Consumer medicine information

Hospira Levetiracetam concentrate for IV infusion

Levetiracetam

BRAND INFORMATION

Brand name

Hospira Levetiracetam Concentrate for IV Infusion

Active ingredient

Levetiracetam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hospira Levetiracetam concentrate for IV infusion.

What is in this leaflet

This leaflet answers some common questions about Hospira Levetiracetam concentrate for IV infusion.

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 taking Hospira Levetiracetam concentrate for IV infusion 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 in a safe place. You may need to read it again.

What Hospira Levetiracetam concentrate for IV infusion is used for

Hospira Levetiracetam concentrate for IV infusion 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.

This medicine 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.

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

Your doctor may have prescribed this medicine in addition to your current therapy.

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

There is no evidence that this medicine is addictive.

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

The safety and effectiveness of Hospira Levetiracetam concentrate for IV infusion has not been established in patients less than 4 years of age.

Before you are given Hospira Levetiracetam concentrate for IV infusion

When you must not be given it

You must not be given Hospira Levetiracetam concentrate for IV infusion if you have an allergy to:

  • 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.

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

Before you are given it

Tell your doctor if you have allergies to:

  • any other medicines, especially barbiturates (such as phenobarbitone) or any other antiepileptic medicines (such as carbamazepine, lamotrigine or valproate)
  • any other substances, such as foods, preservatives or dyes.

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

  • kidney problems
  • liver problems.

Tell your doctor if you are pregnant or intend to become pregnant. Hospira Levetiracetam concentrate for IV infusion may affect your developing baby if you take it during pregnancy. However, it is very important to control your seizures while you are pregnant. Your doctor will outline and weigh up all the risks and benefits of taking Hospira Levetiracetam concentrate for IV infusion during pregnancy to help decide whether or not you should take it.

Tell your doctor if you are breastfeeding or plan to breastfeed. The active ingredient in Hospira Levetiracetam concentrate for IV infusion passes into breast milk and there is a possibility that your baby may be affected. Your doctor will discuss the risks and benefits of using Hospira Levetiracetam concentrate for IV infusion if you are breastfeeding.

If you have not told your doctor about any of the above, tell them before you are given Hospira Levetiracetam concentrate for IV infusion.

Taking other medicines

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

Hospira Levetiracetam concentrate for IV infusion does not interact with the oral contraceptive pill.

However, you may be given Hospira Levetiracetam concentrate for IV infusion together with other antiepileptic medicines that do interact and may affect the effectiveness of your contraceptive. Your doctor may advise you to use an additional method of contraception if you take Hospira Levetiracetam concentrate for IV infusion with other antiepileptic medicines

How Hospira Levetiracetam concentrate for IV infusion is given

How much is given

Your doctor will decide how much Hospira Levetiracetam concentrate for IV infusion you will receive. This depends on your age, your condition and whether or not you are taking any other medicines.

How it is given

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

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

If you take too much (overdose)

As Hospira Levetiracetam concentrate for IV 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.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Hospira Levetiracetam concentrate for IV infusion. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Hospira Levetiracetam concentrate for IV infusion

Things you must do

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

Tell your doctor immediately if you have symptoms of depression or thoughts of harming yourself.

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

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

Before you have any surgery or emergency treatment, tell your doctor or dentist that you are being given Hospira Levetiracetam concentrate for IV infusion.

Tell your doctor if you feel Hospira Levetiracetam concentrate for IV infusion is not helping your condition. Your doctor may need to change your medicine.

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

Be sure to keep all of your doctor’s appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time. This helps to prevent unwanted side effects.

Stopping Hospira Levetiracetam concentrate for IV infusion suddenly may cause unwanted side effects or make your condition worse.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. Children should be careful doing things like riding bicycles or climbing trees. As with other antiepileptic medicines, Hospira Levetiracetam concentrate for IV infusion 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.

Be careful when drinking alcohol while taking this medicine. Combining Hospira Levetiracetam concentrate for IV infusion and alcohol can make you more drowsy. Your doctor may suggest you avoid alcohol while you are being treated with Hospira Levetiracetam concentrate for IV infusion.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Hospira Levetiracetam concentrate for IV infusion. This medicine helps most people with epilepsy, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

If you get any side effects, do not stop taking Hospira Levetiracetam concentrate for IV infusion without first talking to your doctor or pharmacist.

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.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

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.

The above list includes serious side effects that may require 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
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, mouth, throat or tongue 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.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

After you have been given Hospira Levetiracetam concentrate for IV infusion

Storage

Hospira Levetiracetam concentrate for IV infusion will be stored in the pharmacy or on the ward. The vials are kept in a cool dry place where the temperature stays below 25°C.

Product description

What it looks like

Hospira Levetiracetam concentrate for IV infusion is a clear, colourless solution.

Ingredients

Each vial of Hospira Levetiracetam concentrate for IV infusion contains 500 mg/5 mL levetiracetam.

It also contains:

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

Sponsor

Hospira Levetiracetam concentrate for IV infusion is supplied by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number:
1800 675 229
www.pfizer.com.au.

Australian registration number

Hospira Levetiracetam concentrate for IV infusion: AUST R 211468

Date of Preparation

December 2019

™ Trademark

© Pfizer Australia Pty Ltd 2019

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Hospira Levetiracetam Concentrate for IV Infusion

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), soluble 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: 170.2.

Chemical structure.


CAS number.

102767-28-2.

2 Qualitative and Quantitative Composition

Hospira Levetiracetam concentrate for IV infusion contains 500 mg of levetiracetam in 5 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated injection for intravenous infusion.
Hospira Levetiracetam concentrate for IV infusion is a clear, colourless and sterile aqueous 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 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 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 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, noninferiority comparison of levetiracetam and controlled released (CR) formulation of carbamazepine 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)). These different types of seizures were classified according to the International Classification of Epileptic Seizures. The study was performed in 85 centres 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 carbamazepine CR (N = 291) or levetiracetam (N = 285), for up to 121 weeks depending on response. Conservatively, carbamazepine CR 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 (levetiracetam 1000 mg/carbamazepine CR 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 (levetiracetam 2000 mg/ carbamazepine 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 strategy was applied 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 (levetiracetam 3000 mg/ carbamazepine 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 carbamazepine CR or by 500 mg/day for levetiracetam) 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.
Five hundred and seventy six (576) subjects were randomised. Approximately one-half of the patients in each treatment group completed the study (53.6% of the patients randomised to carbamazepine CR and 54.0% of the patients randomised to levetiracetam), 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 carbamazepine CR and 73.4% of subjects randomised to levetiracetam in the per protocol (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 levetiracetam arm were seizure free for at least 6 months at the last evaluated dose, compared to 171 subjects (72.8%) in the carbamazepine CR arm. The adjusted absolute difference levetiracetam and carbamazepine CR (95% two sided confidence interval 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 CI (-7.8%) was above the noninferiority limit set by protocol (-15%) for this primary efficacy analysis, and therefore levetiracetam can be considered as noninferior to carbamazepine CR 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 endpoint, 56.6% and 58.5% of subjects on levetiracetam and carbamazepine CR respectively were seizure free for 1 year.

Add on therapy.

The effectiveness of levetiracetam tablets as adjunctive therapy (added to other antiepileptic drugs (AEDs)) 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 AEDs) 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 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 AEDs) 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 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 PGTC 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 pediatric 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 PGTC 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 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 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 postdose 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. During the first 48 hours, the cumulative urinary excretion of levetiracetam and its major metabolite (ucb L057) accounted for 66% and 24% of the dose respectively.
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 endstage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during inter- and intradialytic 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 were 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

Hospira Levetiracetam concentrate for IV infusion after dilution is an alternative for patients when oral administration is temporarily not feasible.
Levetiracetam 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; 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.

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.
Hospira Levetiracetam concentrate 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 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.
To date, there are no data to support the use of levetiracetam in patients less than 4 years of age. No data on the interaction of levetiracetam with alcohol are available.

Suicidal behaviour and ideation.

AEDs, including levetiracetam, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients 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.

Use in hepatic impairment.

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 renal impairment.

The administration of levetiracetam to patients with renal impairment may require dose adaptation. See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Elderly (65 years and older).

Paediatric use.

No data available.

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. non-steroidal anti-inflammatory drugs, sulphonamides, and methotrexate is unknown.
Premarketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing AEDs (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 (ethinylestradiol 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)
Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed.
Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
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 AEDs receive pre-pregnancy 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 midtrimester ultrasound should be offered.
To date, insufficient clinical data on exposed pregnancies are available. 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. There have been reports of decreased levetiracetam concentrations during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy).
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 AED 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 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 white blood cells, 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 6.
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. About 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.

Postmarketing experience.

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

Blood and lymphatic system disorders.

Pancytopenia with bone marrow suppression identified in some of these cases, leucopenia and neutropenia.

Psychiatric disorders.

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

Nervous system disorders.

Choreoathetosis, dyskinesia, lethargy.

Skin and subcutaneous tissue disorders.

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

Musculoskeletal and connective tissue disorders.

Muscular weakness.

Liver and biliary system disorders.

Hepatitis, hepatic failure and abnormal liver function test.

Metabolic and nutritional disorders.

Weight loss, pancreatitis.

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.

4.2 Dose and Method of Administration

Dosage.

Levetiracetam therapy can be initiated with either intravenous or oral administration (oral dosage forms including tablets and oral solution are available as other registered products). Conversion to or from oral to intravenous can be done directly without titration. The total daily dose and frequency of administration should be maintained.
Hospira Levetiracetam concentrate 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 (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).

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.

Dosage adjustment.

Elderly (65 years and older).

Adjustment of the dose is recommended in the elderly with compromised renal function (see Patients with renal impairment 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.
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. See Table 1.

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 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.

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 < 60 mL/min/1.73 m2.

Method of administration.

Incompatibilities.

The formation of precipitate has been observed when mixing the infusion with phenytoin sodium in a PVC bag.
Hospira Levetiracetam concentrate for IV infusion must not be mixed with other medicinal products except those mentioned below.

Instructions for use and handling.

Table 3 provides a summary for the recommended preparation and administration of Hospira 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.
Hospira Levetiracetam concentrate 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.
Hospira Levetiracetam concentrate for IV infusion is for single use in one patient only. Discard any residue. To reduce microbiological hazard, 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 be not 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 system (CNS) related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles, or operating machinery.

4.9 Overdose

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 postmarketing use.
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, contact the Poisons Information Centre (telephone 13 11 26) (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 and nitrogen.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration, Incompatibilities.

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

Hospira Levetiracetam concentrate for IV infusion is stored below 25°C.

6.5 Nature and Contents of Container

Hospira Levetiracetam concentrate for IV infusion is a sterile, clear and colourless aqueous solution presented in clear glass vials. Each vial contains 500 mg of levetiracetam (500 mg/5 mL). The vial is closed with bromobutyl rubber stopper and aluminum seal with plastic flip-off top.
Hospira Levetiracetam concentrate for IV infusion is supplied in single-use 5 mL vials and available in cartons of 10 vials. Each vial contains a slight excess of approximately 0.4 mL of the labelled volume to permit withdrawal and administration of the labelled volume.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes