Levetiracetam TBM is indicated as adjunctive therapy

• in the treatment of partial onset seizures with or without secondary generalisation in

  adults, adolescents and children from 1 month 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 6 years of age with idiopathic generalised epilepsy.
  Levetiracetam TBM concentrate is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

1. Dosing for Partial Onset Seizures
   Adults 16 Years and Older

   Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2

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weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Paediatric Patients

1 Month to < 6 Months
Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group. The effectiveness of lower doses has not been studied.

6 Months to < 4 Years
Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily). If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

4 Years to < 16 Years
Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day.

Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

Dosing for Primary Generalized Tonic-Clonic Seizures

Adults 16 Years and Older

Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately

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studied.

Levetiracetam injection, 100 mg/mL

Paediatric Patients Ages 6 to <16 Years

Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

Switching from Oral Dosing

When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetirace ta m.

Switching to Oral Dosing

At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous
administr at io n.

Preparation and Method of administration

Levetiracetam TBM for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration. If a smaller volume is required (e.g. paediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution. Consideration should also be given to the total daily fluid intake of the patient. Levetiracetam TBM should be administered as a 15- minute IV infusion. One vial of Levetiracetam TBM contains 500 mg levetiracetam (500 mg/5 mL). For instructions on preparation of the medicinal product before administration, see section 6.6.

Paediatric Patients
When using Levetiracetam TBM for paediatric patients, dosing is weight-based (mg per kg). The following calculation should be used to determine the appropriate daily dose of Levetiracetam TBM for paediatric patients:
Total daily dose (mL/day) = Daily dose (mg/kg/day) x Patient weight (Kg)

100 mg/mL

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Dosage Adjustments in Adult Patients with Renal Impairment

Levetiracetam TBM dosing must be individualised according to the patient's renal function status. Recommended dosage adjustments for adults with renal impairment are shown in Table 1. Information is unavailable for dosage adjustments in paediatric patients with renal impairment. In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

CLcr= [140-age (years)] × weight (kg) (× 0.85 for female patients) 72 × serum creatinine (mg/dL)

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

CLcr (mL/min/1.73m2)= CLcr (mL/min) × 1.73

Table 1: Dose adjustment regimen for adult patient with renal impairment

2 BSA subject (m )

Group

Normal
Mild
Moderate
Severe
ESRD patients using dialysis

Creatinine Clearance (mL/min/1.73 m2 ) >80
50-80
30-50
<30
----

Dosage

500 to 1500 500 to 1500 250 to 750 250 to 750 500 to 1000*

Frequency

Every 12 hours Every 12 hours Every 12 hours Every 12 hours Every 24 hours *

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*Following dialysis, a 250 to 500 mg supplemental dose is recommended.

Behavioural Abnormalities and Psychotic Symptoms

Levetiracetam injection, 100 mg/mL

Levetiracetam may cause behavioural abnormalities and psychotic symptoms. Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms.

Behavioural abnormalities
In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam- treated patients and 38% of paediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and paediatric placebo-treated patients, experienced non- psychotic behavioural symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).

A randomised, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioural effects of an oral formulation of levetiracetam as adjunctive therapy in paediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in Levetiracetam-treated patients on aggressive behaviour (one of eight behaviour dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behaviour Checklist (CBCL/6-18).

In clinical studies in paediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioural adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo- treated patients. Overall, 11% of Levetiracetam-treated paediatric patients experienced behavioural symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.

Psychotic symptoms
In clinical studies using an oral formulation of Levetiracetam, 1% of Levetiracetam -treated adult patients, 2% of Levetiracetam -treated paediatric patients 4 to 16 years of age, and 17% of Levetiracetam-treated paediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioural effects of an oral formulation of Levetiracetam in paediatric patients 4 to 16 years of age, 1.6% of Levetiracetam -treated patients experienced paranoia, compared to 0% of placebo-treated

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patients. In the same study, 3.1% of Levetiracetam -treated patients experienced confusional state, compared to 0% of placebo-treated patients.
In clinical studies, two (0.3%) Levetiracetam-treated adult patients were hospitalised, and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug- and placebo-treated patients in the incidence of the paediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.

Somnolence and Fatigue

Somnolence
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving Levetiracetam 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group. About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of Levetiracetam-treated patients and 0.9% of placebo- treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalised due to somnolence.
Asthenia
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the paediatric partial onset seizure studies, and in paediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.

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Anaphylaxis and Angioedema

Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the post marketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, Levetiracetam should be discontinued and the patient should seek immediate medical attention. Levetiracetam should be discontinued permanently if a clear alternative aetiology for the reaction cannot be established. (see section 4.3)

Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both paediatric and adult patients treated with Levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following re-challenge with Levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Coordination Difficulties

Levetiracetam may cause coordination difficulties. In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled clinical studies discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalised due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect their ability to drive or operate machine r y.

Levetiracetam injection, 100 mg/mL

Withdrawal Seizures

Antiepileptic drugs, including Levetiracetam TBM, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalities

Levetiracetam TBM can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cells counts (RBC); decreases in haemoglobin and haematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the post-marketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

Partial Onset Seizures
Adults
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 × 10 /mm), mean haemoglobin (0.09 g/dL), and mean haematocrit (0.38%), were seen in Levetiracetam-treated patients.
A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 × 10 /L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 × 10 /L) decreased neutrophil count. Of the Levetiracetam-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Paediatric Patients 4 Years to < 16 Years
In a controlled study in paediatric patients age 4 years to <16 years, statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam-treated patients, as compared to placebo. The mean decreases from baseline in the Levetiracetam-treated group were -0.4 × 10 /L and -0.3 × 10 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant). More Levetiracetam-treated patients had a possibly clinically significant abnormally low

Levetiracetam injection, 100 mg/mL

WBC value (3% of Levetiracetam-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with res pect to neutrophil count (5% on Levetiracetam versus 4.2% on placebo). No patient was discontinued because of low WBC or neutrophil count. In a randomised, double-blind, placebo-controlled study to assess the neurocognitive and behavioural effects of an oral formulation of Levetiracetam as adjunctive therapy in paediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7×10 /L).

Increase in Blood Pressure

In a randomised, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to placebo- treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the Levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults. Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.

Seizure Control During Pregnancy

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive,

Levetiracetam injection, 100 mg/mL

probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

Phenytoin
Levetiracetam (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam was also not affected by phenytoin.

Valproate
Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, levetiracetam.

Other Antiepileptic Drugs
Potential drug interactions between Levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics oflevetiracetam.

Effect of AEDs in Paediatric Patients
There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with enzyme-inducing AEDs. Dose adjustment is not recommended. Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

Oral Contraceptives
Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Co-administration of this oral contraceptive did not influence the pharmacokinetics oflevetiracetam.

Levetiracetam injection, 100 mg/mL

Digoxin
Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Co-administration of digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin
Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Co-administration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid
Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. Cssmax of the metabolite, levetiracetam, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of levetiracetam in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of levetiracetam. The effect of Levetiracetam on probenecid was not studied.

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

Pregnancy
Levetiracetam blood levels may decrease during pregnancy.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor foetal skeletal abnormalities and retarded offspring growth pre-

and/or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m basis) and with increased pup mortality and offspring behavioural alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m basis). There was no overt maternal toxicity at the doses used in this study.

Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofoetal mortality and increased incidences of minor foetal skeletal abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m basis) and in decreased foetal weights and increased incidences of foetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m basis). Maternal toxicity was also observed at 1800 mg/kg/day.

When levetiracetam was administered orally to pregnant rats during the period of organogenesis, foetal weights were decreased and the incidence of foetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.

Treatment of rats during the last third of gestation and throughout lactation produced no

adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the

2 MRHD on a mg/m basis).

Labour and Delivery
The effect of Levetiracetam on labour and delivery in humans is unknown.

Lactation
Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Levetiracetam may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue and be advised not to drive or operate machinery until they have

gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

The following adverse reactions are discussed in more details in section 4.4 Special warnings and precautions for use:

• Behavioural Abnormalities and Psychotic Symptoms

• Somnolence and Fatigue

• Anaphyla xis and Angioede ma

• Serious Dermatological Reactions

• Coordination Difficulties

• Hematologic Abnormalities

• Increase in Blood Pressure

  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 postmarketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented (Table 2) 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).

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System Organ Class

Infections and infestations

Ve ry common Nasopharyng itis

Common

Frequency category
Uncommon Rare

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Eye disorders

Ear and labyrinth disorders

Diplopia, vision blurred

Infection

Vertigo

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System Organ Class

Hepatobiliary disorders
Renal and Urinary Disorder

Ve ry common

Common

Frequency category Uncommon

Liver function test abnormal

Rare

Hepatic failure, hepatitis
Acute Kidney injury

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*Prevalenceissignificantly higherinJapanesepatientswhencomparedtonon-Japanesepatients.

Pediatric

The safety and effectiveness of levetiracetam in the adjunctive treatment of partial onset seizures in paediatric patients age 1 month to 16 years with epilepsy have been established. (see section 5). The dosing recommendation in these paediatric patients varies according to age group and is weight-based (see section 4.2).

The safety and effectiveness of levetiracetam as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established. (see section 5)
The safety and effectiveness of levetiracetam as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in paediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established (see section 5)

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the

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neurocognitive and behavioural effects of levetiracetam as adjunctive therapy in 98 (levetiracetam N=64, placebo N=34) paediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention.

Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical noninferiority of the drug and placebo. The Achenbach Child Behaviour Checklist (CBCL/6-18), a standardized validated tool used to assess a child's competencies and behavioural/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated, on average, a worsening in levetiracetam -treated patients in aggressive behaviour, one of the eight syndrome scores (see section 4.4).

Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended paediatric dose of 60 mg/kg/day on a mg/m basis) did not indicate a potential for age-specific toxicity.

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.

Geriatric Use
There were 347 subjects in clinical studies of levetiracetam that were 65 years old and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam injection in these patients.
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (see section 5)

Renal Impairment
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance (see section 5). Dosage adjustment is recommended for patients

Levetiracetam injection, 100 mg/mL

with impaired renal function and supplemental doses should be given to patients after dialysis (see section 4.2).

To reports any side effect(s):

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 to the competent authority in Saudi Arabia as per details below:

• Saudi Arabia

The National Pharmacovigilance and Drug Safety Centre (NPC)

• -  Fax: +966-11-205-7662

• -  Call NPC at +966-11-2038222, Ext 2317-2356-2340

• -  SFDA Call Center: 19999

• -  E-mail: npc.drug@sfda.gov.sa

• -  Website: https://ade.sfda.gov.sa/

The highest known dose of oral levetirace ta m received in the clinica l development program was 6000 mg/day. Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma were observed with levetiracetam overdoses.

Management ofoverdose
There is no specific antidote for levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient's clinical status. Treatment of the overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite. A Certified Poison Control Centre should be contacted for up to date information on the management of overdose with levetiracetam.

General properties
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

All clinical studies supporting the efficacy of levetiracetam utilized oral formulations. The finding of efficacy of levetiracetam injection is based on the results of studies using an oral formulation of levetiracetam and on the demonstration of comparable bioavailability of the oral and parenteral formulations.

General properties
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

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Levetiracetam injection, 100 mg/mL

All clinical studies supporting the efficacy of levetiracetam utilized oral formulations. The finding of efficacy of levetiracetam injection is based on the results of studies using an oral formulation of levetiracetam and on the demonstration of comparable bioavailability of the oral and parenteral formulations.

1. Partial Onset Seizures

Effectiveness in Partial Onset Seizures in Adults with Epilepsy

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicentre, randomised, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization. The tablet formulation was used in all these studies. In these studies, 904 patients were randomised to placebo, 1000 mg, 2000 mg, or 3000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.

Study 1

Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing levetiracetam 1000 mg/day (N=97), levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients were randomised to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Study 1 are displayed in Table 3.

Levetiracetam injection, 100 mg/mL

Table 3: Reduction in Mean over Placebo in Weekly Frequency of Partial Onset Seizures in

Study 1

Placebo Levetiracetam Levetiracetam
(N=95) 1000 mg/day (N=97) 3000 mg/day (N=101)

*statistically significant versus placebo
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.

Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1

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Study 2

Levetiracetam
1000 mg/day (N=97)

Placebo (N=95)

*statistically significant versus placebo

Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centres in Europe comparing levetiracetam 1000 mg/day (N=106), levetiracetam 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily.
The first period of the study (Period A) was designed to be analysed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients were randomised to one

Levetiracetam
3000 mg/day (N=101)

Levetiracetam injection, 100 mg/mL

of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 4.

Table 4: Reduction in Mean over Placebo in Weekly Frequency of Partial Onset Seizures in Study 2

Placebo Levetiracetam Levetiracetam (N=111) 1000 mg/day (N=106) 3000 mg/day (N=105)

*statistically significant versus placebo

The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.

Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A

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Levetiracetam injection, 100 mg/mL

Placebo (N=111) Levetiracetam 1000 mg/day

(N=106) *statistically significant versus placebo

Levetiracetam 3000 mg/day (N=105)

The comparison of levetiracetam 2000 mg/day to levetiracetam 1000 mg/day for responder rate was statistically significant (P=0.02). Analysis of the trial as a cross-over yielded similar results.

Study 3

Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centres in Europe comparing levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients were randomised to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). Table 5 displays the results of the analysis of Study 3.

Levetiracetam injection, 100 mg/mL

Table 5: Reduction in Mean over Placebo in Weekly Frequency of Partial Onset Seizures in Study 3

Placebo Levetiracetam (N=104) 3000 mg/day (N=180)

*statistically significant versus placebo
The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure

3.
Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3

Placebo (N=104)

* statistically significant versus placebo

Effectiveness in Partial Onset Seizures in Paediatric Patients 4 Years to 16 Years with Epilepsy
Study 4 was a multicentre, randomised double-blind, placebo-controlled study, in paediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Study 4 was conducted at 60 sites in North America. The study consisted of an 8- week baseline period and 4-week titration period followed by a 10-week evaluation period. Eligible patients who still experienced, on a stable dose of 1-2 AEDs, at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomised to receive either levetiracetam or placebo. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2- week

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Levetiracetam 3000 mg/day (N=180)

Levetiracetam injection, 100 mg/mL

intervals to the target dose of 60 mg/kg/day. The primary measure of efficacy was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). The enrolled population included 198 patients (levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalised. Table 6 displays the results of Study 4.

Table 6: Reduction in Mean over Placebo in Weekly Frequency of Partial Onset Seizures in Study 4

Placebo Levetiracetam
(N=97) 3000 mg/day (N=101)

*statistically significant versus placebo
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.
Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4

*statistically significant versus placebo

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Levetiracetam injection, 100 mg/mL

Effectiveness in Partial Onset Seizures in Paediatric Patients 1 Month to <4 Years with Epilepsy
Study 5 was a multicentre, randomised double-blind, placebo-controlled study, in paediatric patients 1 month to less than 4 years of age with partial seizures, uncontrolled by standard epileptic drugs (AEDs). Study 5 was conducted at 62 sites in North America, South America, and Europe. Study 5 consisted of a 5-day evaluation period, which included a 1-day titration period followed by a 4-day maintenance period. Eligible patients who experienced, on a stable dose of 1-2 AEDs, at least 2 partial onset seizures during the 48-hour baseline video EEG were randomised to receive either levetiracetam or placebo. Randomisation was stratified by age range as follows: 1 month to less than 6 months of age (N=4 treated with levetiracetam), 6 months to less than 1 year of age (N=8 treated levetiracetam), 1 year to less than 2 years of age (N=20 treated with levetiracetam), and 2 years to less than 4 years of age (N=28 treated with levetiracetam). Levetiracetam dosing was determined by age and weight as follows: children 1 month to less than 6 months old were randomised to a target dose of 40 mg/kg/day, and children 6 months to less than 4 years old were randomised to a target dose of 50 mg/kg/day. The primary measure of efficacy was the responder rate (percent of patients with ≥ 50% reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG performed during the last two days of the 4-day maintenance period. The enrolled population included 116 patients (levetiracetam N=60, placebo N=56) with refractory partial onset seizures, whether or not secondarily generalized. A total of 109 patients were included in the efficacy analysis. A statistically significant difference between levetiracetam and placebo was observed in Study 5 (see Figure 5). The treatment effect associated with levetiracetam was consistent across age groups.

Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5

Levetiracetam injection, 100 mg/mL

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Placebo (N=51)

*statistically significant versus placebo

Levetiracetam (N=58)

2. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Study 6 was a multicentre, randomised, double-blind, placebo-controlled study in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures. Study 6 was conducted at 37 sites in 14 countries. Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomised to either levetiracetam or placebo (levetiracetam N=60, placebo N=60).

Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses. The primary measure of efficacy was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 14 displays the results for the 113 patients with JME in this study. Of 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. The results of Study 6 are displayed in Table 7.

Levetiracetam injection, 100 mg/mL

Table 7: Responder Rate (≥50% Reduction from Baseline) in Myoclonic Seizure Days per Week in Study 6

Placebo (N=59) Levetiracetam (N=54)

*statistically significant versus placebo

3. Primary Generalized Tonic-Clonic Seizures

Effectiveness in Primary Generalized Tonic-Clonic Seizures in Patients ≥6 years of age
Study 7 was a multicentre, randomised, double-blind, placebo-controlled study in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures. Study 7 was conducted at 50 sites in 8 countries. Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4- week prospective baseline period) were randomised to either levetiracetam or placebo. The 8- week combined baseline period is referred to as "baseline" in the remainder of this section. Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a paediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day. The primary measure of efficacy was the percent reduction from baseline in weekly PGTC seizure frequency for levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). The population included 164 patients (levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures. Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population.
There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam -treated patients compared to the placebo-treated patients in Study 7 (see Table 15).

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Levetiracetam injection, 100 mg/mL

Table 8: Median Percent Reduction from Baseline in PGTC Seizure Frequency per Week in Study 7

Placebo (N=84) Levetiracetam (N=78)

*statistically significant versus placebo

The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 6.

Figure 6: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7

Placebo (N=84)

* statistically significant versus placebo

5.2Pharmacokinetics effect

Levetiracetam (N=79)

Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered asa15-minute infusion.

Levetiracetam injection, 100 mg/mL

The pharmacokinetics of levetiracetam has been studied in healthy adult subjects, adults and paediatric patients with epilepsy, elderly subjects, and subjects with renal and hepatic impair me nt.

Overview
Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam injection and tablets are bioequivalent. The pharmacokinetics of levetiracetam are linear and time invariant, with low intra- and inter-subject variability. Levetiracetam is not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half- life of levetiracetam across studies is approximately 6-8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.

Distribut io n
The equivalence of levetiracetam injection and the oral formulation was demonstrated in a bioavailability study of 17 healthy volunteers. In this study, levetiracetam 1500 mg was diluted in 100 mL 0.9% sterile saline solution and was infused over 15 minutes. The selected infusion rate provided plasma concentrations of levetiracetam at the end of the infusion period similar to those achieved at Tmax after an equivalent oral dose. It is demonstrated that levetiracetam 1500 mg intravenous infusion is equivalent to levetiracetam 3 × 500 mg oral tablets. The time independent pharmacokinetic profile of levetiracetam was demonstrated following 1500 mg intravenous infusion for 4 days with BID dosing. The AUC at steady- state was equivalent to AUC following an equivalent single dose.
Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

Metabolism
Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, levetiracetam (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes.

Levetiracetam injection, 100 mg/mL

The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

Elimi nat io n
Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose, route of administration or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite levetiracetam is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with renal impairment.

Specific Populations

Elderly

Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age 61-88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.

Paediatric Patients

Intravenous Formulation
A population pharmacokinetic analysis for the intravenous formulation was conducted in 49 paediatric patients (1 month to < 16 years of age) weighing 3-79 kg. Patients received levetiracetam as a 15-minute IV infusion at doses between 14 mg/kg/day and 60 mg/kg/day twice daily. Plasma concentrations and model derived steady-state exposure AUC (0-12) were within the range of the exposure observed in paediatric patients receiving equivalent doses of the oral solution.

Levetiracetam injection, 100 mg/mL

Oral Formulations
Pharmacokinetics of levetiracetam were evaluated in 24 paediatric patients (age 6-12 years) after single oral dose (20 mg/kg) of the immediate release formulation of levetiracetam. The body weight adjusted apparent clearance of levetiracetam was approximately 40% higher than in adults.
A repeat dose pharmacokinetic study was conducted in paediatric patients (age 4-12 years) at doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day of the immediate release formulation of levetiracetam. The evaluation of the pharmacokinetic profile of levetiracetam and its metabolite (ucb L057) in 14 paediatric patients demonstrated rapid absorption of levetiracetam at all doses, with a T of about 1 hour and a t of 5 hours across all dosing levels. The pharmacokinetics of levetiracetam in paediatric patients was linear between 20 to 60 mg/kg/day. The potential interaction of levetiracetam with other AEDs was also evaluated in these patients. Levetiracetam had no significant effect on the plasma concentrations of carbamazepine, valproic acid, topiramate or lamotrigine. However, there was about a 22% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme- inducing AED (e.g., carbamazepine).
Following single dose administration (20 mg/kg) of a 10% oral solution to paediatric patients with epilepsy (1 month to < 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. Levetiracetam half-life in paediatric patients 1 month to < 4 years with epilepsy was shorter (5.3 h) than in adults (7.2 h), and apparent clearance (1.5 mL/min/kg) was faster than in adults (0.96 mL/min/kg). Population pharmacokinetic analysis showed that body weight was significantly correlated to the clearance of levetiracetam in paediatric patients; clearance increased with an increase in body weight

Pregnancy
Levetiracetam levels may decrease during pregnancy.

Gender
Levetiracetam Cmax and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable.

Race
Formal pharmacokinetic studies of the effects of race have not been conducted. Cross-study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of levetiracetam were comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

Renal Impairment
The disposition of levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (CLcr = 50-80 mL/min), 50% in the moderate group (CLcr = 30-50 mL/min) and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance.
In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4 hour haemodialysis procedure

Hepatic Impairment
In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child- Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment

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

2
in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m 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 embryo mortality 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/m 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 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/m 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/m basis)

Sodium Acetate Trihydrate
Sodium Chloride

Glacial Acetic Acid

Water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Do not store above 30°C
For storage conditions after reconstitution of the medicinal product, see section 6.3.

Levetiracetam TBM is a clear and colourless solution containing 100 mg of Levetiracetam per mL. The product is filled as 500 mg in 5 mL USP Type I clear glass vial, stoppered with 20 mm Bromobutyl rubber stoppers and sealed with 20 mm aluminium flip off seals.

Instructions for use: For single use only.
Levetiracetam TBM may be mixed with the following diluents and antiepileptic drugs (AED) and may be stored in polyvinyl chloride (PVC) bags. The diluted solution should not be stored for more than 4 hours at controlled room temperature (15-30°C)

Dilue nts :

• Sodium Chloride 9 mg/ml (0.9%) solution for injection

• Lactated Ringer's solution for injectio n

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

  Other Antiepileptic Drugs:

• Lorazepam

• Diazepam

• Valproate sodium
  There are no data to support the physical compatibility of Levetiracetam TBM with antiepileptic drugs that are not listed above.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.
  Any unused portion of the Levetiracetam TBM vial contents should be discarded.

Adults
The recommended preparation and administration of Levetiracetam TBM for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.

Table 9: Preparation and Administration of Levetiracetam TBM for Adults

Dose 500 mg 1000 mg 1500 mg

Withdraw Volume
5 mL (5 vial)
10 mL (two 5 mL vials) 15 mL (three 5 mL vials)

Volume of Diluent 100 mL
100 mL
100 mL

Infusion Time 15 minutes 15 minutes 15 minutes

For example, to prepare a 1000 mg dose, dilute 10 mL of Levetiracetam TBM in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.