Consumer medicine information

Levitam Tablets

Levetiracetam

BRAND INFORMATION

Brand name

Levitam Tablets

Active ingredient

Levetiracetam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Levitam Tablets.

What is in this leaflet

This leaflet answers some common questions about LEVITAM. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking LEVITAM against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What LEVITAM is used for

LEVITAM is used to control epilepsy.

Epilepsy is a condition where you have repeated seizures (fits). There are many different types of seizures, ranging from mild to severe.

LEVITAM belongs to a group of medicines called antiepileptics. These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

LEVITAM may be used alone, or in combination with other medicines, to treat your condition. Your doctor may prescribe this medicine in addition to your current therapy.

Ask your doctor if you have any questions about why it has been prescribed for you.

LEVITAM is not recommended for use in children under the age of 4, as there have been no studies of its effects in children of this age group.

This medicine is available only with a doctor's prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take LEVITAM if you are allergic to medicines containing levetiracetam or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take LEVITAM if you are pregnant or intend to become pregnant, without talking to your doctor first.

Like most antiepileptic medicines, LEVITAM is not recommended for use during pregnancy. However, it is very important to control your fits while you are pregnant. If it is necessary for you to take this medicine, your doctor can help you decide whether or not to take it during pregnancy.

Do not take it if you are breastfeeding.

LEVITAM passes into breast milk and may affect your baby.

Do not take it if the expiry date (Exp.) printed on the pack has passed.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

LEVITAM may affect your developing baby if you take it during pregnancy. However, it is very important to control your fits while you are pregnant. If it is necessary for you to take LEVITAM, your doctor can help you decide whether or not to take it during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed.

It is recommended that you do not breastfeed while taking LEVITAM.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • kidney problems
  • liver problems.

Your doctor may want to take special care if you have any of these conditions.

If you have not told your doctor about any of the above, tell them before you start taking LEVITAM.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking LEVITAM.

How to take it

How much to take

For patients 12 years of age and older, the dosage is generally between 1000 mg and 3000 mg each day.

For children 4 to 11 years of age the dose is 20 mg/kg to 60 mg/kg each day.

There is no data to support the use of LEVITAM for patients less than 4 years of age.

Your doctor will tell you how much LEVITAM you will need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.

Your doctor may recommend that you start with a low dose of LEVITAM and slowly increase the dose to the lowest amount needed to control your epilepsy/seizures (fits).

Follow all directions given to you by your doctor and pharmacist carefully.

How to take it

Swallow the tablets with a glass of water.

If you forget to take it

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

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take it for

Most anticonvulsant medicines take time to work, so do not be discouraged if you do not feel better straight away.

Continue taking LEVITAM for as long as your doctor tells you to.

This medicine helps control your condition, but does not cure it. Therefore you must take your medicine every day, even if you feel well.

Do not stop taking LEVITAM, or change the dosage, without checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.

Stopping treatment suddenly may cause unwanted effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much LEVITAM. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much LEVITAM, you may feel drowsy.

While you are taking it

Things you must do

Tell your doctor immediately if you notice an increase in seizures.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking LEVITAM.

Before starting any new medicine, tell your doctor or pharmacist that you are taking LEVITAM.

Before you have any surgery or emergency treatment, tell your doctor or dentist that you are taking LEVITAM.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may change your treatment unnecessarily.

Visit your doctor regularly so they can check on your progress.

You doctor may also want to take some tests from time to time. This helps to prevent unwanted side effects.

Things you must not do

Do not stop taking LEVITAM, or lower the dose, without checking with your doctor.

Do not use it to treat any other conditions unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how LEVITAM affects you.

It may cause drowsiness, in some people, especially in the beginning of treatment. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.

Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling drowsy or sleepy.

Be careful when drinking alcohol while taking LEVITAM.

Combining it with alcohol can make you drowsier.

Your doctor may suggest you avoid alcohol while you are being treated with LEVITAM.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking LEVITAM.

Like all other medicines, it may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • dizziness
  • feeling weak
  • common cold and upper respiratory tract infections
  • feeling tired, drowsy or sleepy.

These are the more common side effects of LEVITAM and are usually short-lived.

Other side effects reported are:

  • mood changes such as depression, nervousness, aggression, anger, anxiety, confusion, hallucination, irritability.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

If you experience more frequent or more severe seizures, tell your doctor immediately or go to Accident and Emergency at your nearest hospital.

Tell your doctor immediately if you experience any of the following:

  • suicidal thoughts
  • suicidal attempts.

Tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

After using it

Storage

Keep your medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store LEVITAM or any other medicine in the bathroom or near a sink.

Do not leave LEVITAM in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking LEVITAM, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

LEVITAM comes in 3 strengths of tablets:

  • LEVITAM 250 - blue, oval shaped, film coated tablet marked ‘LE 250’ on one side and a scoreline on the other
  • LEVITAM 500 - yellow, oval shaped film coated tablet marked ‘LE 500’ on one side and a scoreline on the other
  • LEVITAM 1000 - white, oval shaped film coated tablet marked ‘LE 1000’ on one side and a scoreline on the other

Each pack contains 60 tablets.

Ingredients

The active ingredient in LEVITAM is levetiracetam.

  • each LEVITAM 250 tablet contains 250 mg of levetiracetam
  • each LEVITAM 500 tablet contains 500 mg of levetiracetam
  • each LEVITAM 1000 tablet contains 1000 mg of levetiracetam.

The tablets also contain:

  • maize starch
  • povidone
  • purified talc
  • colloidal anhydrous silica
  • magnesium stearate
  • Opadry II 85F60833 Blue (250 mg tablets)
  • Opadry II 85F62663 Yellow (500 mg tablets)
  • Opadry II 85F18378 White (1000 mg tablets).

Tablets are gluten, lactose and sucrose free.

Sponsor

Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

Australian registration numbers:
LEVITAM 250 - AUST R 143659
LEVITAM 500 - AUST R 143695
LEVITAM 1000 - AUST R 143700

Date of preparation:
April 2010.

BRAND INFORMATION

Brand name

Levitam Tablets

Active ingredient

Levetiracetam

Schedule

S4

 

Name of the medicine

Levetiracetam.

Excipients.

Maize starch, povidone, purified talc, anhydrous colloidal silica, magnesium stearate, Opadry II 85F60833 Blue (250 mg tablets), Opadry II 85F62663 Yellow (500 mg tablets), Opadry II 85F63149 Orange (750 mg tablets) and Opadry II 85F18378 White (1000 mg tablets). The tablets are gluten free.

Description

Chemical name: (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide. Molecular formula: C8H14N2O2. MW: 170.21. CAS: 102767-28-2. Levetiracetam is a white to off white powder with a faint odour and a bitter taste. It is very soluble in water (104 g/100 mL), freely soluble in chloroform (65.3 mg/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.

Pharmacology

Mechanism of action.

The precise mechanism of action by which levetiracetam induces seizure protection still remains to be fully elucidated, but appears to be unrelated to the mechanisms of current antiepileptic drugs. 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 (gamma-aminobutyric acid) 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 antiseizure 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 drug.

Pharmacodynamics in animals.

Levetiracetam is not active in the classical screening models for anticonvulsants, however it induces potent protection in a broad range of animal models of partial and primary generalised seizures, with an unusually high safety margin between therapeutic doses and doses inducing adverse effects.
Levetiracetam also displays potential antiepileptogenic properties by dose dependently inhibiting the development of kindling, even after discontinuation of the active substance.
Withdrawal from chronic treatment did not decrease the seizure threshold. Anxiolytic action and an absence of undesirable effects on cognitive function have also been observed.
The major metabolite, ucb L057, is inactive in seizure models.

Pharmacodynamics in humans.

Both partial and generalised epilepsy models (epileptiform discharge/ photoparoxysmal response) confirmed the broad spectrum preclinical pharmacological profile.

Pharmacokinetics.

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear and time independent with low intra and intersubject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.
Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg body weight. Therefore there is no need for plasma level monitoring of levetiracetam.
A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/ plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours postdose for oral solution formulation).
A single dose of 1500 mg of levetiracetam diluted in 100 mL of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as three 500 mg tablets.
The intravenous administration of doses up to 4000 mg diluted in 100 mL of 0.9% sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 mL of 0.9% sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns.

Adults and adolescents.

Absorption.

Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (Cmax) are achieved at 0.75 hours after dosing. Steady state is achieved after two days of a twice daily administration schedule. Peak concentrations (Cmax) are typically 28 and 43 microgram/mL following a single 1,000 mg dose and repeated 1,000 mg bid (twice daily) dose respectively. The extent of absorption is dose independent and is not altered by food, but the rate of absorption is slightly reduced.

Distribution.

No tissue distribution data are available in humans. Neither levetiracetam nor its major metabolite (ucb L057) are significantly bound to plasma proteins (< 10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, a value close to the volume of distribution of intracellular and extracellular water.

Metabolism.

The major metabolic pathway (24% of the dose) is an enzymatic hydrolysis of the acetamide group. Production of this metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including whole blood but not plasma. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other one by opening of the pyrrolidone ring (0.9% of the dose).
Other unidentified components accounted for only 0.6% of the dose.
No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its major metabolite ucb L057.
In vitro, leveitracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.
In human hepatocytes in vitro, levetiracetam had no effect on CYP1A/2 or UGT isoform activities (including ethinylestradiol conjugation). Levetiracetam caused mild induction of CYP2B6 and CYP3A4, but only at high concentrations not considered to be clinically relevant. Therefore the interaction of levetiracetam with other substances, or vice versa, is unlikely.

Excretion.

The plasma half-life in adults was 7.4 ± 0.8 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was a mean of 0.96 mL/minute/kg.
The major route of excretion was via urine, accounting for a mean 95% of the dose, with approximately 93% of the dose excreted within 48 hours. Excretion via faeces accounted for only 0.3% of the dose. The cumulative urinary excretion of levetiracetam and its major metabolite (ucb L057) accounted for 66 and 24% of the dose respectively during the first 48 hours.
The renal clearance of levetiracetam is 0.6 mL/minute/kg, indicating that it is excreted by glomerular filtration with subsequent tubular reabsorption. The renal clearance of the major metabolite, ucb L057, is 4.2 mL/minute/kg indicating active tubular secretion in addition to glomerular filtration.

Elderly.

In elderly patients, the half-life is increased by about 40% (ten to eleven hours) and is attributed to the decrease in renal function in this population (see Dosage and Administration).

Children (4 to 12 years of age).

Following single dose administration (20 mg/kg) to epileptic children (6 to 12 years of age), the half-life of levetiracetam was 6.0 ± 1.1 hours. The apparent body clearance was approximately 30% higher than in epileptic adults.
Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years of age), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately five hours. The apparent body clearance was 1.1 mL/minute/kg.

Infants and children (1 month to 4 years of age).

Following single dose administration (20 mg/kg) of a 10% oral solution to epileptic children (1 month to 4 years of age), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 mL/min/kg) than for adults (0.96 mL/min/kg).

Renal impairment.

The apparent body clearance of both levetiracetam and its major metabolite (ucb L057) is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Levitam, based on creatinine clearance in patients with moderate and severe renal impairment (see Dosage and Administration).
In anuric endstage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods respectively. The fractional removal of levetiracetam was 51% during a typical four hour dialysis session.

Hepatic impairment.

In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to concomitant renal impairment (see Dosage and Administration).

Clinical Trials

Effectiveness in partial onset seizures.

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 generalisation. In these studies, 904 patients were randomised to placebo, 1,000, 2,000 or 3,000 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 antiepileptic drugs (AEDs). Patients enrolled in study 3 had refractory partial onset seizures for at least one 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 four partial onset seizures during each four 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 1,000 mg/day (n = 97), levetiracetam 3,000 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 six 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 greater than or equal to 50% reduction from baseline in partial onset seizure frequency). The results of the analysis of study 1 are displayed in Table 1.
The percentage of patients (y-axis) who achieved greater than or equal to 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.

Study 2.

Study 2 was a double blind, placebo controlled, crossover study conducted at 62 centres in Europe comparing levetiracetam 1,000 mg/day (n = 106), levetiracetam 2,000 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 of the three treatment groups described above. The 16 week treatment period consisted of the four 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 greater than or equal to 50% reduction from baseline in partial onset seizure frequency). The results of the analysis of period A are displayed in Table 2.
The percentage of patients (y-axis) who achieved greater than or equal to 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.
The comparison of levetiracetam 2,000 mg/day to levetiracetam 1,000 mg/day for responder rate was statistically significant (p = 0.02). Analysis of the trial as a crossover yielded similar results.

Study 3.

Study 3 was a double blind, placebo controlled, parallel group study conducted at 47 centres in Europe comparing levetiracetam 3,000 mg/day (n = 180) and placebo (n = 104) in patients with refractory partial onset seizures, with or without secondary generalisation, 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 four 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 greater than or equal to 50% reduction from baseline in partial onset seizure frequency). Table 3 displays the results of the analysis of study 3.
The percentage of patients (y-axis) who achieved greater than or equal to 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.

Effectiveness in partial onset seizures in paediatric patients with epilepsy.

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in paediatric patients was established in a multicentre, randomised double blind, placebo controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Eligible patients on a steady dose of one to two AEDs, who still experienced at least four partial onset seizures during the four weeks prior to screening, as well as at least four partial onset seizures in each of the two four week baseline periods, were randomised to receive either levetiracetam or placebo. The population included 198 patients (levetiracetam n = 101, placebo n = 97) with uncontrolled partial onset seizures, whether or not secondarily generalised. The study consisted of an eight week baseline period and four week titration period followed by a ten week evaluation period. Dosing was initiated at a target 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 two week intervals to the target dose of 60 mg/kg/day (or 40 mg/kg/day as a maximum tolerated dose).
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 greater than or equal to 50% reduction from baseline in partial onset seizure frequency per week). Table 4 displays the results of this study.
The percentage of patients (y-axis) who achieved greater than or equal to 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.

Indications

Use in epileptic patients aged 4 years and older, initially as add on therapy, in the treatment of partial onset seizures with or without secondary generalisation.

Contraindications

Hypersensitivity to any levetiracetam or other pyrrolidone derivatives or any of the excipients (see Excipients).

Precautions

In accordance with current clinical practice, if Levitam has to be discontinued it is recommended to withdraw it gradually.
The administration of Levitam to patients with renal impairment may require dose adaptation. Monitoring of renal function in severely hepatically impaired patients is recommended before dose selection (see Dosage and Administration).

Suicidal behaviour and ideation.

Antiepileptic drugs, including phenobarbitone, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any antiepileptic drugs 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 antiepileptic drugs showed that patients randomised to one of the antiepileptic drugs had approximately twice the risk (adjusted relative risk 1.8, 95% Cl: 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 antiepileptic drug 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 antiepileptic drugs was observed as early as one week after starting drug treatment with antiepileptic drugs 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 antiepileptic drugs of varying mechanisms of action and across a range of indications suggests that the risk applies to all antiepileptic drugs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 5 shows absolute and relative risk by indication for all evaluated antiepileptic drugs.
The relative risk for suicidal thoughts or behaviour 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 phenobarbitone or any other antiepileptic drugs must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptic drugs 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.
Patients, their caregivers, and families should be informed that antiepileptic drugs 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.

Impaired renal function.

The administration of Levitam to patients with renal impairment may require dose adaptation. Monitoring of renal function in severely hepatically impaired patients is recommended before dose selection (see Dosage and Administration).

Impaired hepatic function.

See Impaired renal function.
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.

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.

(Category B3)
In rats and rabbits, levetiracetam and/or its metabolites cross the placenta and the fetal 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 fetal 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 embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses greater than or equal to 600 mg/kg/day (about three times the maximal human dose on a mg/m2 basis) and in decreased fetal weights and increased incidences of minor fetal skeletal anomalies at a dose of 1,800 mg/kg/day (ten times the maximal human dose on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (approximately 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 fetal weight and increased incidence of embryofetal mortality and increased incidence of fetal skeletal variations at a dose of 3,600 mg/kg/day (eleven times the maximal human dose on a mg/m2 basis). The developmental no effect dose was 1,200 mg/kg/day (four 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 1,800 mg/kg/day (six 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 1,800 mg/kg/day corresponding to 30 times the maximal 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 fetus of uncontrolled epilepsy.
It is recommended that:
women on antiepileptic drugs (AEDs) receive prepregnancy counselling with regard to the risk of fetal 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 12 weeks after conception;
specialist prenatal diagnosis including detailed midtrimester ultrasound should be offered.
To date, insufficient clinical data on exposed pregnancies are available. Levitam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentrations during pregnancy.

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 Levitam, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Carcinogenicity.

There was no evidence of carcinogenicity following administration of levetiracetam in the diet to rats or orally to mice for 104 weeks, associated with respective systemic exposures (plasma AUC) up to four and eightfold that in humans at the maximal recommended clinical dose of 3,000 mg/day.

Genotoxicity.

Levetiracetam was negative in gene mutation assays (bacterial, Chinese hamster ovary/ HGPRT locus) and in assays for chromosomal damage in vitro and in vivo (Chinese hamster ovary cells, mouse micronucleus assay). The hydrolysis product and major human metabolite (ucb L057) was not mutagenic in bacterial reverse mutation assays or the in vitro mouse lymphoma assay.

Effect on ability to drive or operate machinery.

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 CNS related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery.

Interactions

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. NSAIDs, sulphonamides 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, 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 and valproate. 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 (ethinyloestradiol and levonorgestrel) and warfarin. Endocrine parameters (LH and progesterone) and prothrombin times were not modified.
No data on the influence of antacids on the absorption of levetiracetam are available.

Adverse Effects

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 adult 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, 47.1 and 40.1% of patients experienced drug related, treatment emergent adverse events in the levetiracetam group and placebo group, respectively. 3.3 and 2.1% 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 (> 10%).

The very common adverse events (> 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 6.
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, etc.). Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 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 (≤ 2.8 x 109/L) decreased WBC, and 2.4% for treated and 1.4% of placebo patients had at least one possible significant (≤ 1.0 x 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 (> 1%, < 10%).

See Table 7.
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 8.
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, thrombocytopenia, leucopenia and neutropenia.

Psychiatric disorders.

Abnormal behaviour, aggression, anger, confusion, hallucination, irritability and psychotic disorder, suicide, suicide attempt and suicidal ideation.

Skin and subcutaneous tissue disorders.

Alopecia; in several cases, recovery was observed when levetiracetam was discontinued.

Liver and biliary system.

Hepatitis and abnormal liver function test.

Nervous system.

Paraesthesia.

Metabolic and nutritional disorders.

Weight loss, pancreatitis.

Dosage and Administration

Levetiracetam therapy can be initiated with either intravenous or oral administration. Conversion to or from oral to intravenous levetiracetam can be done directly without titration. The total daily dose and frequency of administration should be maintained.
Levitam must be taken orally, swallowed with liquid. The tablets may be taken with or without food. The daily dose is administered in two equally divided doses.

Adults (> 18 years of age) and adolescents (aged 12 to 17 years of age) weighing 50 kg or more.

As adjunctive therapy, the therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.
Depending upon the clinical response and tolerance, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increments or decrements every two to four weeks.
When satisfactory control of seizures has been attained, monotherapy with levetiracetam may be envisaged by progressively decreasing and withdrawing the concomitant antiepileptic medication.

Elderly (65 years and older).

Adjustment of the dose is recommended in the elderly with compromised renal function (see Patients with renal impairment).

Children (aged 4 to 11 years of age) and adolescents (aged 12 to 17 years of age) weighing less than 50 kg.

The initial therapeutic dose is 10 mg/kg twice daily. See Table 9.
Depending on the clinical response and tolerance, the daily dose can be increased up to 60 mg/kg daily (in two 30 mg/kg doses). Dose changes can be made in 10 mg/kg twice daily dose increments or decrements every two weeks. The lowest effective dose should be used.
The dosage in children 50 kg or greater is the same as in adults.
The doctor should prescribe the most appropriate strength according to weight and dose.

Infants and children less than 4 years of age.

There are insufficient data to recommend the use of levetiracetam in children under 4 years of age.

Patients with renal impairment.

The levetiracetam daily dose must be individualised according to renal function. For adult patients, see Table 10 and adjust the dose as indicated.
To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed. The CLcr in mL/min may be estimated from serum creatinine (micromol/L) determination using the following formula.
Then CLcr is adjusted for body surface area (BSA) as follows.
For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

Patients with hepatic impairment.

No dose adjustment is needed in patients with mild and moderate hepatic impairment.
In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore, a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is < 70 mL/minute.

Overdosage

Symptoms.

The highest known dose of levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse events 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.

Treatment.

There is no specific antidote for levetiracetam. Treatment for an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60% for levetiracetam and 74% for the major metabolite (ucb L057).
For further information on the management of overdosage, advice may be sought from the Poisons Information Centre (telephone 131 126).

Presentation

Tablets (oval, film coated), 250 mg (blue, marked LE 250 on one side, scored on reverse), 500 mg (yellow, marked LE 500 on one side, scored on reverse), 750 mg* (orange, marked LE 750 on one side, > on reverse), 1000 mg (white, marked LE 1000 on one side, scored on reverse): 60's (blister pack).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.