Spritam

1 INDICATIONS AND USAGE SPRITAM is indicated for the treatment of partial-onset seizures in patients 4 years of age and older weighing more than 20 kg ( 1.1 ) SPRITAM is indicated for adjunctive therapy for the treatment of: Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3 ) 1.1 Partial-Onset Seizures SPRITAM is indicated for the treatment of partial-onset seizures in patients 4 years of age and older weighing more than 20 kg. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy SPRITAM is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures SPRITAM is indicated as adjunctive therapy for the treatment of primary generalized tonic‑clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

2 DOSAGE AND ADMINISTRATION SPRITAM is intended to disintegrate in the mouth when taken with a sip of liquid. Swallow only after the tablet disintegrates. Do not swallow tablet(s) intact. Partial tablet(s) should not be administered ( 2.1 ) Alternately, add whole SPRITAM tablet(s) to a small volume of liquid in a cup (one tablespoon or enough to cover the medicine). Allow the tablet(s) to disperse prior to consuming entire contents immediately ( 2.1 ) SPRITAM may also be administered via nasogastric or gastrostomy feeding tubes ( 2.1 ) Recommended dosage ( 2.2 ): Age and Body Weight Initial Dosage Titration Regimen Maximum or Recommended Dosage Adults and pediatric patients weighing over 40 kg 500 mg twice daily Increase by 500 mg twice daily every 2 weeks Partial-Onset Seizures Maximum dosage of 1,500 mg twice daily Myoclonic ± and PGTC ± Recommended dosage of 1,500 mg twice daily Pediatric patients weighing 20 kg to 40 kg 250 mg twice daily Increase by 250 mg twice daily every 2 weeks Maximum 750 mg twice daily Adult Patients with Renal Impairment Dose adjustment is recommended based on creatinine clearance ( 2.3 , 8.6 ) 2.1 Important Preparation and Administration Instructions The SPRITAM dosing regimen depends on the indication, age group, and renal function. Administer SPRITAM with or without food. Do not administer partial tablets. Patients should be instructed not to push the tablet through the foil. The foil should be peeled away from the blister by bending up and lifting the peel tab around the blister seal. Oral Administration SPRITAM is intended to disintegrate in the mouth when taken with a sip of liquid, one tablet at a time. As a primary method of administration, place one tablet on the tongue with a dry hand, follow with a sip of liquid and swallow only after the tablet disintegrates. Repeat this step, if needed, until the full dose has been administered. Do not swallow tablet(s) intact. SPRITAM disintegrates in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth when taken with a sip of liquid. Alternately, add whole SPRITAM tablet(s) to a small volume of liquid in a cup (one tablespoon or enough liquid to cover the medicine). Allow the tablet(s) to fully disperse, then immediately consume the entire contents by mouth using the cup or an oral syringe. After administration of the suspension, re-suspend any residue by adding an additional small volume of liquid to the cup, swirl, then swallow the entire contents. Nasogastric Tube (NG Tube) or Gastrostomy Tube (G-Tube) Administration For patients who have a NG tube or G tube (French size 10 to 14) in place, administer SPRITAM as follows: Place the number of whole tablets needed for the prescribed dose in a small dosing cup, Add approximately 10 mL of room temperature water. Gently swirl the cup until the tablet(s) disperse. Draw up the mixture into a 10 mL oral catheter-tip syringe, hold the syringe in a vertical position, and administer immediately via feeding tube. After administration, flush the feeding tube twice, as follows: Add another 10 mL of room temperature water to the dosing cup that contained the dispersion. Swirl the cup to re-suspend any tablet residue. Draw up the mixture into the same oral syringe and immediately push through the feeding tube. 2.2 Recommended Dosage See Table 1 for the recommended dosage for patients with partial-onset seizures, myoclonic seizures with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures. Table 1: Recommended Dosage for Patients with: Partial-Onset Seizures (4 years age and older)*, Myoclonic Seizures (12 years of age and older), and Primary Generalized Tonic-Clonic Seizures (PGTC) (6 years of age and older) * The recommended dosing for monotherapy and adjunctive therapy is the same. ** There is no evidence that doses greater than 3,000 mg daily confer additional benefit. ± The effectiveness of doses lower than 3,000 mg daily has not been adequately studied. Age and Body Weight Initial Dosage Titration Regimen Maximum or Recommended Dosage Adults and pediatric patients weighing over 40 kg 500 mg twice daily (1,000 mg daily) Increase by 500 mg twice daily (1,000 mg daily) every 2 weeks Partial-Onset Seizures** Maximum dosage of 1,500 mg twice daily (3,000 mg daily)** Myoclonic ± and PGTC ± Recommended dosage of 1,500 mg twice daily (3,000 mg daily) Pediatric patients weighing 20 kg to 40 kg 250 mg twice daily (500 mg daily) Increase by 250 mg twice daily (500 mg daily) every 2 weeks Maximum dosage of 750 mg twice daily (1,500 mg daily) 2.3 Dosage Adjustments in Adult Patients with Renal Impairment SPRITAM dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 2 . In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: Then CLcr is adjusted for body surface area (BSA) as follows: Table 2: Dosing Regimen For Adult Patients With Renal Impairment 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. Group Creatinine Clearance (mL/min/1.73m 2 ) SPRITAM Dosage (mg) Frequency Normal >80 500 to 1,500 Every 12 hours Mild 50-80 500 to 1,000 Every 12 hours Moderate 30-50 250 to 750 Every 12 hours Severe <30 250 to 500 Every 12 hours ESRD patients using dialysis — 500 to 1,000 1 Every 24 hours 1 Recommended Dosage Adjustment Formula Recommended Dosage Adjustment Formula 2.4 Discontinuation of SPRITAM Avoid abrupt withdrawal of SPRITAM in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.8) ].

4 CONTRAINDICATIONS SPRITAM is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4) ] . Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 , 5.4 )

5 WARNINGS AND PRECAUTIONS Behavioral Abnormalities: Psychotic symptoms, irritability, and aggressive behavior have been observed: Monitor for signs and symptoms ( 5.1 ) Suicidal Behavior and Ideation: Monitor for new or worsening depression, suicidal thoughts/behavior, and/or changes in mood or behavior ( 5.2 ) Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained experience on SPRITAM ( 5.3 ) Serious Dermatological Reactions: Discontinue SPRITAM at the first sign of rash unless clearly not drug related ( 5.5 ) Drug Reaction with Eosinophilia and Systemic Symptoms / Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.6 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. Advise patients to not drive or operate machinery until they have gained experience on SPRITAM ( 5.7 ) Withdrawal Seizures: SPRITAM must be gradually withdrawn ( 5.8 ) 5.1 Behavioral Abnormalities and Psychotic Symptoms SPRITAM may cause behavioral abnormalities and psychotic symptoms. Patients treated with SPRITAM should be monitored for psychiatric signs and symptoms. Behavioral abnormalities In clinical studies, 13% of adult levetiracetam-treated patients and 38% of pediatric levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, respectively, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder). A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18). In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the levetiracetam-treated patients compared to 0% of placebo-treated patients. In clinical studies, 1.7% of adult levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult levetiracetam-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients. Psychotic symptoms In clinical studies, 1% of levetiracetam-treated adult patients, 2% of levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of levetiracetam-treated pediatric patients 1 month to < 4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In the controlled study that assessed the neurocognitive and behavioral effects of levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of levetiracetam-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use in Specific Populations (8.4) ] . In clinical studies, two (0.3%) levetiracetam-treated adult 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. There was no difference between drug and placebo‑treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including SPRITAM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing SPRITAM or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.3 Somnolence and Fatigue SPRITAM may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on SPRITAM to gauge whether it adversely affects their ability to drive or operate machinery. Somnolence In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated 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 levetiracetam-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-treated patients. In 1.4% of levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the levetiracetam-treated patients were hospitalized due to somnolence. Asthenia In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial-onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial-onset seizure studies. 5.4 Anaphylaxis and Angioedema SPRITAM 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, SPRITAM should be discontinued and the patient should seek immediate medical attention. SPRITAM should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ] . 5.5 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult 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. SPRITAM 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. 5.6 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. SPRITAM should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindication (4) ] . 5.7 Coordination Difficulties SPRITAM may cause coordination difficulties. In controlled clinical studies in adult patients with partial-onset seizures, 3.4% of adult levetiracetam-treated patients experienced coordination difficulties (reported as either ataxia, abnormal gait, or incoordination), compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled clinical studies discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the levetiracetam-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 SPRITAM to gauge whether it could adversely affect their ability to drive or operate machinery. 5.8 Withdrawal Seizures As with most antiepileptic drugs, SPRITAM should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered. 5.9 Hematologic Abnormalities SPRITAM can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials with levetiracetam and included decreases in white blood cell (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders. Partial-Onset Seizures Adults Minor, but statistically significant decreases compared to placebo, in total mean RBC count (0.03 x 10 6 /mm 3 ), 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 levetiracetam‑treated and 1.8% of placebo‑treated patients had at least one possibly significant (≤ 2.8 × 10 9 /L) decreased WBC, and 2.4% of levetiracetam‑treated and 1.4% of placebo‑treated patients had at least one possibly significant (≤ 1.0 × 10 9 /L) decreased neutrophil count. Of the levetiracetam‑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. Pediatric Patients 4 Years to Less Than 16 Years of Age Statistically significant decreases in WBC and neutrophil counts were seen in levetiracetam‑treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam‑treated group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam‑treated patients, compared to a decrease of 4% in placebo‑treated patients (statistically significant). In a controlled trial, more levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% of levetiracetam‑treated patients versus 0% of placebo‑treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% of levetiracetam‑treated patients versus 4.2% of placebo‑treated patients). No patient was discontinued secondary to low WBC or neutrophil counts. In a controlled cognitive and neuropsychological safety study, 5 patients (8.6%) in the levetiracetam‑treated group and two patients (6.1%) in the placebo‑treated group had high eosinophil count values that were possibly clinically significant (≥ 10% or ≥ 0.7×10 9 /L). 5.10 Increase in Blood Pressure In a randomized, placebo-controlled study in patients 1 month to < 4 years of age, a significantly higher risk of increased diastolic blood pressure was observed in levetiracetam-treated patients (17%), compared to the placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the levetiracetam and placebo treatment groups was not observed in the studies of older pediatric patients or in adults. Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure. 5.11 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Behavioral Abnormalities and Psychotic Symptoms [see Warnings and Precautions (5.1) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Somnolence and Fatigue [see Warnings and Precautions (5.3) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.4) ] Serious Dermatological Reactions [see Warnings and Precautions (5.5) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.6) ] Coordination Difficulties [see Warnings and Precautions (5.7) ] Hematologic Abnormalities [see Warnings and Precautions (5.9) ] Increase in Blood Pressure [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥ 5% more than placebo) include: Adults: somnolence, asthenia, infection, and dizziness ( 6.1 ) Pediatrics: fatigue, aggression, nasal congestion, decreased appetite, and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aprecia Pharmaceuticals, LLC at 1-844-882-7732 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical 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. Partial-Onset Seizures Adults In controlled clinical studies in adults with partial-onset seizures [see Clinical Studies (14.1) ] , the most common adverse reactions in 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 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam 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. Table 4: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults with 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 In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 5 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 5: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Pooled Placebo-Controlled Studies in Adults with Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Pediatric Patients 4 Years to Less Than 16 Years of Age The adverse reaction data presented below was obtained from a pooled analysis of two controlled clinical studies in pediatric patients 4 to less than 16 years of age with partial-onset seizures. The most common adverse reactions in pediatric patients 4 to less than 16 years of age receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 6 lists adverse reactions from the pooled pediatric controlled studies (4 to less than 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Table 6: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients 4 to 16 Years of Age with Partial-Onset Seizures Adverse Reaction Levetiracetam (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Cough 9 5 Nasal Congestion 9 2 Upper Abdominal Pain 9 8 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Altered Mood 3 1 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In the controlled pooled pediatric clinical studies in patients 4 years to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction. Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset 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 in patients 12 years of age and older with myoclonic seizures, [see Clinical Studies (14.2) ] , the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic 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 7: 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 In the placebo-controlled study, 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 8 . Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study 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-onset 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 trial in patients with PGTC seizures [see Clinical Studies (14.3) ] , the most common adverse reaction in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis. Table 9 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 9: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Patients 4 Years of Age and Older 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 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 discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Table 5 and Table 8 ). In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision. Comparison of Gender, Age, and Race The overall adverse reaction profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions 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. The listing is alphabetized: abnormal liver function test, acute kidney injury, agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures including in patients with SCN8A mutations. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including SPRITAM, during pregnancy. Encourage women who are taking SPRITAM 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 (5.11) ] . 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 developmental 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).