LEVETIRACETAM HOSPIRA

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.

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. 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. 2 Posology and method of administration Posology Levetiracetam 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. 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 […]

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).

Frequency category MedDRA SOC Very common Common Uncommon Rare Very rare Infections and infestations Nasopharyn gitis Infection Blood and lymphatic system disorders Thrombocytop enia, leukopenia Pancytopenia, neutropenia, agranulocytosi s Immune system disorders Drug reaction with eosinophilia and systemic symptoms (DRESS)(1), Hypersensitivit y (including angioedema and anaphylaxis) Metabolism and nutrition disorders Anorexia Weight decreased, weight increase Hyponatraemia Psychiatric disorders Depression, hostility/aggres sion, anxiety, insomnia, nervousness/irr itability Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic Completed suicide, personality disorder, thinking abnormal, delirium Obsessive compulsiv e disorder(2) Frequency category MedDRA SOC Very common Common Uncommon Rare Very rare attack, affect lability/mood swings, agitation Nervous system disorders Somnolence, headache Convulsion, balance disorder, dizziness, lethargy, tremor Amnesia, memory impairment, coordination abnormal/ataxi a, paraesthesia, disturbance in attention Choreoathetosi s, dyskinesia, hyperkinesia, gait disturbance, encephalopath y, seizures aggravated, Neuroleptic malignant syndrome(3) Eye disorders Diplopia, vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Electrocardiog ram QT prolonged Respiratory, thoracic and mediastinal disorders Cough Gastrointesti nal disorders Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea Pancreatitis Hepatobiliar y disorders Liver function test abnormal Hepatic failure, hepatitis Skin and subcutaneou s tissue disorders Rash Alopecia, eczema, pruritus Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme Musculoskel etal and connective Muscular weakness, myalgia Rhabdomyolys is and blood creatine Frequency category MedDRA SOC Very common Common Uncommon Rare Very rare tissue disorders phosphokinase increased(3) Renal and urinary disorders Acute kidney injury General disorders and administrati on site conditions Asthenia/fatigu e Injury, poisoning and procedural complication s 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 authorisation 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 […]

Renal impairment The administration of levetiracetam to patients with renal impairment may require dose adjustment. 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.

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. 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.

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.

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