LEVEPSY 250/500/750 Tablets (Levetiracetam)

Table of Content

For the use of a Neurologist only

Qualitative and Quantitative Composition

LEVEPSY 250 Tablets

Each film-coated tablet contains:

Levetiracetam IP…… 250 mg

LEVEPSY 500 Tablets

Each film-coated tablet contains:

Levetiracetam IP …… 500 mg

LEVEPSY 750 Tablets

Each film-coated tablet contains:

Levetiracetam IP………..750 mg

Dosage Form(S) and Strength(S)

250 mg, 500 mg, and 750 mg film-coated tablets

Clinical Particulars

Therapeutic Indications

  • As monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
  • As adjunctive therapy in the following:
  • Treatment of partial-onset seizures in adults with epilepsy.
  • Treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy (JME).

Posology and Method of Administration

Important Administration Instructions

Levetiracetam is given orally with or without food. The levetiracetam dosing regimen depends on the indication, age group, dosage form and renal function.

Levetiracetam should be swallowed whole. Levetiracetam should not be chewed or crushed.

Dosing for Partial-Onset Seizures

The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.

Adults 16 Years of Age and Older

Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

Dosing for Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy

Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been studied.

Dose Adjustments in Adult Patients with Renal Impairment

Levetiracetam dosing must be individualized according to the patient’s renal function status. Recommended dosage adjustment for adults are shown in table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance (CLcr) adjusted for the body surface area (BSA) must be calculated. To do this, an estimate of the patient’s CLcr in mL/min must first be calculated using the following formula:

Then, the CLcr is adjusted for the BSA as follows:

Table1: Dosing adjustment regimen for adults patients with renal impairment

Group

Creatinine Clearance

(ml/min/1.73m2)

Dosage (mg)

Frequency

Normal

 

Mild

 

Moderate

 

Severe

 

End-stage renal disease patients using dialysis

>80

 

50–80

 

30–50

 

<30

 

 

-

500 to 1,500 mg

 

500 to 1,000 mg 

 

250 to 750 mg

 

250 to 500 mg

 

500 to 1,000 mg1

Every 12 hours

 

Every 12 hours

 

Every 12 hours

 

Every 12 hours

 

Every 24 hours1

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

Discontinuation of Levetiracetam

Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus.

Contraindications

Levetiracetam is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema.

Special Warnings and Precautions for Use

Behavioral Abnormalities and Psychotic Symptoms

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

Behavioral Abnormalities

In clinical studies, 13% of adult levetiracetam-treated patients, compared to 6% of adult placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).

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.

Psychotic Symptoms

In clinical studies, 1% of levetiracetam-treated adult patients experienced psychotic symptoms, compared to 0.2%in the corresponding age groups treated with placebo.

In clinical studies, two (0.3%) levetiracetam-treated adult patients were hospitalized, 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.

Suicidal Behaviour and Ideation

Antiepileptic drugs (AEDs); including levetiracetam, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo

Patients with

Events Per

1000 Patients

Drug Patients

With Events Per

1000 Patients

Relative Risk:

Incidence of Events

In Drug Patients/Incidence

in Placebo Patients

Risk Difference:

Additional Drug

Patients with

Events Per 1000

Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviours with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Somnolence and Fatigue

Levetiracetam may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and 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.

Somnolence

In controlled trials of adult patients with epilepsy experiencing 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 where there was no titration, about 45% of patients receiving 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 hospitalized due to somnolence.

Asthenia

In controlled clinical studies of adult patients with epilepsy experiencing 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.

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 postmarketing 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, LEVEPSY Tablets should be discontinued and the patient should seek immediate medical attention. LEVEPSY Tablets should be discontinued permanently if a clear alternative etiology for the reaction cannot be established

Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in adults 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 rechallenge with levetiracetam has also been reported. LEVEPSY Tablets 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 in adult patients with partial-onset seizure studies,  3.4% of adult levetiracetam-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait or incoordination) compared with 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared with 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 levetiracetam-treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms 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 machinery.

Withdrawal Seizures

As with most AEDs, levetiracetam should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Hematologic Abnormalities

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

Partial-Onset Seizures

Adults

Minor, but statistically significant, decreases compared to placebo in the total mean RBC count (0.03 × 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials.

A total of 3.2% of levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 × 109/L) decreased WBC, and 2.4% of levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 × 109/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 due to secondary-to-low neutrophil counts.

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.

Drug Interactions

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 CYP450 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, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

Phenytoin

Levetiracetam (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. The pharmacokinetics of levetiracetam were also not affected by phenytoin.

Valproate

Levetiracetam (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in adult 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, ucb L057.

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 of levetiracetam.

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 of levetiracetam.

Digoxin

Levetiracetam (1,000 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 (1,000 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 1,000 mg twice daily. The Cssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of the tubular secretion of ucb L057. The effect of levetiracetam on probenecid was not studied.

Use in Special Population

Patients with Renal Impairment

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis.

Patients with 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.

Pregnant Women

Risk Summary

Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades. In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Levetiracetam blood levels may decrease during pregnancy.

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. Dose adjustments may be necessary to maintain clinical response.

Data

Human Data

While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage.

Animal Data

When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested.  There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m2) basis.  

Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m2 basis. 

Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m2 basis. 

Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis).

Lactating Women

Risk Summary

Levetiracetam is excreted in human milk. There are no data on the effects of levetiracetam on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levetiracetam and any potential adverse effects on the breastfed infant from levetiracetam or from the underlying maternal condition.

Pediatric Patients

Levetiracetam is not indicated as monotherapy in partial-onset seizures with or without secondary generalization in patients less than 16 years of age. It is not indicated as adjunctive therapy in the patients with myoclonic seizures less than 12 years of age.

Geriatric Patients

There were 347 subjects in clinical studies of levetiracetam that were 65 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 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.

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.

Undesirable Effects

The following adverse reactions are discussed in more details in other sections of labeling:

  • Behavioral Abnormalities and Psychotic Symptoms
  • Suicidal Behavior and Ideation
  • Somnolence and Fatigue
  • Anaphylaxis and Angioedema
  • Serious Dermatological Reactions
  • Coordination Difficulties
  • Hematologic Abnormalities
  • Increase in Blood Pressure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness.

Partial-Onset Seizures

Adults

In controlled clinical studies in adults with partial-onset seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo,   were somnolence, asthenia, infection and dizziness. Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy.

Table 3: Adverse reactions in pooled placebo-controlled, adjunctive studies in adults experiencing partial-onset seizures

 

Levetiracetam (N=769)

%

Placebo (N=439)

%

Asthenia

15

9

Somnolence

15

8

Headache

14

13

Infection

13

8

Dizziness

9

4

Pain

7

6

Pharyngitis

6

4

Depression

4

2

Nervousness

4

2

Rhinitis

4

3

Anorexia

3

2

Ataxia

3

1

Vertigo

3

1

Amnesia

2

1

Anxiety

2

1

Cough Increased

2

1

Diplopia

2

1

Emotional Lability

2

0

Hostility

2

1

Paresthesia

2

1

Sinusitis

2

1

In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients.

Table 4: Adverse reactions that resulted in discontinuation or dose reduction in pooled placebo-controlled studies in adult patients experiencing partial onset seizures

Adverse Reaction

Levetiracetam (N=769)

 (%)

Placebo (N=439)

 (%)

Dizziness

1

0

Somnolence

4

2

Myoclonic Seizures

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared with partial-onset seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial-onset seizures.

In the controlled clinical study in patients 12 years of age and older with myoclonic seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain and pharyngitis.

Table 5 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy.

Table 5: Adverse reactions in a placebo-controlled, adjunctive study in patients 12 years of age and older with myoclonic seizures

 

Levetiracetam (N=60) %

Placebo (N=60) %

Somnolence

12

2

Neck pain

8

2

Pharyngitis

7

0

Depression

5

2

Influenza

5

2

Vertigo

5

3

In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 6.

Table 6: Adverse reactions that resulted in discontinuation or dose reduction in patients with juvenile myoclonic epilepsy

Adverse Reaction

Levetiracetam (N=60) %

Placebo

(N=60) %

Anxiety

3

2

Depressed mood

2

0

Depression

2

0

Diplopia

2

0

Hypersomnia

2

0

Insomnia

2

0

Irritability

2

0

Nervousness

2

0

Somnolence

2

0

Comparison of Gender, Age and Race

The overall adverse experience profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide. The listing is: abnormal liver function test (LFT), acute kidney injury, anaphylaxis, anencephaly, angioedema, anger, agitation, aggression, agranulocytosis, affect lability, abdominal pain, balance disorder, blood creatine phosphokinase increased*, choreoathetosis, confusional state, convulsion, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, delirium, disturbance in attention, diarrhea, dyspepsia, erythema multiforme, eczema, encephalopathy, gait disturbances, injury, hepatic failure, hepatitis, hypokalemia, hyponatremia, hallucination, hyperkinesia, hypersensitivity, leukopenia, lethargy, muscular weakness, mood swings, memory impairment, myalgia, neutropenia, nausea, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, personality disorder, pruritus, thrombocytopenia, and weight loss, weight increase, rash, rhabdomyolysis, vision blurred, vomiting, Stevens-Johnson syndrome, toxic epidermal necrolysis, tremor and thinking abnormal. Alopecia has been reported with levetiracetam use; recovery was observed in the majority of cases where levetiracetam was discontinued.

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

If you experience any side-effects write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

The highest known dose of levetiracetam received in the clinical development programme was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use.

Management of Overdose

There is no specific antidote for an overdose with levetiracetam. If indicated, elimination of the unabsorbed drug should be attempted by emesis or gastric lavage; the usual precautions should be observed to maintain the airways. General supportive care of the patient is indicated, including monitoring of vital signs and observation of the patient's clinical status.

Hemodialysis

Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.

Pharmacological Properties

Mechanism of Action

The precise mechanism(s) by which levetiracetam exerts its anti-epileptic effect is unknown.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

Pharmacodynamic Properties

Effects on QTc Interval

The effect of levetiracetam on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of levetiracetam (1000 mg or 5000 mg) in 52 healthy subjects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 milliseconds. Therefore, there was no evidence of significant QTc prolongation in this study.

Pharmacokinetic Properties

The pharmacokinetics of levetiracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

Absorption and Distribution

Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500-5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. 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, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. 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.

Elimination

Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose 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 ucb L057 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.

Special 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.

Pregnancy

Levetiracetam levels may decrease during pregnancy.

Gender

Levetiracetam Cmax and the AUC were 20% higher in women compared to men. However, the clearances adjusted for body weight were comparable.

Race

Formal pharmacokinetic studies on the effects of race have not been conducted. Cross-study comparisons involving Caucasians and Asians, however, show that the pharmacokinetics of levetiracetam was comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in the CLcr, the pharmacokinetic differences due to race are not expected.

Renal Impairment

in patients with impaired renal function, total body clearance of levetiracetam is reduced by 40% in the mild group (CLcr = 50 to 80 mL/min), 50% in the moderate group (CLcr = 30 to 50 mL/min) and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is correlated with CLcr.

In anuric (end-stage renal disease) patients, the total body clearance decreased by 70% compared with normal subjects (CLcr >80 mL/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), the 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.

Nonclincal Properties

Animal Toxicology or Pharmacology

Carcinogenesis

Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300, and 1800 mg/kg/day. Plasma exposure (AUC) at the highest dose was approximately 6 times that in humans at the maximum recommended daily human dose (MRHD) of 3000 mg.  There was no evidence of carcinogenicity.  In mice, oral administration of levetiracetam for 80 weeks (doses up to 960 mg/kg/day) or 2 years (doses up to 4000 mg/kg/day, lowered to 3000 mg/kg/day after 45 weeks due to intolerability) was not associated with an increase in tumors. The highest dose tested in mice for 2 years (3000 mg/kg/day) is approximately 5 times the MRHD on a body surface area (mg/m2) basis.

Mutagenesis

Levetiracetam was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (mouse micronucleus) assays.  The major human metabolite of levetiracetam (ucb L057) was negative in in vitro (Ames, mouse lymphoma) assays.

Impairment of Fertility

No adverse effects on male or female fertility or reproductive performance were observed in rats at oral doses up to 1800 mg/kg/day, which were associated with plasma exposures (AUC) up to approximately 6 times that in humans at the MRHD.

Description

LEVEPSY is an antiepileptic drug available as 250 mg, 500 mg, 750 mg and 1000 mg tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and its molecular weight is 170.21.  Levetiracetam is chemically unrelated to existing AEDs. 

Levetiracetam powder has a faint odor and a bitter taste.  It is very soluble in water (104.0 g/100 mL).  It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane (Solubility limits are expressed as g/100 mL solvent.).

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-Life

As on the pack

Packaging Information

LEVEPSY 250 mg   .................       Blister Pack of 15 tablets

LEVEPSY 500 mg   .................         Blister Pack of 15 tablets

LEVEPSY 750 mg   .................       Blister Pack of 10 tablets

Storage and Handling Instructions

Store below 30°C.

Keep out of the reach of the children.

Patient Counselling Information

Read all of this leaflet information carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What LEVEPSY is and what it is used for?

Levetiracetam is an antiepileptic medicine (a medicine used to treat seizures in epilepsy).

LEVEPSY is used: 

  • on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to treat a certain form of epilepsy i.e. partial-onset seizures. Epilepsy is a condition where the patients have repeated fits (seizures). Levetiracetam is used for the epilepsy form in which the fits initially affect only one side of the brain, but could thereafter extend to larger areas on both sides of the brain (partial onset seizure with or without secondary generalisation). Levetiracetam has been given to you by your doctor to reduce the number of fits.
  • as an add-on to other antiepileptic medicines to treat:
  • partial onset seizures in adults
  • myoclonic seizures (short, shock-like jerks of a muscle or group of muscles) in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy

What you need to know before you take LEVEPSY?

Do not take LEVEPSY -

  • If you are allergic to levetiracetam, pyrrolidone derivatives or any of the other ingredients of this medicine. 

Warnings and Precautions

Talk to your doctor before taking LEVEPSY

  • If you suffer from kidney problems, follow your doctor’s instructions. He/she may decide if your dose should be adjusted.
  • If you notice any slow down in the growth or unexpected puberty development of your child, please contact your doctor.
  • A small number of people being treated with anti-epileptics such as levetiracetam have had thoughts of harming or killing themselves. If you have any symptoms of depression and/or suicidal ideation, please contact your doctor.

Tell your doctor or pharmacist if any of the following side effects gets serious or last longer than a few days:

  • Abnormal thoughts, feeling irritable or reacting more aggressively than usually, or if you or your family and friends notice important changes in mood or behaviour.

 Children and Adolescents

• Levetiracetam is not indicated in children and adolescents below 16 years on its own (monotherapy). 

Other Medicines and Levetiracetam

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Do not take macrogol (a drug used as laxative) for one hour before and one hour after taking levetiracetam as this may results in a loss of its effect. 

Pregnancy and Breast-feeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Levetiracetam can be used during pregnancy, only if after careful assessment it is considered necessary by your doctor.

You should not stop your treatment without discussing this with your doctor.

A risk of birth defects for your unborn child cannot be completely excluded. 

Breast-feeding is not recommended during treatment.

Driving and Using Machines

Levetiracetam may impair your ability to drive or operate any tools or machinery, as it may make you feel sleepy. This is more likely at the beginning of treatment or after an increase in the dose. You should not drive or use machines until it is established that your ability to perform such activities is not affected.

How to take LEVEPSY?

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take the number of tablets following your doctor’s instructions. Levetiracetam must be taken twice a day, once in the morning and once in the evening, at about the same time each day.

Partial-onset Seizures  

Dose in Adults and Adolescents (from 16 years of age)

General dose: between 1000 mg and 3,000 mg each day.

When you will first start taking levetiracetam, your doctor will prescribe you a lower dose during 2 weeks before giving you the lowest general dose.

Example: if your daily dose is 1000 mg, your reduced starting dose is 2 tablets of 250 mg in the morning and 2 tablets of 250 mg in the evening.

Myoclonic Seizures

Dose in Adults and Adolescents (12 to 17 years)

General dose: between 1,000 mg and 3,000 mg each day.

Example: if your daily dose is 1,000 mg, you might take 2 tablets of 250 mg in the morning and 2 tablets of 250 mg in the evening.

Method of Administration

Swallow levetiracetam tablets with a sufficient quantity of liquid (e.g. a glass of water). You may take levetiracetam with or without food. After oral administration the bitter taste of levetiracetam may be experienced.

Duration of Treatment

  • Levetiracetam is used as a chronic treatment. You should continue levetiracetam treatment for as long as your doctor has told you.
  • Do not stop your treatment without your doctor’s advice as this could increase your seizures. 

If You Take More Levetiracetam than You Should

The possible side effects of an overdose of levetiracetam are sleepiness, agitation, aggression, decrease of alertness, inhibition of breathing and coma.

Contact your doctor if you took more tablets than you should. Your doctor will establish the best possible treatment of overdose.

If You Forget to Take Levetiracetam

Contact your doctor if you have missed one or more doses. 

Do not take a double dose to make up for a forgotten tablet. 

If You Stop Taking Levetiracetam

If stopping treatment, levetiracetam should be discontinued gradually to avoid an increase of seizures.

Should your doctor decide to stop your levetiracetam treatment, he/she will instruct you about the gradual withdrawal of levetiracetam.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible Side-effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately, or go to your nearest emergency department, if you experience:

  • weakness, feel light-headed or dizzy or have difficulty breathing, as these may be signs of a serious allergic (anaphylactic) reaction
  • swelling of the face, lips, tongue and throat (Quincke’s oedema)
  • flu-like symptoms and a rash on the face followed by an extended rash with a high temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes (Drug Reaction with Eosinophilia and Systemic Symptoms )
  • symptoms such as low urine volume, tiredness, nausea, vomiting, confusion and swelling in the legs, ankles or feet, as this may be a sign of sudden decrease of kidney function
  • a skin rash which may form blisters and look like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme)
  • a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome) • a more severe form of rash causing skin peeling in more than 30% of the body surface (toxic epidermal necrolysis)
  • signs of serious mental changes or if someone around you notices signs of confusion, somnolence (sleepiness), amnesia (loss of memory), memory impairment (forgetfulness), abnormal behaviour or other neurological signs including involuntary or uncontrolled movements. These could be symptoms of an encephalopathy.

 The most frequently reported side effects are nasopharyngitis, somnolence (sleepiness), headache, fatigue and dizziness. At the beginning of the treatment or at dose increase side effects like sleepiness, tiredness and dizziness may be more common. These effects should however decrease over time.

Very common: may affect more than 1 in 10 people

  • nasopharyngitis;
  • somnolence (sleepiness), headache.

 Common: may affect up to 1 in 10 people

  • anorexia (loss of appetite);
  • depression, hostility or aggression, anxiety, insomnia, nervousness or irritability;
  • convulsion, balance disorder (equilibrium disorder), dizziness (sensation of unsteadiness), lethargy (lack of energy and enthusiasm), tremor (involuntary trembling);
  • vertigo (sensation of rotation);
  • cough;
  • abdominal pain, diarrhea, dyspepsia (indigestion), vomiting, nausea;
  • rash;
  • asthenia/fatigue (tiredness).

Uncommon: may affect up to 1 in 100 people

  • decreased number of blood platelets, decreased number of white blood cells; 
  • weight decrease, weight increase;
  • suicide attempt and suicidal ideation, mental disorder, abnormal behaviour, hallucination, anger, confusion, panic attack, emotional instability/mood swings, agitation;
  • amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia (impaired coordinated movements), paraesthesia (tingling), disturbance in attention (loss of concentration);
  • diplopia (double vision), vision blurred;
  • elevated/abnormal values in a liver function test;
  • hair loss, eczema, pruritus;
  • muscle weakness, myalgia (muscle pain);
  • injury.

Rare: may affect up to 1 in 1,000 people

  • infection;
  • decreased number of all blood cell types; 
  • severe allergic reactions (DRESS, anaphylactic reaction , Quincke’s oedema );
  • decreased blood sodium concentration;
  • suicide, personality disorders (behavioural problems), thinking abnormal (slow thinking, unable to concentrate);
  • delirium;
  • encephalopathy (see sub-section “Tell your doctor immediately” for a detailed description of symptoms);
  • uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling movements, hyperkinesia (hyperactivity);
  • pancreatitis;
  • liver failure, hepatitis;
  • sudden decrease in kidney function;
  • skin rash, which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme), a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and  genitals (Stevens–Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body surface (toxic epidermal necrolysis);
  • rhabdomyolysis (breakdown of muscle tissue) and associated blood creatine phosphokinase increase. Prevalence is significantly higher in Japanese patients when compared to nonJapanese patients.
  • limp or difficulty walking.

Reporting of Side-effects

If you experience any side-effects, talk to your doctor or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

How to Store LEVEPSY?

  • Store LEVEPSY below 30°C.
  • Keep LEVEPSY out of the reach of children

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

License Number: MNB/05/109

Date – 23/04/2018

Date of Revision

09/04/2020