Elimination

The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.

The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.

The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.

Elderly

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population.

Renal impairment

The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Tirbas, based on creatinine clearance in patients with moderate and severe renal impairment.

In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.

The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.

Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50 % due to a concomitant renal impairment.

Paediatric population

Children (4 to 12 years)

The pharmacokinetics in paediatric patients has not been investigated after intravenous administration. However, based on the pharmacokinetic characteristics of levetiracetam, the pharmacokinetics in adults after intravenous administration and the pharmacokinetics in children after oral administration, the exposure (AUC) of levetiracetam is expected to be similar in paediatric patients aged 4 to 12 years after intravenous and oral administration.

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.

No adverse reactionson male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.

Two embryo-foetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in foetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for foetuses.

Four embryo-foetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in foetal weight associated with increased incidence of foetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the foetuses (equal to the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with Tirbas doses of 70, 350 and 1800 mg/kg/day. The NOAEL was > 1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis).

Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6- 17 the MRHD on a mg/m2 basis).

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.

No adverse reactions on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.

Two embryo-foetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in foetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for fetuses.

Four embryo-foetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in foetal weight associated with increased incidence of fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was > 1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning.(x 6 the MRHD on a mg/m2 basis).

Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6-17 the MRHD on a mg/m2 basis)

See Table 1 for the recommended preparation and administration of Tirbas Beacon concentrate for solution for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg, or 3000 mg in two divided doses.

Table 1. Preparation and administration of Tirbas Beacon concentrate for solution for infusion.

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

Tirbas Beacon concentrate for solution for infusion was found to be physically compatible and chemically stable for at least 24 hours when mixed with the following diluents and stored in PVC bags at controlled room temperature 15-25°C.

Diluents:

- Sodium chloride 9 mg/ml (0.9%) solution for injection - Lactated Ringer's solution for injection

- Dextrose 50 mg/ml (5%) solution for injection

Medicinal product with particulate matter or discoloration should not be used.

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

See Table 1 for the recommended preparation and administration of Tirbas concentrate for solution for infusion to achieve a total daily dose of 500 mg, 1,000 mg, 2,000 mg, or 3,000 mg in two divided doses.

Table 1. Preparation and administration of Tirbas concentrate for solution for infusion

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

Tirbas concentrate for solution for infusion was found to be physically compatible and chemically stable for at least 24 hours when mixed with the following diluents and stored in PVC bags at controlled room temperature 15-25 °C.

Diluents:

- Sodium chloride 9 mg/ml (0.9%) solution for injection

- Lactated Ringer's solution for injection

- Dextrose 50 mg/ml (5%) solution for injection

Medicinal product with particulate matter or discoloration should not be used.

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