LEVECETAM Film-coated tablet Ref.[50751] Active ingredients: Levetiracetam

In accordance with current clinical practice, if levetiracetam has to be discontinued it is recommended to withdraw it gradually.

Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. There is no need therefore for plasma level monitoring of levetiracetam.

To date, there are no data to support the use of levetiracetam in patients less than 4 years of age.

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

Suicidal behaviour and ideation

Antiepileptic drugs, 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 randomised 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 randomised 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 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3. Risk by indication for antiepileptic drugs in the pooled analysis:

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

Anyone considering prescribing levetiracetam or other AED must balance this risk 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 suicide 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.

Patients, their caregivers, and families should be informed that the AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence of worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Psychiatric reactions and changes in behaviour

Levetiracetam may cause changes in behaviour (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms. Patients treated with levetiracetam should be monitored for psychiatric signs and symptoms.

Seizure Worsening

A paradoxical reaction of worsening of seizure may be observed especially when starting treatment or at increase in dose.

Blood cell count

Cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (See Section 4.8 Adverse effects (undesirable effects)).

Use in hepatic impairment

See section 4.2 Dose and Method of Administration and Section 5.2 Pharmacokinetic Properties.

Use in renal impairment

The administration of levetiracetam to patients with renal impairment may require dose adaptation. Monitoring of renal function in severely hepatic impairment patients is recommended before dose selection (see section 4.2 DOSE AND METHOD OF ADMINISTRATION).

Use in the elderly

See section 4.2 DOSE AND METHOD OF ADMINISTRATION and section 5.2 PHARMACOKINETIC PROPERTIES.

Paediatric use

To date, there are no data to support the use of levetiracetam in patients less than 4 years of age.

Effects on laboratory tests

No data available.

In vitro, levetiracetam and its major metabolite (ucb L057) have been shown not to inhibit the major human liver cytochrome P450 isoforms, glucuronyl transferase, (valproic acid) and epoxide hydroxylase activities. In human hepatocytes in culture, levetiracetam did not cause enzyme induction.

Probenecid (500 mg four times daily) has been shown to inhibit the renal clearance of the major metabolite (ucb L057) but not levetiracetam. Nevertheless, the concentration of ucb L057 remains low. It is expected that other drugs excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted drugs e.g. nonsteroidal antiinflammatory drugs (NSAIDs), sulfonamides and methotrexate is unknown.

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

Consistent with formal pharmacokinetic studies in adults, there has been no clear evidence of clinically significant drug interactions in paediatric patients receiving up to 60 mg/kg/day.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine, valproate, topiramate and lamotrigine. However, data suggested that enzyme inducing antiepileptic medicinal products increase levetiracetam clearance by 22%. Dosage adjustment is not required.

Pharmacokinetic studies demonstrated a lack of interaction with digoxin, oral contraceptives (ethinylestradiol and levonorgestrel) and warfarin. Endocrine parameters (luteinising hormone (LH) and progesterone) and prothrombin times were not modified.

No data on the influence of antacids on the absorption of levetiracetam are available.

Effects on fertility

There are no human data on the effects of levetiracetam on male or female fertility. No adverse effects on male or female fertility or reproductive performance were observed in rats at oral doses of levetiracetam up to 1,800 mg/kg/day (corresponding to approximately six times the maximal recommended clinical dose on a mg/m² basis) administered for at least two weeks prior to, and throughout, mating.

Use in pregnancy – Pregnancy Category B3

In rats and rabbits, levetiracetam and/or its metabolites cross the placenta and the foetal levels approximate maternal plasma levels. In these species, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses.

Oral administration to female rats from two weeks prior to mating and throughout pregnancy and lactation was associated with increased incidences of minor foetal skeletal abnormalities and retarded offspring growth prenatally and/or postnatally at doses greater than or equal to 350 mg/kg/day (approximately equivalent to the maximal recommended clinical dose of 3,000 mg/day on a mg/m² basis) and with increased pup mortality and offspring behavioural alterations at a dose of 1,800 mg/kg/day (six times the maximal human dose on a mg/m² basis). The developmental no effect dose was 70 mg/kg/day (equivalent to 0.2 times the maximal human dose on a mg/m² basis). There was no overt maternal toxicity at the doses used in this study.

Oral administration to pregnant rabbits during the period of organogenesis resulted in increased embryo foetal mortality and increased incidences of minor foetal skeletal abnormalities at doses greater than or equal to 600 mg/kg/day (about four times the maximal human dose on a mg/m² basis) and in decreased foetal weights and increased incidences of minor foetal skeletal abnormalities at a dose of 1,800 mg/kg/day (12 times the maximum human dose on a mg/m² basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the maximal human dose on a mg/m² basis). Maternal toxicity was also observed at 1,800 mg/kg/day.

Oral administration to pregnant rats during the period of organogenesis resulted in reduced foetal weight and increased incidence of embryo foetal mortality and increased incidence of foetal skeletal variations at a dose of 3,600 mg/kg/day (12 times the maximal human dose on a mg/m² basis). The developmental no effect dose was 1,200 mg/kg/day (4 times the maximal human dose on a mg/m² basis). There was no overt maternal toxicity.

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

Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses of up to 1800 mg/kg/day corresponding to (30 times the maximum recommended human dose).

The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.

It is recommended that:

• women on antiepileptic drugs (AEDs) receive prepregnancy counselling with regard to the risk of foetal abnormalities;
• AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
• folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
• specialist prenatal diagnosis including detailed mid trimester ultrasound should be offered.
• As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.

Generally, therapy with multiple antiepileptic drugs (including polytherapy containing levetiracetam) is associated with a higher risk of major malformations than monotherapy.

Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. A decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. To monitor the outcome of pregnancy in women exposed to levetiracetam, doctors are encouraged to register pregnant patients taking levetiracetam on the Australian Pregnancy Register for Women on Antiepileptic Medication with Epilepsy and Allied Conditions by calling 1800 069 722.

Use in lactation

Levetiracetam and/or its metabolites are excreted in milk in lactating rats; peak milk concentrations occurred three hours after oral administration (milk:plasma ratio 0.9). Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in breastfeeding infants from levetiracetam, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

No studies on the effects on the ability to drive and use machines have been performed.

Due to possible different individual sensitivity, some patients might experience, at the beginning of treatment or following a dosage increase, somnolence or other central nervous system (CNS) related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery.

The prescriber should be aware that the following data were obtained from studies where levetiracetam was added to concomitant antiepileptic therapy. Therefore, it was not possible in all cases to determine which agent(s), if any, was associated with the adverse events. It is also difficult to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies.

Adult patients

Levetiracetam has been administered to more than 3,000 subjects and patients. Of these, 780 patients were treated for more than six months, 592 for more than one year, 366 for more than two years and 185 for more than three years.

1,023 patients with epilepsy participated in controlled clinical trials (672 patients were treated with levetiracetam and 351 patients with placebo).

From placebo controlled studies conducted in adults, 46.4 and 42.2% of patients experienced drug related, treatment emergent adverse events in the levetiracetam group and placebo group, respectively. 2.4 and 2.0% of patients experienced serious drug related, treatment emergent adverse events in the levetiracetam group and placebo group, respectively.

During monotherapy treatment with levetiracetam, 79.6% of subjects experienced at least one adverse event and 49.8% experienced at least one drug related undesirable effect. The most frequently reported adverse effects were fatigue and somnolence.

Very common adverse events (greater than or equal to 10%)

The very common adverse events (greater than or equal to 10%) were somnolence, asthenia, infection, headache and accidental injury. Of these, somnolence, asthenia and infection appeared to occur more frequently in levetiracetam treated patients than in placebo treated patients, whereas accidental injury was more common in the placebo group and headache was similarly reported in the two groups. (See Table 4.) Please refer to table 4.

Table 4. Incidence (%) of very common treatment emergent adverse events in adult placebo controlled studies, by body system:

In the pooled safety analysis, there was no clear dose response relationship but incidence and severity of CNS related undesirable effects decreased over time.

More than 93% of events categorised under the COSTART preferred term ‘infection’ are symptoms of community acquired infections (common cold and upper respiratory tract infections). There was no increase in incidence of other infections (lower respiratory tract infections, urinary tract infections). Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 × 10⁶/mm²), mean haemoglobin (0.9 g/L), and mean haematocrit (0.38%) were seen in levetiracetam treated patients in controlled trials. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (less than or equal to 2.8 × 10⁹/L) decreased WBC, and 2.4% for treated and 1.4% of placebo patients had at least one possible significant (less than or equal to 1.0 × 10⁹/L) decreased neutrophil count. Of the 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.

Common adverse events (greater than or equal to 1% and <10%). (See Table 5.) Please refer to table 5.

Table 5. Incidence (%) of common treatment emergent adverse events in adult placebo controlled studies, by body system:

The incidence of serious adverse events in placebo controlled studies was 9.9% in the levetiracetam group versus 8.9% in the placebo group. Many of the serious adverse events are typical for a population of patients with epilepsy.

The serious adverse events which occurred in more than 1% of patients were convulsion (1.8% in levetiracetam group versus 1.4% in placebo group) and accidental injury (1.6% in both levetiracetam and placebo group).

Paediatric patients.

A study conducted in paediatric patients (4 to 16 years of age) showed that 55.4 and 40.2% of the paediatric patients experienced undesirable effects in the levetiracetam and placebo groups, respectively, and that 0.0 and 1.0% of the paediatric patients experienced serious undesirable effects in the levetiracetam and placebo groups, respectively. In the paediatric clinical study, 16.8% of patients receiving levetiracetam and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The most commonly reported undesirable effects in the paediatric population were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache. Safety results in paediatric patients were consistent with the safety profile of levetiracetam in adults, except for behavioural and psychiatric undesirable effects which were more common in children than in adults (38.6 versus 18.6%). However, the relative risk was similar in children as compared to adults as there was also a higher incidence of behavioural psychiatric adverse events in the placebo group in children as compared to adults (27.8 versus 10.5%). (See Table 6.) Please refer to table 6.

Table 6. Incidence () of treatment emergent adverse events in a placebo controlled, addon study in paediatric patients aged 4-16 years, by body system (adverse events occurred in at least 2 of levetiracetam treated patients and occurred more frequently than placebo treated patients):

Other events occurring in 2% or more of paediatric patients treated with levetiracetam but as or more frequent in the placebo group were the following: abdominal pain, allergic reaction, ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea, otitis media, rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor and urinary incontinence.

Other controlled clinical trials

The following adverse effects, listed by body system, have been observed in additional controlled clinical trials.

General disorders

Very common: fatigue

Respiratory system

Common: nasopharyngitis

Nervous system

Common: balance disorder, disturbance in attention, memory impairment.

Skin and subcutaneous tissue disorders

Common: eczema, pruritus.

Eye disorders

Common: vision blurred.

Blood and lymphatic system disorders

Common: thrombocytopenia.

Musculoskeletal and connective tissue disorders

Common: myalgia.

Psychiatric disorders

Common: irritability, mood swings, personality disorder.

Postmarketing experience

In postmarketing experience, nervous system and psychiatric disorders have been most frequently reported.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported in postmarketing experience. Data are insufficient to support an estimate of their incidence in the population to be treated.

Blood and lymphatic system disorders: Pancytopenia with bone marrow suppression identified in some of these cases, agranulocytosis, leucopenia and neutropenia, thrombocytopenia.

Cardiac disorders: Electrocardiogram QT prolonged.

Immune system disorders: Anaphylaxis, drug reaction with eosinophilia and systemic symptoms (DRESS)

Psychiatric disorders: Abnormal behaviour, aggression, anger,panic attack, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicidal ideation and delirium

Nervous system disorders: Choreoathetosis, dyskinesia, lethargy, gait disturbance, seizures aggravated Skin and subcutaneous tissue disorders. Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme and alopecia; in several cases, recovery was observed when levetiracetam was discontinued.

Musculoskeletal and connective tissue disorders: Muscular weakness, rhabdomyolysis and blood creatine phosphokinase increased.

Liver and biliary system disorders: Hepatitis, hepatic failure and abnormal liver function test.

Renal and urinary disorders: Acute kidney injury.

Metabolic and nutritional disorders: Weight loss, pancreatitis, hyponatraemia.

Description of selected adverse reactions

The prevalence of rhabdomyolysis and blood creatine phosphokinase increase is significantly higher in Japanese patients compared to non-Japanese patients. Evidence also suggests a possible predisposition of the Japanese population to neuroleptic malignant syndrome (NMS).

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

Rare cases of QT prolongation have been seen in post-marketing surveillance.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.