Levetiracetam in Sodium Chloride Injection is indicated for adjunct therapy in adults (≥16 years of age) with the following seizure types when oral administration is temporarily not feasible: Partial-onset seizures ( 1.1 ) Myoclonic seizures in patients with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures ( 1.3 )
1.1Partial-Onset Seizures Levetiracetam in Sodium Chloride
Injection is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy.
1.2Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam in Sodium Chloride
Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.
1.3Primary Generalized Tonic-Clonic Seizures Levetiracetam in Sodium Chloride
Injection is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.
1.4Limitations of Use Levetiracetam in Sodium Chloride
Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible.
Contraindications
Levetiracetam in Sodium Chloride Injection is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.3) ]. Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 )
Warnings and precautions
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Psychiatric Reactions: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms ( 5.1 ) Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam ( 5.2 ) Serious Dermatological Reactions: Discontinue Levetiracetam at the first sign of rash unless clearly not drug related.
( 5.4 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.5 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. ( 5.6 ) Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( 5.7 )
5.1Psychiatric Reactions
In some patients levetiracetam causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial-onset seizure studies. A total of 13.3% of adult levetiracetam-treated patients compared to 6.2% of placebo patients experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, and nervousness).
A total of 1.7% of adult levetiracetam-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult levetiracetam-treated patients and in 0.5% of placebo patients. One percent of adult levetiracetam-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients. Two (0.3%) adult levetiracetam-treated patients were hospitalized and their treatment was discontinued due to psychosis.
Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. The above psychiatric signs and symptoms should be monitored.
5.2Somnolence and Fatigue
In some patients, levetiracetam causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial-onset seizure studies. In general, the incidences of somnolence and fatigue in the myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial-onset seizure studies. 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 levetiracetam-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia 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 due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
5.3Anaphylaxis and Angioedema
Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, levetiracetam should be discontinued and the patient should seek immediate medical attention.
Levetiracetam should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ].
5.4Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.
If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including levetiracetam. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Levetiracetam should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4) ] .
5.6Coordination Difficulties
Coordination difficulties were only observed in the adult partial-onset seizure studies. A total of 3.4% of adult 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. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
5.7 Withdrawal Seizures As with most antiepileptic drugs, levetiracetam should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.
5.8Hematologic Abnormalities
Levetiracetam can cause hematologic abnormalities. He
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Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam, during pregnancy. Encourage women who are taking levetiracetam injection during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades [see Human Data].
In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions (5.9) ]. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester.
Dose adjustments may be necessary to maintain clinical response. Data Human Data While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested.
There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis. Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity.
The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis. Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested.
There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m 2 basis. Oral administration of levetiracetam to rats during the latter part 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/m 2 basis).
Adverse reactions
The following serious adverse reactions are discussed in more details in other sections of labeling: Psychiatric Reactions [see Warnings and Precautions (5.1) ] Somnolence and Fatigue [see Warnings and Precautions (5.2) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.3) ] Serious Dermatological Reactions [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5) ] Coordination Difficulties [see Warnings and Precautions (5.6) ] Withdrawal Seizures [see Warnings and Precautions (5.7) ] Hematologic Abnormalities [see Warnings and Precautions (5.8) ] Seizure Control During Pregnancy [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence in levetiracetam-treated patients is ≥5% more than in placebo-treated patients) include: somnolence, asthenia, infection, and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Caplin Steriles Limited at 1-866-978-6111 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials 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 C max , C min , and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.
Partial-Onset Seizures In controlled clinical studies using levetiracetam tablets in adults with partial-onset seizures [see Clinical Studies (14.1) ], the most common adverse reactions in adult patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness. Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.
Table 2 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets 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. Table 2: Adverse Reactions* In Placebo-Controlled, Adjunctive Studies In Adults Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 *Adverse reactions occurred in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In controlled adult clinical studies using levetiracetam tablets, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.
Table 3 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. Table 3: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo-Controlled Studies in Adults Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Myoclonic Seizures 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 controlled clinical study using levetiracetam tablets in patients with myoclonic seizures, the most common adverse reactions in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 4 lists 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. Table 4: Adverse Reactions* in a Placebo-Controlled, Adjunctive Study in Patients 12 Years of Age and Older with Myoclonic Seizures Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Somnolence 12 2 Neck pain 8 2 Pharyngitis 7 0 Depression 5 2 Influenza 5 2 Vertigo 5 3 * Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In the placebo-controlled study using levetiracetam tablets in patients with JME, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.
The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 5. Table 5: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Patients with Juvenile Myoclonic Epilepsy Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures 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 primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures. In the controlled clinical study that included patients with PGTC seizures, the most common adverse reaction in patients receiving levetiracetam oral formulation in combination with other AEDs, for events with rates greater than placebo was nasopharyngitis.
Table 6 lists 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. Table 6: Adverse Reactions* in a Placebo-Controlled, Adjunctive Study in Patients with PGTC Seizures Adverse Reaction Levetiracetam (N=79) % Placebo (N=84) % Nasopharyngitis 14 5 Fatigue 10 8 Diarrhea 8 7 Irritability 6 2 Mood swings 5 1 * Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.
This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuati
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Composition
Active ingredients
LEVETIRACETAM 1GM/100ML (10MG/ML)
Strengths and forms
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