levETIRAcetam 500 MG 24HR Extended Release Oral Tablet

Generic Name: LEVETIRACETAM
Brand Name: Levetiracetam
  • Substance Name(s):
  • LEVETIRACETAM

DRUG INTERACTIONS

7 7.1 General Information In vitro data on metabolic interactions indicate that levetiracetam extended-release tablet is unlikely to produce, or be subject to, pharmacokinetic interactions.

Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP‑glucuronidation enzymes.

In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening with immediate-release levetiracetam tablets in the placebo-controlled clinical studies in epilepsy patients.

The following are the results of these studies.

The potential for drug interactions for levetiracetam extended-release tablet is expected to be essentially the same as that with immediate-release levetiracetam tablets.

7.2 Phenytoin Immediate-release levetiracetam tablets (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy.

Pharmacokinetics of levetiracetam were also not affected by phenytoin.

7.3 Valproate Immediate-release levetiracetam tablets (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers.

Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion.

There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.

7.4 Other Antiepileptic Drugs Potential drug interactions between immediate-release levetiracetam tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies.

These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.

7.5 Oral Contraceptives Immediate-release levetiracetam tablets (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely.

Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.

7.6 Digoxin Immediate-release levetiracetam tablets (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day.

Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

7.7 Warfarin Immediate-release levetiracetam tablets (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin.

Prothrombin time was not affected by levetiracetam.

Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

7.8 Probenecid Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily.

C ss max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same.

Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057.

The effect of immediate-release levetiracetam tablets on probenecid was not studied.

OVERDOSAGE

10 Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans The signs and symptoms for levetiracetam extended-release tablets overdose are expected to be similar to those seen with immediate-release levetiracetam tablets.

The highest known dose of oral immediate-release levetiracetam tablets received in the clinical development program was 6000 mg/day.

Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials.

Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release levetiracetam overdoses in postmarketing use.

Treatment Or Management Of Overdose There is no specific antidote for overdose with levetiracetam extended-release tablets.

If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway.

General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status.

A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam extended-release tablets.

Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose.

Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

DESCRIPTION

11 Levetiracetam extended-release tablet is an antiepileptic drug available as 500 mg and 750 mg (white to off-white) extended-release tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8H14N2O2 and its molecular weight is 170.21.

Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).

It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste.

It is very soluble in water (104.0 g/100 mL).

It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane.

(Solubility limits are expressed as g/100 mL solvent.) Levetiracetam extended-release tablets contain the labeled amount of levetiracetam.

Inactive ingredients: Colloidal silicon dioxide, hydroxypropyl cellulose, magnesium stearate and opadry II white Y-22-7719 which contains hypromellose, macrogol, polydextrose, titanium dioxide and triacetin.

this is the structure

CLINICAL STUDIES

14 The effectiveness of the immediate-release formulation of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo controlled clinical studies in 904 patients who had refractory partial onset seizures with or without secondary generalization for at least two years and had taken two or more classical AEDs.

The effectiveness of levetiracetam extended-release tablets as adjunctive therapy (added to other antiepileptic drugs) was established in one multicenter, randomized, double-blind, placebo-controlled clinical study across 7 countries in patients who had refractory partial onset seizures with or without secondary generalization.

Patients enrolled had at least eight partial seizures with or without secondary generalization during the 8 week baseline period and at least two partial seizures in each 4 week interval of the baseline period.

Patients were taking a stable dose regimen of at least one and could take a maximum of three AEDs.

After a prospective baseline period of 8 weeks, 158 patients were randomized to placebo (N=79) or levetiracetam extended- release tablets (2×500 mg tablets) (N=79) given once daily over a 12 week treatment period.

The primary efficacy endpoint was the percent reduction over placebo in mean weekly frequency of partial onset seizures.

The median percent reduction in weekly partial onset seizure frequency from baseline over the treatment period was 46.1% in the levetiracetam extended-release tablets 1000 mg treatment group (N=74) and 33.4% in the placebo group (N=78).

The estimated percent reduction over placebo in weekly partial onset seizure frequency over the treatment period was 14.4% (statistically significant).

The relationship between the effectiveness of the same daily dose of levetiracetam extended- release tablets and immediate-release levetiracetam tablets has not been studied and is unknown.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Levetiracetam extended-release tablets 500 mg are white to off-white, capsule shaped, biconvex tablets, debossed with “P” on one side and “204” on the other.

They are supplied in white HDPE bottles containing 60 tablets (NDC 49884-204-02) and 500 tablets (NDC 49884-204-05).

Levetiracetam extended-release tablets 750 mg are white to off-white, capsule shaped, biconvex tablets, debossed with “P” on one side and “205” on the other.

They are supplied in white HDPE bottles containing 60 tablets (NDC 49884-205-02) and 500 tablets (NDC 49884-205-05).

16.2 Storage Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container with a child-resistant closure

RECENT MAJOR CHANGES

Warnings and Precautions ( 5) [04/2009] Patient Counseling Information ( 17) [04/2009]

GERIATRIC USE

8.5 Geriatric Use There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam extended-release tablets in these patients.

It is expected that the safety of levetiracetam extended-release tablets in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release levetiracetam tablets.

Of the total number of subjects in clinical studies of immediate-release levetiracetam, 347 were 65 and over.

No overall differences in safety were observed between these subjects and younger subjects.

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release levetiracetam in these patients.

A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice daily doses of immediate-release levetiracetam tablets for 10 days showed no pharmacokinetic differences related to age alone.

Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

DOSAGE FORMS AND STRENGTHS

3 Levetiracetam extended-release tablets 500 mg are white to off-white, capsule shaped, biconvex tablets, debossed with “P” on one side and “204” on the other.

Levetiracetam extended-release tablets 750 mg are white to off-white, capsule shaped, biconvex tablets, debossed with “P” on one side and “205” on the other.

•500 mg white to off-white, film-coated extended-release tablet (3) •750 mg white to off-white, film-coated extended-release tablet (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures.

Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests.

Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization.

Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state.

The predictive value of these animal models for specific types of human epilepsy is uncertain.

In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N‑methyl-D-aspartate), re-uptake sites, and second messenger systems.

Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission.

However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam.

Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis.

Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice.

These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

INDICATIONS AND USAGE

1 Levetiracetam extended-release tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy.

( 1) Levetiracetam extended-release tablet is an antiepileptic drug indicated for adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy ( 1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of levetiracetam extended-release tablets in patients below the age of 16 years have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.

In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses.

Levetiracetam extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m 2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis).

The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis).

There was no overt maternal toxicity at the doses used in this study.

Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (approximately 4 times MRHD on a mg/m 2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis).

The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis).

Maternal toxicity was also observed at 1800 mg/kg/day.

When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD).

1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose.

There was no evidence of maternal toxicity in this study.

Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at oral doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).

Pregnancy Registry To provide information regarding the effects of in utero exposure to levetiracetam extended-release, physicians are advised to recommend that pregnant patients taking levetiracetam extended-release enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry.

This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves.

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

NUSRING MOTHERS

8.3 Nursing Mothers Levetiracetam is excreted in breast milk.

Because of the potential for serious adverse reactions in nursing infants from levetiracetam extended-release tablets, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Suicidal Behavior and Ideation.

(5.1) • Neuropsychiatric Adverse Reactions: Levetiracetam extended-release tablets causes somnolence, dizziness, and behavioral abnormalities.

The adverse reactions that may be seen in patients receiving levetiracetam extended-release tablets are expected to be similar to those seen in patients receiving immediate-release levetiracetam tablets.

(5.2) •In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, immediate-release levetiracetam causes somnolence and fatigue, coordination difficulties, and behavioral abnormalities (e.g., psychotic symptoms, suicidal ideation, and other abnormalities).

(5.2) • Withdrawal Seizures: Levetiracetam extended-release tablets must be gradually withdrawn.

(5.3) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including levetiracetam-extended release tablets, increase the risk of suicidal thoughts or behavior 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 behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior 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 behavior 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 behavior 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 behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

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 analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing levetiracetam extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesss for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior 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 behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.2 Neuropsychiatric Adverse Reactions Levetiracetam Extended-Release Tablets In some patients experiencing partial onset seizures, levetiracetam extended-release tablets causes somnolence, dizziness, and behavioral abnormalities.

In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of levetiracetam extended-release tablets treated patients experienced somnolence compared to 2.5% of placebo treated patients.

Dizziness was reported in 5.2% of levetiracetam extended-release tablets treated patients compared to 2.5% of placebo treated patients.

A total of 6.5% of levetiracetam extended-release tablets treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo treated patients.

Irritability was reported in 6.5% of levetiracetam extended-release tablets treated patients.

Aggression was reported in 1.3% of levetiracetam extended-release tablets treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to levetiracetam extended-release tablet was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials.

Therefore, certain adverse reactions observed in the immediate-release levetiracetam controlled trials may also occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, immediate-release levetiracetam causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of immediate-release levetiracetam treated patients reported somnolence, compared to 8.4% of placebo patients.

There was no clear dose response up to 3000 mg/day.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients.

A total of 3.4% of immediate-release levetiracetam treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients.

Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-release levetiracetam treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient.

A total of 13.3% of immediate-release levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.

5.3 Withdrawal Seizures Antiepileptic drugs, including levetiracetam extended-release tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency.

5.4 Hematologic Abnormalities Although there were no obvious hematologic abnormalities observed in treated patients in the levetiracetam extended-release tablets controlled study, the limited number of patients makes any conclusion tentative.

The data from the partial seizure patients in the immediate-release levetiracetam controlled studies should be considered to be relevant for levetiracetam extended-release tablets treated patients.

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 6/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam treated patients.

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% of treated and 1.4% of placebo patients had at least one possibly 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.

5.5 Hepatic Abnormalities There were no meaningful changes in mean liver function tests (LFT) in the levetiracetam extended-release tablets controlled trial.

No patients were discontinued from the controlled trial for LFT abnormalities.

There were no meaningful changes in mean liver function tests (LFT) in controlled trials of immediate-release levetiracetam tablets in adult patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%).

No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

5.6 Laboratory Tests Although effects on laboratory tests were not clinically significant with levetiracetam extended- release tablets treatment, it is expected that the data from immediate-release levetiracetam tablets controlled studies would be considered relevant for levetiracetam extended-release tablets treated patients.

Although most laboratory tests are not systematically altered with immediate-release levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking levetiracetam extended-release tablets.

The Medication Guide may also be found in the full prescribing information for levetiracetam extended- release tablets posted on http://www.parpharm.com or by calling 1-800-828-9393.

Patients should be instructed to take levetiracetam extended-release tablets only as prescribed Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam extended- release tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that levetiracetam extended-release tablets may cause irritability and aggression.

In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of levetiracetam, which include agitation, anger, anxiety, apathy, depression, hostility, irritability and, in rare cases, psychotic symptoms.

Patients should be instructed to only take levetiracetam extended-release tablets as prescribed and to swallow the tablets whole.

They should not be chewed, broken, or crushed.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll free number 1-888-233-2334.

Patients should be advised that levetiracetam extended-release tablets may cause dizziness and somnolence.

Accordingly, patients should be advised not to drive or operate heavy machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam extended- release tablets to gauge whether it adversely affects their performance of these activities.

Rx only Manufactured by: Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977 Revised 02/2012

DOSAGE AND ADMINISTRATION

2 Treatment should be initiated with a dose of 1000 mg once daily.

The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg.

Treatment should be initiated with a dose of 1000 mg once daily.

The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg ( 2).

See full prescribing information for use in patients with impaired renal function ( 2.1).

2.1 Adult Patients With Impaired Renal Function Levetiracetam extended-release tablets dosing must be individualized according to the patient’s renal function status.

Recommended doses and adjustment for dose for adults are shown in Table 1.

To use this dosing table, an estimate of the patient’s creatinine clearance (CLcr) in mL/min is needed.

CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula: CLcr = [140-age (years)] x weight (kg)x 1 0.85 72 x serum creatinine (mg/dL) 1.

For female patients Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min) CLcr (mL/min/1.73m 2)= —————————- x 1.73 BSA subject (m 2) Table 1: Dosing Adjustment Regimen For Adult Patients With Impaired Renal Function Group Creatinine Clearance (mL/min/1.73m2) Dosage (mg) Frequency Normal > 80 1000 to 3000 Every 24 h Mild 50 – 80 1000 to 2000 Every 24 h Moderate 30 – 50 500 to 1500 Every 24 h Severe < 30 500 to 1000 Every 24 h