4.1. Therapeutic indications

Levetiracetam Amarox 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.

Levetiracetam 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.

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

4.2. Posology and method of administration

Posology

Levetiracetam Amarox 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.

Partial onset seizures

The recommended dosing for monotherapy (from 16 years of age) and adjunctive therapy is the same; as outlined below.

All indications

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. However, a lower initial dose of 250 mg twice daily may be given based on physician assessment of seizure reduction versus potential side effects. This can be increased to 500 mg twice daily after two weeks.

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 250 mg or 500 mg twice daily increases or decreases every two to four weeks.

Adolescents (12 to 17 years) weighing below 50 kg and children from 4 years of age

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight, age and dose. Refer to Paediatric population section for dosing adjustments based on weight.

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 weighing 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 weighing 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:

Group

Creatinine clearance (ml/min/1.73m2)

Dose and frequency

Normal

Mild

Moderate

Severe

End-stage renal disease patients undergoing dialysis (1)

≥ 80

50-79

30-49

< 30

-

500 to 1,500 mg twice daily

500 to 1,000 mg twice daily

250 to 750 mg twice daily

250 to 500 mg twice daily

500 to 1,000 mg once daily (2)

(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 adolescent patients weighing less than 50 kg with impaired renal function:

Group

Creatinine clearance (ml/min/1.73m2)

Dose and frequency

Children from 4 years and adolescents weighing less than 50 kg

Normal

≥ 80

10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily

Mild

50-79

10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily

Moderate

30-49

5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily

Severe

< 30

5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily

End-stage renal disease patients undergoing dialysis

--

10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (1) (2)

(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 levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.

No data are available.

Adolescents (16 and 17 years of age) weighing 50 kg or more with partial onset seizures with or without secondary generalisation with newly diagnosed epilepsy

Please refer to the above section on Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more.

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 for all indications.

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

Please refer to the above section on Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more for all indications.

Dose recommendations for children and adolescents:

Weight

Starting dose:

10 mg/kg twice daily

Maximum dose:

30 mg/kg twice daily

15 kg (1)

150 mg twice daily

450 mg twice daily

20 kg (1)

200 mg twice daily

600 mg twice daily

25 kg

250 mg twice daily

750 mg twice daily

From 50 kg (2)

500 mg twice daily

1500 mg twice daily

(1) Children 25 kg or less should preferably start the treatment with levetiracetam 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 levetiracetam concentrate for solution for infusion in infants and children less than 4 years have not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.

Method of administration

Levetiracetam Amarox 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 (see section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 (see section 4.2).

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. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8).

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.

Abnormal and aggressive behaviours

Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2.

Worsening of seizures

As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy.

Lack of efficacy or seizure worsening has for example been reported in patients with epilepsy associated with sodium voltage-gated channel alpha subunit 8 (SCN8A) mutations.

Electrocardiogram QT interval prolongation

Rare cases of ECG QT interval prolongation have been observed during the post-marketing surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

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), equivalent to 2.85% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

4.5. Interaction with other medicinal products and other forms of interaction

Antiepileptic medicinal products

Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.

Probenecid

Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.

Methotrexate

Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs

Oral contraceptives and other pharmacokinetics interactions

Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Alcohol

No data on the interaction of levetiracetam with alcohol are available.

4.6. Fertility, pregnancy and lactation

Women of child bearing potential

Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.

Pregnancy

A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not suggest an increase in the risk for major congenital malformations. Limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. Data from two observational population-based registry studies undertaken in largely the same dataset from the Nordic countries and including more than 1000 children born to women with epilepsy prenatally exposed to levetiracetam monotherapy do not suggest an increased risk of autism spectrum disorders or intellectual disability compared to children born to women with epilepsy not exposed to an antiepileptic drug in utero. The mean follow-up time of children in the levetiracetam group was shorter than for the group of children non exposed to any antiepileptic drug (e.g. 4.4 years vs 6.8 years in one of the studies).

Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended.

Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.

Breastfeeding

Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.

However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breast-feeding.

Fertility

No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 levetiracetam intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of levetiracetam intravenous will rely on levetiracetam 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).

MedDRA SOC

Frequency category

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

Nasopharyngitis

Infection

Blood and lymphatic system disorders

Thrombocytopenia, leukopenia

Pancytopenia, neutropenia, agranulocytosis

Immune system disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS)(1), Hypersensitivity (including angioedema and anaphylaxis)

Metabolism and nutrition disorders

Anorexia

Weight decreased, weight increase

Hyponatraemia

Psychiatric disorders

Depression, hostility/ aggression, anxiety, insomnia, nervousness/irritability

Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation

Completed suicide, personality disorder, thinking abnormal, delirium

Obsessive compulsive disorder(2)

Nervous system disorders

Somnolence, headache

Convulsion, balance disorder, dizziness, lethargy, tremor

Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention

Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizures aggravated, Neuroleptic malignant syndrome(3)

Eye disorders

Diplopia, vision blurred

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Electrocardiogram QT prolonged

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea

Pancreatitis

Hepatobiliary disorders

Liver function test abnormal

Hepatic failure, hepatitis

Renal and Urinary Disorders

Acute Kidney injury

Skin and subcutaneous tissue disorders

Rash

Alopecia, eczema, pruritus,

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme

Musculoskeletal and connective tissue disorders

Muscular weakness, myalgia

Rhabdomyolysis and blood creatine phosphokinase increased(3)

General disorders and administration site conditions

Asthenia/fatigue

Injury, poisoning and procedural complications

Injury

(1) See Description of selected adverse reactions.

(2) Very rare cases of development of obsessive-compulsive disorders (OCD) in patients with underlying history of OCD or psychiatric disorders have been observed in post-marketing surveillance.

(3) Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Description of selected adverse reactions

Multiorgan hypersensitivity reactions

Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported rarely in patients treated with levetiracetam. Clinical manifestations may develop 2 to 8 weeks after starting treatment. These reactions are variable in expression, but typically present with fever, rash, facial oedema, lymphadenopathies haematologic abnormalities and can be associated with involvement of different organ systems, mostly the liver. If multiorgan hypersensitivity reaction is suspected, levetiracetam should be discontinued.

The risk of anorexia is higher when levetiracetam is co-administered 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.

Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

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 levetiracetam 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 levetiracetam 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 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: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Symptoms

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