Consumer medicine information

Levetiracetam APOTEX Solution for Infusion

Levetiracetam

BRAND INFORMATION

Brand name

Levetiracetam IV APOTEX

Active ingredient

Levetiracetam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Levetiracetam APOTEX Solution for Infusion.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you being given this medicine against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

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

What this medicine is used for

The name of your medicine is Levetiracetam APOTEX Solution for Infusion. It contains the active ingredient levetiracetam.

It is used to control epilepsy.

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

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

Levetiracetam solution for infusion may be used alone, or in combination with other medicines, to treat your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

There is no evidence that this medicine is addictive.

This medicine should not be used in children. The safety and effectiveness of this medicine has not been established in patients less than 4 years of age.

Before you are given this medicine

When you must not be given it

You should not be given this medicine if you have an allergy to:

  • any medicine containing levetiracetam
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

You should not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • kidney problems
  • liver problems
  • depression.

Tell your doctor if you are pregnant or plan to become pregnant. This medicine may affect your developing baby if you are given it during pregnancy. However, it is very important to control your seizures while you are pregnant.

You should not be given this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.

Do not stop levetiracetam solution for infusion until you have discussed it with your doctor. If you stop this medication suddenly, it may cause unwanted side effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

Tell your doctor if you are currently breastfeeding or you plan to breastfeed.

You should not be given this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.

Levetiracetam in this medicine passes into breast milk and there is a possibility that your baby may be affected.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interact with levetiracetam. These include other antiepileptic drugs.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are being given this medicine. Other medicines may also interact with this medicine.

How this medicine is given

How much is given

Your doctor will decide how much of this medicine you will receive. This will depend on your age, your condition and whether you are taking any other medicines.

How it is it given

Levetiracetam solution for infusion is diluted and given as an infusion (intravenous drip) into a vein.

Levetiracetam solution for infusion must only be given by a doctor, nurse or other trained person.

If you are given too much (overdose)

As levetiracetam solution for infusion is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience severe side effects tell your doctor immediately.

Symptoms of an overdose may include feeling drowsy, agitation, aggression or coma.

If you think that you or anyone else may have been given too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are being given this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while being given this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are being given this medicine.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell your doctor if you feel levetiracetam solution for infusion is not helping your condition. Your doctor may need to change your medicine.

Stopping levetiracetam solution for infusion suddenly may cause unwanted side effects or make your condition worse.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. As with other antiepileptic medicines, this medicine may cause dizziness or drowsiness in some people. This is more frequent at the beginning of treatment or after an increase in the dose.

If you are feeling dizzy or drowsy 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 dizzy or drowsy.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being given this medicine.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

  • dizziness
  • feeling weak
  • headache
  • common cold
  • upset stomach
  • diarrhoea
  • feeling tired, drowsy or sleepy.

Tell your doctor as soon as possible if you notice any of the following:

  • mood changes such as depression, nervousness, aggression, anger, anxiety, confusion, hallucination, irritability
  • feelings of depression
  • upper respiratory tract infections
  • weight loss.

These may be serious side effects and you may need medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • thoughts of harming yourself
  • more frequent or more severe seizures
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Other side effects not listed above may occur in some patients.

Some of these side effects, such as changes to your blood cell count, can only be found when your doctor does tests from time to time to check your progress.

Storage and disposal

Storage

Levetiracetam solution for infusion will be stored in the pharmacy or kept at the hospital.

The vials should be kept in a cool dry place where the temperature stays below 25°C.

Product description

What Levetiracetam APOTEX Solution for Infusion looks like

Levetiracetam concentrate solution is intended for IV infusion after dilution. It is a clear, colourless, sterile solution. AUST R 222092.

The primary container is a glass vial closed with a grey rubber stopper and sealed with an aluminium/ polypropylene flip off cap.

Available in a carton containing 10 vials.

Ingredients

One vial of levetiracetam solution for infusion contains 500 mg of levetiracetam (500 mg/5 mL) as the active ingredient.

It also contains the following inactive ingredients:

  • sodium acetate trihydrate
  • sodium chloride
  • glacial acetic acid
  • water for injections

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Latex free.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was last updated in January 2020.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Levetiracetam IV APOTEX

Active ingredient

Levetiracetam

Schedule

S4

 

1 Name of Medicine

Levetiracetam.

6.7 Physicochemical Properties

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). 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.
Chemical Name: (S)-α-ethyl-2-oxo -1-pyrrolidineacetamide.
Molecular Formula: C8H14N2O2.
Molecular Weight: 170.21.

Chemical structure.


CAS number.

102767-28-2.

2 Qualitative and Quantitative Composition

Levetiracetam concentrate solution for IV infusion contains 500 mg of levetiracetam (500 mg/5 mL) as the active ingredient.
One vial of levetiracetam concentrate solution for IV infusion contains 500 mg of levetiracetam (500 mg/5 mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The concentrated solution for IV infusion is a clear, colourless, sterile solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 anti-epileptic 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 γ-amino butyric acid (GABA) and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the drug.

Pharmacological actions.

In animals.

Levetiracetam is not active in the classical screening models for anticonvulsants however 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.

In man.

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

Clinical trials.

Effectiveness in partial onset seizures in adults and adolescents.

Monotherapy.

The monotherapy study was designed as a double-blind, parallel group, non-inferiority comparison of levetiracetam and carbamazepine controlled released in patients 16 years of age or older with newly diagnosed epilepsy. The seizures were to be either unprovoked partial seizures (type IA (simple partial seizures with unimpaired consciousness), IB (complex partial seizures with impaired consciousness), or IC (partial seizures secondarily generalised (with clear focal origin)) or IIE (generalised tonic-clonic seizure (without clear focal origin)), classifiable according to the International Classification of Epileptic Seizures. The study was performed in 85 centers in 13 countries (Europe and South Africa).
At the end of the 1-week screening period, eligible subjects were stratified by seizure type (IA/IB/IC or IC/IIE without clear focal origin) and randomly assigned to receive CBZ CR (N = 291) or LEV (N = 285), for up to 121 weeks depending on response. Conservatively, a controlled release (CR) formulation of carbamazepine was used to minimise adverse effects. The maximal duration for an individual subject was 121 weeks.
After a 1-week screening period (no study drug intake), the subject was randomized and entered a 2-week up-titration period to the first target daily dose (LEV 1000 mg /CBZ 400 mg), followed by a one-week stabilization period and an evaluation period of 26 weeks in order to achieve a 6-month seizure freedom (primary efficacy endpoint), and followed by a maintenance period of 26 additional weeks in order to assess safety and maintenance of efficacy.
If a seizure occurred during the evaluation period, dose escalation (made over a 2-week period) to the second target daily dose (LEV 2000 mg/ CBZ 800 mg) was foreseen. This was followed by a 1-week stabilization period, a new evaluation period of 26 weeks and a maintenance period of 26 additional weeks. The same was true if a seizure occurred during the evaluation period at the second dose level: dose escalation (made over a 2-week period) to the third target daily dose (LEV 3000 mg/ CBZ 1200 mg), followed by a one week stabilization period, a new evaluation period of 26 weeks and a maintenance period of 26 additional weeks. Fall back option: in case a subject did not tolerate the second or third study drug target dose, he/she had the opportunity, during the evaluation or the maintenance period, to have one fallback to an intermediate dose (decrease by 200 mg/day for CBZ or by 500 mg/day for LEV) and to continue in the trial on that basis. The subject could not resume the previous dose and could not have further up-titration in case a new seizure occurred.
576 subjects were randomised. Approximately one half of the patients in each treatment group completed the study (53.6% of the patients randomised to CBZ and 54.0% of the patients randomised to LEV), similar between the two treatment groups. The distribution by seizure type categories was similar in both treatment groups, with around 86.7% of subjects lastly classified as experiencing partial seizures with clear focus origin. The majority of subjects remained at dose level 1 (81.7% of subjects randomised to CBZ and 73.4% of subjects randomised to LEV in the PP population).
The prospectively defined primary endpoint was the proportion of subjects from the PP population with 6-month seizure freedom at the last evaluated dose.
One hundred seventy three (73.0%) of the PP subjects in the LEV arm were seizure-free for at least 6 months at the last evaluated dose, compared to 171 subjects (72.8%) in the CBZ arm. The adjusted absolute difference LEV and CBZ (95% two-sided CI) obtained from a logistic regression model including a factor for the seizure type category as last assessed (IA/IB/IC versus IC/IIE) equalled 0.2% (-7.8%; 8.2%). The lower limit of the confidence interval (-7.8%) was above the non-inferiority limit set by protocol (-15%) for this primary efficacy analysis, and therefore LEV can be considered as non-inferior to CBZ on the proportion of subjects seizure-free at least 6 months at the first evaluated dose in the PP population. Considering the other clinically relevant end-point, 56.6% and 58.5% of subjects on LEV and CBZ respectively were seizure free for 1 year.

Add-on therapy.

The effectiveness of levetiracetam tablets 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, 1000 mg, 2000 mg or 3000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least 2 years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4 week period.

Study 1.

Study 1 was a double blind, placebo controlled, parallel-group study conducted at 41 sites in the United States comparing levetiracetam 1000 mg/day (N = 97), levetiracetam 3000 mg/day (N = 101) and placebo (N = 95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients were randomised to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Study 1 are displayed in Table 8.
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.

Study 2.

Study 2 was a double blind, placebo controlled, crossover study conducted at 62 centres in Europe comparing levetiracetam 1000 mg/day (N = 106), levetiracetam 2000 mg/day (N = 105) and placebo (N = 111) given in equally divided doses twice daily.
The first period of the study (Period A) was designed to be analysed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients were randomised to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 9.
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.
The comparison of levetiracetam 2000 mg/day to levetiracetam 1000 mg/day for responder rate was statistically significant (P = 0.02). Analysis of the trial as a 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 3000 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 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomised treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency). Table 10 displays the results of the analysis of Study 3.
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3.

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 multicenter, 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 1-2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomised to receive either levetiracetam or placebo. 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 8-week baseline period and 4-week titration period followed by a 10-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 2-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 ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 11 displays the results of this study.
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.

Effectiveness in myoclonic seizures in patients ≥ 12 years of age with juvenile myoclonic epilepsy (JME).

The effectiveness of levetiracetam as adjunctive therapy in patients 12 years of age and older with juvenile myoclonic epilepsy experiencing myoclonic seizures was established in one multicenter, randomised, double blind, placebo controlled study, conducted at 37 sites in 14 countries. Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomised to either levetiracetam or placebo. The population included 120 patients (levetiracetam N = 60, placebo N = 60) with idiopathic generalised epilepsy which included juvenile myoclonic epilepsy, juvenile absence epilepsy, or epilepsy with generalised tonic-clonic seizures on awakening. The majority were patients with juvenile myoclonic epilepsy. Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses.
The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Secondary outcome variables included seizure frequency per week over the treatment period. Table 12 displays the results of this study.

Effectiveness in primary generalised tonic-clonic seizures in patients ≥ 4 years of age with idiopathic generalised epilepsy.

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 4 years of age and older with idiopathic generalised epilepsy experiencing primary generalised tonic-clonic (PGTC) seizures was established in one multicenter, randomised, double blind, placebo controlled study, conducted at 50 sites in 8 countries. Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomised to either levetiracetam or placebo. The 8-week combined baseline period is referred to as “baseline” in the remainder of this section. The population included 164 patients (levetiracetam N = 80, placebo N = 84) with idiopathic generalised epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalised tonic-clonic seizures. Each of these syndromes of idiopathic generalised epilepsy was well represented in this patient population. Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a paediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day.
The primary measure of effectiveness was the percent reduction from baseline in weekly PGTC seizure frequency for levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam treated patients compared to the placebo treated patients. (See Table 13).
The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomised treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 5.
When levetiracetam was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.

5.2 Pharmacokinetic Properties

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear and time independent with low intra- and inter-subject 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 bodyweight. 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 post dose for oral solution formulation).
A single dose of 1500 mg 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 1.3 hours after dosing. Steady state is achieved after two days of a twice daily administration schedule. Peak concentrations (Cmax) are typically 31 microgram/mL and 43 microgram/mL following a single 1000 mg dose and repeated 1000 mg b.i.d. 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, levetiracetam 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 CYP1A1/2 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 ± 1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 mL/min/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/min/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/min/kg indicating active tubular secretion in addition to glomerular filtration.

Elderly.

In elderly patients, the half life is increased by about 40% (10 to 11 hours) and is attributed to the decrease in renal function in this population (see Section 4.2 Dose and Method of 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 5 hours. The apparent body clearance was 1.1 mL/min/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 levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment (see Section 4.2 Dose and Method of Administration).
In anuric end stage renal disease adult subjects the half life was approximately 25 and 3.1 hours during inter- and intra-dialytic periods respectively. The fractional removal of levetiracetam was 51% during a typical 4-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 Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

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.

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 4 fold and 8 fold that in humans at the maximal recommended clinical dose of 3000 mg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Levetiracetam concentrate solution for IV infusion is indicated for:
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;
monotherapy in the treatment of partial onset seizures, with or without secondary generalisation, in patients from 16 years of age with newly diagnosed epilepsy;
add on therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy (JME) and;
add on therapy in the treatment of primary generalized tonic-clonic seizures in adults and children from 4 years of age with idiopathic generalized epilepsy (IGE).
Levetiracetam concentrate solution for IV infusion after dilution is an alternative for patients when oral administration is temporarily not feasible.

4.3 Contraindications

Hypersensitivity to levetiracetam or other pyrrolidone derivatives or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

In accordance with current clinical practice, if levetiracetam has to be discontinued it is recommended to withdraw it gradually.
Levetiracetam concentrate solution for IV infusion should not be administered by rapid infusion or direct IV injection.
To date, there is no data to support the use of levetiracetam concentrate solution for IV infusion for status epilepticus.
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.
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 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 4 shows absolute and relative risk by indication for all evaluated AEDs.
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 levetiracetam or any 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 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 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.

Acute kidney injury.

The use of levetiracetam has been associated with acute kidney injury.

Blood cell counts.

Decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been reported 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)).

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.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; 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 severe hepatic impaired 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; 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.

4.5 Interactions with Other Medicines and Other Forms of 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.
Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.
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 (ethinyl-estradiol 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.

4.6 Fertility, Pregnancy and Lactation

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 1800 mg/kg/day (corresponding to approximately 6 times the maximal recommended clinical dose on a mg/m2 basis) administered for at least two weeks prior to, and throughout, mating.
(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 pre- and/or postnatally at doses ≥ 350 mg/kg/day (approximately equivalent to the maximal recommended clinical dose of 3000 mg/day on a mg/m2 basis) and with increased pup mortality and offspring behavioural alterations at a dose of 1800 mg/kg/day (6 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 embryofoetal mortality and increased incidences of minor foetal skeletal abnormalities at doses ≥ 600 mg/kg/day (about 4 times the maximal human dose on a mg/m2 basis) and in decreased foetal weights and increased incidences of minor foetal skeletal anomalies at a dose of 1800 mg/kg/day (12 times the maximal 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 1800 mg/kg/day.
Oral administration to pregnant rats during the period of organogenesis resulted in reduced foetal weight and increased incidence of embryofoetal mortality and increased incidence of foetal skeletal variations at a dose of 3600 mg/kg/day (12 times the maximal human dose on a mg/m2 basis). The developmental no-effect dose was 1200 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.
A large amount of post-marketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not indicate increased risk of major malformations.
Limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. Information available from published epidemiological studies does not suggest an increased risk of neurodevelopmental disorders or delays.
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 (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. To monitor 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.
Levetiracetam and/or its metabolites are excreted in milk in lactating rats; peak milk concentrations occurred 3 hours after oral administration (milk:plasma ratio 0.9). Levetiracetam is excreted in human 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.

4.8 Adverse Effects (Undesirable Effects)

The prescriber should be aware that 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 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 3000 subjects and patients. Of these, 780 patients were treated for more than 6 months, 592 for more than 1 year, 366 for more than 2 years and 185 for more than 3 years.
1023 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, 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 (≥ 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 5).
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 Coding Symbol for Thesaurus of Adverse Reaction Times (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. (See Table 6).

Common adverse events (≥ 1%, < 10%).


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 7).
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.

Post-marketing experience.

In post-marketing 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 post-marketing 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.

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, suicidal ideation and delirium.

Nervous system disorders.

Choreoathetosis, dyskinesia, lethargy, gait disturbance.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme and alopecia; in several alopecia cases, recovery was observed when levetiracetam was discontinued.

Musculoskeletal and connective tissue disorders.

Muscular weakness, rhabdomyolysis, 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, hyponatremia.
Cases of encephalopathy have been rarely observed after levetiracetam administration.

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.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Levetiracetam IV Apotex concentrate solution is intended for IV infusion.

Dosage.

Levetiracetam therapy can be initiated with either intravenous or oral administration. Conversion to or from oral to intravenous can be done directly without titration. The total daily dose and frequency of administration should be maintained.
Levetiracetam concentrate solution for IV infusion is for intravenous use only and must be diluted in at least 100 mL of a compatible diluent and administered as a 15 minute intravenous infusion.

Monotherapy.

The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after 2 weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy.

Adults (≥ 18 years of age) and adolescents (aged 12-17 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 1500 mg twice daily. Dose changes can be made in 500 mg twice daily increments or decrements every 2 to 4 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 Renal impairment section below).

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

The initial therapeutic dose is 10 mg/kg twice daily. See Table 1.
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 physician should prescribe the most appropriate pharmaceutical form and 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.

Renal impairment.

The levetiracetam daily dose must be individualised according to renal function. For adult patients, see Table 2 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 (see Equation 1):
Then CLcr is adjusted for body surface area (BSA) as follows (see Equation 2):
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.

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 < 60 mL/min/1.73 m2.

Concentrate solution for IV infusion incompatibilities.

The formation of precipitate has been observed when mixing levetiracetam concentrate solution for IV infusion and phenytoin sodium in a polyvinyl chloride (PVC) bag.
This medicinal product must not be mixed with other medicinal products except those mentioned below.

Instructions for use and handling of the concentrate solution for IV infusion.

Table 3 provides a summary for the recommended preparation and administration of levetiracetam concentrate solution for IV infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg or 3000 mg in two divided doses.
Levetiracetam concentrate solution for IV infusion is for single use in one patient only.
Levetiracetam concentrate solution for IV infusion was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in PVC bags at controlled room temperature 15-30°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

Diluents.

Sodium chloride (0.9%) injection, Lactated Ringer’s injection, dextrose 5% injection.

Other antiepileptic medicinal products.

Lorazepam, diazepam, sodium valproate.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

Symptoms.

The highest known dose of levetiracetam received in the clinical development program was 6000 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 post-marketing 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 information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium acetate trihydrate, sodium chloride, glacial acetic acid, water for injections.

6.2 Incompatibilities

The formation of precipitate has been observed when mixing levetiracetam concentrate solution for IV infusion and phenytoin sodium in a polyvinyl chloride (PVC) bag.
This medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. See Section 4.2 Dose and Method of Administration for information on storage following dilution.

6.5 Nature and Contents of Container

Levetiracetam Apotex concentrate solution for IV infusion.
The primary container is glass vial closed with a grey stopper and sealed with an aluminium/polypropylene flip off cap. Available in a carton containing 10 vials.
AUST R 222092.
Apotex is a registered trade mark of Apotex Inc.
Latex free.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes