Abbott-Levetiracetam: Indications, Dosage, Precautions, Adverse Effects
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Abbott-Levetiracetam - Product Information

Manufacture: Abbott
Country: Canada
Condition: Epilepsy, Seizures (Convulsions)
Class: Pyrrolidine anticonvulsants
Form: Tablets
Ingredients: Contain the labeled amount of levetiracetam, corn starch, sodium starch glycolate, colloidal silicon dioxide, povidone, talc, magnesium stearate, purified water, hypromellose, polyethylene glycol, titanium dioxide, FD & C blue #2 (250 mg only), ferric oxide yellow (500 mg only), ferric oxide red (750 mg only) and FD & C yellow #6 (750 mg only).

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
oral Tablet 250 mg, 500 mg and 750 mg None
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

Adults

Abbott-Levetiracetam (levetiracetam) is indicated as adjunctive therapy in the management of patients with epilepsy who are not satisfactorily controlled by conventional therapy.

Geriatrics (≥ 65 Years of Age)

There were insufficient numbers of elderly patients in controlled trials for epilepsy to adequately assess the efficacy or safety of levetiracetam in these patients. Only 9 of 672 patients treated with levetiracetam were 65 or over (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Pediatrics (<18 Years of Age)

Safety and efficacy in patients below the age of 18 have not been studied (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics).

Contraindications

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

Warnings and Precautions

Neurologic

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 somnolence or other central nervous system related symptoms, at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery.

Dependence/Tolerance

As with all antiepileptic drugs, levetiracetam should be withdrawn gradually to minimize the potential of increased seizure frequency.

Psychiatric

Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.

An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behavior in patients treated with these drugs. The mechanism of this risk is not known.

There were 43892 patients in the placebo controlled clinical trials that were included in the meta- analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behavior from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behavior for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug- placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.

Skin

Hypersensitivity Reactions

Serious hypersensitivity reactions with dermatological involvement have been reported in both children and adults in association with levetiracetam use, including Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Such serious skin reactions may be life-threatening, and some patients have required hospitalization with very rare reports of fatal outcome. There is no way to tell if a mild rash will become a severe skin reaction. If any of these hypersensitivity reactions are suspected, and an alternative cause cannot be established, Abbott-Levetiracteam should be discontinued. Recurrence of the serious skin reactions following re-challenge with levetiracetam has been reported.

The median time to onset for reported cases of SJS and TEN was 12 days. The reporting rate of TEN and SJS associated with levetiracetam use, which is generally accepted to be an underestimate due to underreporting, is 9 cases/million patient years. This exceeds the background incidence rate estimates for these serious skin reactions in the general population; background estimates range between 0.5 to 6 cases per million-person years.

The time to onset of DRESS may be longer than for SJS and TEN, e.g. up to 6 weeks or more after treatment initiation. Typically, although not exclusively, DRESS initially presents with fever and rash, and then with other organ system involvement that may or may not include eosinophilia, lymphadenopathy, hepatitis, nephritis, and/or myocarditis. Because DRESS is variable in its expression, other organ system signs and symptoms not noted here may also occur. Organ involvement may be more severe than skin involvement.

Carcinogenesis and Mutagenesis

See Scientific Information: TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data.

Hematologic

Statistically significant decreases compared to placebo were seen in total mean RBC count, mean hemoglobin, and mean hematocrit in levetiracetam-treated patients in controlled trials. For hemoglobin values, the percentage of levetiracetam or placebo treated patients with possibly clinically significant abnormalities were less than 0.5% each. For hematocrit values, a total of 5.1% of levetiracetam treated versus 3.2% of placebo patients had at least one possibly significant decrease in hematocrit (≤ 37% in males and 32% in females).

For white blood cells (WBC), 2.9% of treated versus 2.3% of placebo patients had at least one possibly clinically significant decrease in WBC count (≤ 2.8 x 109/L), while 2.6% of treated vs. 1.7% of placebo patients had at least one possibly significant decrease in neutrophil count (≤ 1.0 x 109/L). Of the levetiracetam treated patients with a low neutrophil count, all but one rose towards or reached baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Special Populations

Patients With Renal Impairment

Renal excretion of unchanged drug accounts for approximately 66% of administered levetiracetam dose. Consistent with this, pharmacokinetic studies in renally-impaired patients indicate that apparent clearance is significantly reduced in subjects with renal impairment (see ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

In patients with renal impairment levetiracetam dosage should be appropriately reduced. Patients with end stage renal disease, i.e. those undergoing dialysis should be given supplemental doses after dialysis (see DOSAGE AND ADMINISTRATION).

Pregnant Women

In reproductive toxicity studies in rats and rabbits, levetiracetam induced developmental toxicity at exposure levels similar to or greater than the human exposure. There was evidence of increased skeletal variations/minor anomalies, retarded growth, embryonic death, and increased pup mortality. In the rat, fetal abnormalities occurred in the absence of overt maternal toxicity. The systemic exposure at the observed no effect level in the rabbit was about 4 to 5 times the human exposure.

There are no adequate and well-controlled studies on the use of levetiracetam in pregnant women. Levetiracetam and/or its metabolites cross the placental barrier in animal species and in humans.

Information about the potential risk for humans is limited. Pregnancy registry data indicate that the risk of having a child with a birth defect is greater for women on antiepileptic polytherapy, including levetiracetam as a component, than for women not treated with antiepileptic drugs. Levetiracetam should not be used during pregnancy unless potential benefits to mother and fetus are considered to outweigh potential risks to both. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.

As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). It is recommended that clinical response should be monitored carefully in women receiving levetiracetam treatment during pregnancy, and determination of changes in plasma concentrations should be considered to ensure that adequate seizure control is maintained throughout pregnancy. In the event that medication is increased during pregnancy, the dose may need to be adjusted postpartum.

Pregnancy Registry

Pregnant patients taking levetiracetam should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888- 233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://www.aedpregnancyregistry.org/

Nursing Women

Levetiracetam is excreted in breast milk. Therefore, there is a potential for serious adverse reactions from Abbott -Levetiracetam in nursing infants. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother, and the as-yet uncharacterized risks to the infant.

Pediatrics (< 18 Years of Age)

Safety and efficacy in patients below the age of 18 have not been studied.

Geriatrics (≥ 65 Years of Age)

Renal function can be decreased in the elderly and levetiracetam is known to be substantially excreted by the kidney, the risk of adverse reactions to the drug may be greater in patients with impaired renal function. A pharmacokinetic study in 16 elderly subjects (age 61-88 years) showed a decrease in clearance by about 40% with oral administration of both single dose and 10 days of multiple twice-daily dosing. This decrease is most likely due to the expected decrease in renal function in these elderly subjects. Care should therefore be taken in dose selection for elderly patients, and it may be useful to monitor renal function.

Adverse Reactions

Adverse Drug Reaction Overview

In well-controlled clinical studies, the most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, dizziness and infection. Of the most frequently reported adverse events, asthenia, somnolence and dizziness appeared to occur predominantly during the first four weeks of treatment with levetiracetam.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Central Nervous System Adverse Events

Levetiracetam use is associated with the occurrence of central nervous system (CNS) adverse events; the most significant of these can be classified into the following categories:

1) somnolence and fatigue, 2) behavioral/psychiatric symptoms and 3) coordination difficulties.

There was no clear dose response relationship for any of the three categories of CNS adverse events, within the recommended dose range of up to 3000 mg/day. Somnolence/asthenia and coordination difficulties occurred most frequently within the first four weeks of treatment and usually resolved while patients remained on treatment. In the case of behavioral/psychiatric symptoms (including such adverse events as aggression, agitation, anger, anxiety, emotional lability, hostility, irritability), approximately half of the patients reported these events within the first four weeks, with the remaining events occurring throughout the duration of the trials.

The following CNS adverse events were observed in controlled clinical trials.

Table 1: Total Combined Incidence Rate For Each Of The Three Categories Of CNS Adverse Events In Placebo-Controlled Add-On Clinical Trials.
Category of CNS
Adverse Event
Levetiracetam* + AED
Therapy (N=672)
Placebo + AED
Therapy (N=351)
Somnolence and fatigue    
Somnolence 15% 10%
Asthenia 14% 10%
Behavioral/ psychiatric symptoms    
Nonpsychotic1 14% 6%
Psychotic2 1% 0%
Coordination difficulties3 3% 2%

*Reflects levetiracetam doses of 1000 mg, 2000 mg, 3000 mg, and 4000 mg per day.

1”Non-psychotic behavioral/psychiatric symptoms” encompasses the following terms: agitation, antisocial reaction, anxiety, apathy, depersonalization, depression, emotional lability, euphoria, hostility, nervousness, neurosis, personality disorder and suicide attempt.

2”Psychotic behavioral/psychiatric symptoms” encompasses the following terms: hallucinations, paranoid reaction, psychosis and psychotic depression.

3”Coordination difficulties” encompasses the following terms: ataxia, abnormal gait, incoordination.

See, Table 2 for incidence rate of individual AEs contained within the categories.

Behavioral/psychiatric symptoms (including agitation, emotional lability, hostility, anxiety etc.) have been reported approximately equally in patients with and without a psychiatric history.

There was no clear dose response relationship for any of the three categories of CNS adverse events, within the recommended dose range of up to 3000 mg/day. In a controlled study including a dose of 4000 mg, administered without titration, the incidence rate of somnolence during the first four weeks of treatment for patients receiving the high dose was 42%, compared to 21% for patients receiving 2000 mg/day.

Table 2: Incidence (%) Of Treatment-Emergent Adverse Events In Placebo-Controlled, Add- On Studies By Body System. (Adverse Events Occurred In At Least 1% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients.) (Studies N051, N052, N132 and N138)
Body System/ Adverse Event Levetiracetam + AED Therapy
(N = 672)
Placebo + AED Therapy
(N=351)
Body as a Whole
Asthenia
Infection*
 
14%
13%
 
10%
7%
Digestive System
Tooth Disorders
 
2%
 
1%
Hemic and Lymphatic System
Ecchymosis
 
2%
 
1%
Nervous System
Amnesia
Anxiety
Ataxia
Depression
Dizziness
Emotional Lability
Hostility
Nervousness
Personality Disorders
Somnolence
Thinking Abnormal
Vertigo
 
2%
2%
3%
4%
9%
2%
2%
4%
1%
15%
2%
3%
 
0%
1%
1%
2%
4%
0%
1%
2%
0%
10%
1%
1%
Respiratory System
Pharyngitis
Rhinitis
Sinusitis
 
6%
4%
2%
 
4%
3%
1%

*In levetiracetam-treated patients, the majority of “Infection” events (93%) were coded to reported terms of “common cold” or “infection upper respiratory”.

Other events reported by 1% or more of patients treated with levetiracetam but as or more frequent in the placebo group were: abdominal pain, accidental injury, amblyopia, anorexia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, cough increased, diarrhea, diplopia, drug level increased, dysmenorrhea, dyspepsia, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, headache, insomnia, nausea, otitis media, pain, paresthesia, rash, tremor, urinary tract infection, vomiting and weight gain.

Additional Events Observed in Placebo Controlled Trials

Lack of Dose Related Incidence of Adverse Events within Therapeutic Range

Based on the data from the controlled clinical trials, there was no evidence of dose relationship within the recommended dose range of 1000 to 3000 mg/day.

Discontinuation or Dose Reduction in Well-Controlled Clinical Studies

In well-controlled clinical studies, 14.3% of patients receiving levetiracetam and 11.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 3 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction.

Table 3: Adverse Events That Most Commonly Resulted In Discontinuation Or Dose Reduction In Placebo-Controlled Studies In Patients With Epilepsy
  Levetiracetam
(N = 672)
Placebo
(N = 351)
Asthenia 9 (1.3%) 3 (0.9%)
Headache 8 (1.2%) 2 (0.6%)
Convulsion 16 (2.4%) 10 (2.8%)
Dizziness 11 (1.6%) 0
Somnolence 31 (4.6%) 6 (1.7%)
Rash 0 5 (1.4%)

The overall adverse experience profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.

The following adverse events were seen in well-controlled studies of levetiracetam for indications in epilepsy other than those approved in this labeling: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, nasopharyngitis, pruritus, mood swings, and vision blurred, aggression, agitation, depression, and irritability.

Post-Market Adverse Drug Reactions

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

Blood and lymphatic disorders: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia.

Nervous system disorders: agranulocytosis, paraesthesia, choreoathetosis, dyskinesia, lethargy Metabolism and nutrition disorders: weight decreased, hyponatremia

Musculoskeletal and connective tissue disorders: muscular weakness

Hepatic/Biliary/Pancreatic: abnormal liver function test, hepatitis, hepatic failure, pancreatitis (see Hepatic Failure section below)

Psychiatric: abnormal behavior, anger, panic attack, anxiety, confusional state, hallucination, psychotic disorders, (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Central Nervous System Adverse Events) suicidal behavior (including completed suicide) (see WARNINGS AND PRECAUTIONS, Psychiatric)

Skin and subcutaneous tissue disorders: Toxic Epidermal Necrolysis, Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptom (DRESS), erythema multiforme (see WARNINGS AND PRECAUTIONS, Skin), alopecia: in several alopecia cases, recovery was observed when levetiracetam was discontinued.

Immune System Disorders: Hypersensitivity reactions such as SJS, TEN, and DRESS (see WARNINGS AND PRECAUTIONS, Skin).

Hepatic Failure: Reports of increases in liver function tests in patients taking levetiracetam, with and without other medications, have been received. Reports of hepatitis and hepatic failure in patients taking levetiracetam, with and without other medications, have been received.

Fetal toxicity associated with concomitant use of levetiracetam and other antiepileptic drugs has been reported in pregnancy registries.

Drug Interactions

Overview

In Vitro Studies on Metabolic Interaction Potential

In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C8/9/10, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (paracetamol UGT i.e. UCT1A6, ethinyl estradiol UGT i.e. UGT1A1 and p-nitrophenol UGT i.e. UGT [p16.2]) and epoxide hydrolase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. In human hepatocytes in culture, levetiracetam did not cause enzyme induction.

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

Thus in vitro data, in combination with the pharmacokinetic characteristics of the drug, indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions.

Drug-Drug Interactions

Other Antiepileptic Drugs (AEDs)

Potential drug interactions between levetiracetam and other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) were assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data suggest that levetiracetam may not significantly influence the plasma concentrations of these other AEDs, and that the other AEDs may not significantly influence the plasma concentrations of levetiracetam.

For two of these AEDs-phenytoin and valproate - formal pharmacokinetic interaction studies with levetiracetam were performed. Levetiracetam was co-administered with either phenytoin or valproate at doses of 3000 mg/day and 1000 mg/day respectively. No clinically significant interactions were observed.

Based on post-market experience, concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity (e.g. nystagmus, nausea, vomiting).

Antacids

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

Alcohol

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

Oral Contraceptives

A pharmacokinetic clinical interaction study has been performed in healthy subjects between the oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgesterol, and the lowest therapeutic dose of levetiracetam (500 mg bid). No clinically significant pharmacokinetic interactions were observed.

However, pharmacokinetic interaction studies using levetiracetam as adjunctive therapy and covering the recommended dosage range, have not been conducted. Therefore, physicians should advise their female patients to be alert to any irregular vaginal bleeding or spotting, and to immediately report to them any occurrences.

Digoxin

Levetiracetam (1000 mg bid) 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.

Warfarin

Levetiracetam (1000 mg bid) did not influence the pharmacokinetics of R and S warfarin (2.5 mg, 5 mg or 7.5 mg daily). Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

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 bid. Css max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid and the renal clearance of the metabolite ucb L057 was decreased by 60%; this alteration is likely related to competitive inhibition of tubular secretion of ucb L057. The effect of levetiracetam on probenecid was not studied.

Drug-Food Interactions

Levetiracetam is rapidly and almost completely absorbed after oral administration. The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Tests Interactions

Interactions with laboratory tests have not been reported.

Dosage and Administration

Recommended Dose and Dosage Adjustment

Adults

Treatment should be initiated at a dose of 1000 mg/day, given as twice daily dosing (500 mg bid). Depending on clinical response and tolerability, the daily dose may be increased every two weeks by increments of 1000 mg, to a maximum recommended daily dose of 3000 mg.

In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice a day dosing, were shown to be effective. Although there was a tendency toward greater response rate with higher dose, a consistent statistically significant increase in response with increased dose has not been shown. There are limited safety data from controlled clinical trials at doses higher than 3000 mg/day (approximately 40 patients), therefore these doses are not recommended.

Abbott-Levetiracetam (levetiracetam) is given orally with or without food.

Patients with Impaired Renal Function

Renal excretion of unchanged drug accounts for approximately 66% of administered levetiracetam dose. Consistent with this, levetiracetam dosage should be reduced in patients with impaired renal function (see Table 4 below). Patients with end stage renal disease should receive supplemental doses following dialysis. To use this dosing table, an estimate of the patient’s creatinine clearance is needed.

CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Table 4: Dosing Adjustment For Patients With Impaired Renal Function
Group Creatinine Clearance
(ml/min/1.73m2)
Dosage and Frequency
Normal ≥80 500 to 1500 mg twice daily
Mild 50-79 500 to 1000 mg twice daily
Moderate 30-49 250 to 750 mg twice daily
Severe* <30 250 to 500 mg twice daily
End-stage renal disease patients 500 to 1000 mg once daily
undergoing dialysis (1)    

(1) Following dialysis, a 250 to 500 mg supplemental dose is recommended.

*or according to best clinical judgment

Patients with Impaired Hepatic Function

No dose adjustment is needed in patients with mild to 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/1.73m2.

Elderly Patients

Dose selection and titration should proceed cautiously in elderly patients, as renal function decreases with age.

Missed Dose

If the patient misses a dose by a few hours, they should be instructed to take Abbott- Levetiracetam as soon as they remember. If it is close to their next dose, they should be instructed to take their medication at the next regular time. Patients should not take two doses at the same time.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms

The highest reported levetiracetam overdose is approximately 10 times the therapeutic dose. In the majority of overdose cases, multiple drugs were involved. Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma were observed with levetiracetam overdoses. The minimal lethal oral dose in rodents is a least 233 times the maximum clinically studied dose.

Treatment

There is no antidote for overdose with levetiracetam; treatment is symptomatic and may include hemodialysis. 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 clinical status of the patient.

Standard hemodialysis procedures result in significant removal 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.

Action and Clinical Pharmacology

Mechanism of Action

Abbott-Levetiracetam (levetiracetam) is a drug of the pyrrolidine class chemically unrelated to existing antiepileptic drugs (AEDs). As with other drugs in this class, the mechanism of action of levetiracetam in man is not known (see DETAILED PHARMACOLOGY, Preclinical Studies, for experimental in vitro and in vivo data in animals).

Pharmacokinetics

Single- and multiple-dose pharmacokinetics of levetiracetam have included healthy volunteers, adult and pediatric patients with epilepsy, elderly subjects, and subjects with renal and hepatic impairment. Results of these studies indicate that levetiracetam is rapidly and almost completely absorbed after oral administration. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. Food does not affect the extent of absorption of levetiracetam, although the rate is decreased. Levetiracetam is not protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of the dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacodynamic activity and are renally excreted. Plasma half-life of levetiracetam across studies is 6-8 hours. Plasma half-life is increased in subjects with renal impairment, and in the elderly primarily due to impaired renal clearance.

Based on its pharmacokinetic characteristics, levetiracetam is unlikely to produce or to be subject to metabolic interactions.

The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.

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

The pharmacokinetics of levetiracetam have been characterized in single- and multiple-dose PK studies, with doses up to 5000 mg; these studies included healthy volunteers (N=98), patients with epilepsy (N=58 adult patients and N=24 pediatric patients), elderly subjects (N=16) and subjects with renal and hepatic impairment (N=36 and 16, respectively).

Absorption

Levetiracetam is rapidly and almost completely absorbed after oral administration. The oral bioavailability of levetiracetam tablets is 100%. Plasma peak concentrations (Cmax) are achieved at 1.3 hours after dosing. The extent of absorption is independent of both dose and the presence of food, but the latter delays Tmax by 1.5 hours and decreases Cmax by 20%. The pharmacokinetics of levetiracetam are linear over the dose range of 500 – 5000 mg. Steady-state is achieved after two days of a twice daily administration schedule. Mean peak concentrations (Cmax) are 31 and 43 μg/mL, respectively, following a single 1000 mg dose, and a repeated 1000 mg twice daily dose.

Distribution

Neither levetiracetam nor its primary metabolite is significantly bound to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, a value that is close to the total body water volume. No tissue distribution data for humans are available.

Metabolism

Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the pharmacologically inactive carboxylic acid metabolite, ucb L057 (24% of dose). The production of this metabolite is not dependent on any liver cytochrome P450 isoenzymes and is mediated by serine esterase(s) in various tissues, including blood cells. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no evidence for enantiomeric interconversion of levetiracetam or its major metabolite.

Excretion

Levetiracetam plasma half-life in adults is 7 ± 1 hours and was unaffected by dose, route of administration or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug, which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and renal clearance is 0.6 mL/min/kg. Approximately 93% of the dose was excreted within 48 hours. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The primary metabolite, ucb L057, is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance and clearance is thus reduced in patients with impaired renal function (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Special Populations and Conditions

Pediatrics

Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6-12 years) after a single dose. The apparent clearance of levetiracetam adjusted to body weight was approximately 40% higher than in epileptic adults.

Geriatrics

Pharmacokinetics of levetiracetam were evaluated in 16 elderly patients, ranging in age from 61- 88 years, with 11 of the 16 patients aged 75 years of age or over with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of 500 mg bid for 10 days, total body clearance decreased by 38% and the half-life was increased about 40% (10 to 11 hours) when compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.

Gender

Levetiracetam Cmax and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable.

Race

Formal pharmacokinetic studies of the effects of race have not been conducted. Because levetiracetam is primarily renally excreted and there are no known important racial differences in creatinine clearance, significant pharmacokinetic differences due to race are not expected.

Hepatic Insufficiency

A single-dose pharmacokinetic study was performed in 16 subjects with hepatic impairment (N=5 mild/Child-Pugh Grade A; N=6 moderate/Grade B; N=5 severe/Grade C vs 5 healthy controls). For the mild and moderate subgroups neither mean nor individual pharmacokinetic values were clinically different from those of controls. In patients with severe hepatic impairment, mean apparent body clearance was 50% that of normal subjects, with decreased renal clearance accounting for most of the decrease. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 mL/min/1.73 m2 (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency

Single dose pharmacokinetics were performed in 20 subjects with renal impairment (N=7 mild/CLcr of 50-79 mL/min; N=8 moderate/CLcr of 30-49 mL/min; N=5 severe/CLcr<30 mL/min), and N=11 matching healthy volunteers. Clearance of levetiracetam is correlated with creatinine clearance and levetiracetam pharmacokinetics following repeat administration were well predicted from single dose data. The apparent body clearance of the parent drug levetiracetam is reduced in patients with impaired renal function by approximately 40% in the mild group, 50% in the moderate group, and 60% in the severe renal impairment group. For the primary metabolite ucb L057, the decrease in clearance values from baseline was greater than that seen for the parent drug in all subject groups.

In anuric (end stage renal disease) patients, the apparent body clearance was approximately 30% compared to that of normal subjects. Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure.

Dosage should be reduced in patients with impaired renal function receiving levetiracetam, and supplemental doses should be given to patients after dialysis (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Storage and Stability

Store between 15-30oC (59-86oF).

Dosage Forms, Composition and Packaging

Availability of Dosage Forms

Abbott-Levetiracetam (levetiracetam) is available as follows:

250 mg Tablets: Blue colored, oval shaped, film coated tablets, debossed with breakline separating ‘250’ and ‘MG’ on one side and ‘1014’ on the other side.

500 mg Tablets: Yellow colored, oval shaped, film coated tablets, debossed with breakline separating ‘500’ and ‘MG’ on one side and ‘1015’ on the other side.

750 mg Tablets: Orange colored, oval shaped, film coated tablets, debossed with breakline separating ‘750’ and ‘MG’ on one side and ‘1016’ on the other side.

Supplied: 250 mg, 500 mg and 750 mg tablets: bottles of 100 tablets.

Composition

Abbott-Levetiracetam (Levetiracetam Tablets USP) contain the labeled amount of levetiracetam and the following inactive ingredients: corn starch, sodium starch glycolate, colloidal silicon dioxide, povidone, talc, magnesium stearate, purified water, hypromellose, polyethylene glycol, titanium dioxide, FD & C blue #2 (250 mg only), ferric oxide yellow (500 mg only), ferric oxide red (750 mg only) and FD & C yellow #6 (750 mg only).