Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Levetiracetam Injection
Levetiracetam injection is an alternative for adult patients (16 years and older) when oral administration is temporarily not feasible.
Partial Onset Seizures
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.
Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy
Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.
Primary Generalized Tonic-Clonic Seizures
Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.
Levetiracetam Injection Dosage and Administration
General Information
Levetiracetam injection is for intravenous use only and must be diluted prior to administration. Levetiracetam Injection (500 mg/5 mL) should be diluted in 100 mL of a compatible diluent [see Dosage and Administration (2.7)] and administered intravenously as a 15-minute IV infusion.
Product with particulate matter or discoloration should not be used.
Any unused portion of the Levetiracetam Injection vial contents should be discarded.
Initial Exposure to Levetiracetam
Levetiracetam can be initiated with either intravenous or oral administration.
Partial Onset Seizures
In clinical trials of oral levetiracetam, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose [see Clinical Studies (14.1)], a consistent increase in response with increased dose has not been shown.
Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.
Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy
Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.
Primary Generalized Tonic-Clonic Seizures
Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.
Replacement Therapy
When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam and should be administered as a 15-minute intravenous infusion following dilution in 100 mL of a compatible diluent.
Switching to Oral Dosing
At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.
Dosing Instructions
Levetiracetam injection is for intravenous use only and must be diluted prior to administration. One vial of Levetiracetam Injection contains 500 mg levetiracetam (500 mg/5 mL). See Table 1 for the recommended preparation and administration of Levetiracetam Injection to achieve a dose of 500 mg, 1000 mg, or 1500 mg.
| Dose | Withdraw Volume | Volume of Diluent | Infusion Time |
|---|---|---|---|
| 500 mg | 5 mL (5 mL vial) | 100 mL | 15 minutes |
| 1000 mg | 10 mL (two 5 mL vials) | 100 mL | 15 minutes |
| 1500 mg | 15 mL (three 5 mL vials) | 100 mL | 15 minutes |
For example, to prepare a 1000 mg dose, dilute 10 mL of Levetiracetam Injection in 100 mL of a compatible diluent [see Dosage and Administration (2.7)] and administer intravenously as a 15-minute infusion.
Adult Patients with Impaired Renal Function
Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 2. 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:
| 1. For female patients | ||
| CLcr= | [140-age (years)] x weight (kg) | x 1 0.85 |
| - - - - - - - - - - - - - - - - - - - - - - | ||
| 72 x serum creatinine (mg/dL) |
| 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. | |||
| Group | Creatinine Clearance (mL/min) | Dosage (mg) | Frequency |
| Normal | > 80 | 500 to 1,500 | Every 12 h |
| Mild | 50 – 80 | 500 to 1,000 | Every 12 h |
| Moderate | 30 – 50 | 250 to 750 | Every 12 h |
| Severe | < 30 | 250 to 500 | Every 12 h |
| ESRD patients using dialysis | ---- | 500 to 1,000 | 1Every 24 h |
Compatibility and Stability
Levetiracetam injection 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 polyvinyl chloride (PVC) bags at controlled room temperature 15-30°C (59-86°F).
Diluents
Sodium chloride (0.9%) injection, USP
Lactated Ringer’s injection
Dextrose 5% injection, USP
Other Antiepileptic Drugs
Lorazepam
Diazepam
Valproate sodium
There is no data to support the physical compatibility of Levetiracetam Injection with antiepileptic drugs that are not listed above.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Dosage Forms and Strengths
One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).
Contraindications
None
Warnings and Precautions
Neuropsychiatric Adverse Reactions
Partial Onset Seizures
In some adults experiencing partial onset seizures, 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 levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.
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. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced.
A total of 3.4% of levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia.
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%) of levetiracetam-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) levetiracetam-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1-5 months and resolved within 2-7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of 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. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized.
In addition, 4 (0.5%) of treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months [see Patient Counseling Information (17)].
Myoclonic Seizures
During clinical development, the number of patients with myoclonic seizures exposed to levetiracetam was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse reactions was more likely to occur in the myoclonic seizure population. In some patients experiencing myoclonic seizures, levetiracetam causes somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME.
In the double-blind, controlled trial in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of levetiracetam-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of levetiracetam-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence.
Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the levetiracetam-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients compared to 3.3% of placebo patients. A total of 5.0% of levetiracetam-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients.
Primary Generalized Tonic-Clonic Seizures
During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g. somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.
In some patients experiencing primary generalized tonic-clonic seizures, levetiracetam causes behavioral abnormalities.
In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression.
Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One levetiracetam-treated patient experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam.
In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.
Withdrawal Seizures
Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities
Partial Onset Seizures
Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials.
A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% 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.
Juvenile Myoclonic Epilepsy
Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.
Hepatic Abnormalities
There were no meaningful changes in mean liver function tests (LFT) in controlled trials 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.
Laboratory Tests
Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.
Adverse Reactions
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The adverse reactions that result from Levetiracetam Injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion.
The prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.
Partial Onset Seizures
In well-controlled clinical studies using levetiracetam tablets in adults with partial onset seizures, the most frequently reported adverse reactions in patients receiving levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness.
Of the most frequently reported adverse reactions in placebo-controlled studies using levetiracetam tablets in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with levetiracetam.
Table 3 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with levetiracetam tablets participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.
| Body System/ Adverse Reaction | Levetiracetam(N=769) % | Placebo (N=439) % |
| Body as a Whole | ||
| Asthenia | 15 | 9 |
| Headache | 14 | 13 |
| Infection | 13 | 8 |
| Pain | 7 | 6 |
| Digestive System | ||
| Anorexia | 3 | 2 |
| Nervous System | ||
| Somnolence | 15 | 8 |
| Dizziness | 9 | 4 |
| Depression | 4 | 2 |
| Nervousness | 4 | 2 |
| Ataxia | 3 | 1 |
| Vertigo | 3 | 1 |
| Amnesia | 2 | 1 |
| Anxiety | 2 | 1 |
| Hostility | 2 | 1 |
| Paresthesia | 2 | 1 |
| Emotional Lability | 2 | 0 |
| Respiratory System | ||
| Pharyngitis | 6 | 4 |
| Rhinitis | 4 | 3 |
| Cough Increased | 2 | 1 |
| Sinusitis | 2 | 1 |
| Special Senses | ||
| Diplopia | 2 | 1 |
Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study using levetiracetam tablets in patients with myoclonic seizures, the most frequently reported adverse reactions in patients using levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.
Table 4 lists treatment-emergent adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.
| Body System/ Adverse Reaction | Levetiracetam | Placebo (N=60) % |
| Ear and labyrinth disorders | ||
| Vertigo | 5 | 3 |
| Infections and infestations | ||
| Pharyngitis | 7 | 0 |
| Influenza | 5 | 2 |
| Musculoskeletal and connective tissue disorders | ||
| Neck pain | 8 | 2 |
| Nervous system disorders | ||
| Somnolence | 12 | 2 |
| Psychiatric disorders | ||
| Depression | 5 | 2 |
Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse reaction associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.
Table 5 lists treatment-emergent adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.
| Body System/ Adverse Reaction | Levetiracetam | Placebo (N=84) % |
| Gastrointestinal disorders | ||
| Diarrhea | 8 | 7 |
| General disorders and administration site conditions | ||
| Fatigue | 10 | 8 |
| Infections and infestations | ||
| Nasopharyngitis | 14 | 5 |
| Psychiatric disorders | ||
| Irritability | 6 | 2 |
| Mood swings | 5 | 1 |
Partial Onset Seizures
In well-controlled adult clinical studies using levetiracetam tablets, 15.0% of patients receiving levetiracetam and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 6 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients.
| Adverse Reaction | Levetiracetam (N=769) n (%) | Placebo (N=439) n (%) |
| Asthenia | 10 (1.3%) | 3 (0.7%) |
| Dizziness | 11 (1.4%) | 0 |
| Somnolence | 34 (4.4%) | 7 (1.6%) |
Myoclonic Seizures
In the placebo-controlled study using levetiracetam tablets, 8.3% of patients receiving levetiracetam and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse reactions that led to discontinuation or dose reduction in the well-controlled study and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 7.
| Adverse Reaction | Levetiracetam (N=60) n (%) | Placebo (N=60) n (%) |
| Anxiety | 2 (3.3%) | 1 (1.7%) |
| Depressed mood | 1 (1.7%) | 0 |
| Depression | 1 (1.7%) | 0 |
| Diplopia | 1 (1.7%) | 0 |
| Hypersomnia | 1 (1.7%) | 0 |
| Insomnia | 1 (1.7%) | 0 |
| Irritability | 1 (1.7%) | 0 |
| Nervousness | 1 (1.7%) | 0 |
| Somnolence | 1 (1.7%) | 0 |
Primary Generalized Tonic-Clonic Seizures
In the placebo-controlled study, 5.1% of patients receiving levetiracetam and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment-emergent adverse reaction.
This study was too small to adequately characterize the adverse reactions leading to discontinuation. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see tables 6 - 7).
Comparison of Gender, Age and Race
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.
Postmarketing Experience
The following adverse events have been identified during postapproval use of levetiracetam. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In addition to the adverse reactions listed above [see Adverse Reactions (6.1)], the following adverse events have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia and weight loss. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued. There have been reports of suicidal behavior (including completed suicide, suicide attempt and suicidal ideation) with marketed levetiracetam [see Patient Counseling Information (17)].
Drug Interactions
General Information
In vitro data on metabolic interactions indicate that levetiracetam 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 in the placebo-controlled clinical studies in epilepsy patients.
Phenytoin
Levetiracetam (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.
Valproate
Levetiracetam (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.
Other Antiepileptic Drugs
Potential drug interactions between levetiracetam 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.
Oral Contraceptives
Levetiracetam (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.
Digoxin
Levetiracetam (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.
Warfarin
Levetiracetam (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.
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. Cssmax 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 levetiracetam on probenecid was not studied.
USE IN SPECIFIC POPULATIONS
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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.
Administration 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/m2 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.
Treatment of 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/m2 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 pregnant rats were treated 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 during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis).
UCB AED Pregnancy Registry
UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with all UCB antiepileptic drugs including levetiracetam. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free). Patients may also enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).
Labor and Delivery
The effect of levetiracetam on labor and delivery in humans is unknown.
Nursing Mothers
Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of levetirracetam injection in patients below the age of 16 years have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of 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 levetiracetam in these patients.
A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses 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.
Use in Patients with Impaired Renal Function
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6)].
Drug Abuse and Dependence
The abuse and dependence potential of levetiracetam has not been evaluated in human studies.
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