Roweepra XR

Roweepra XR is indicated as adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy.

Roweepra XR is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4)].

5.1  Behavioral Abnormalities and Psychotic Symptoms

Roweepra XR may cause behavioral abnormalities and psychotic symptoms. Patients treated with Roweepra XR should be monitored for psychiatric signs and symptoms.

Behavioral abnormalities

Levetiracetam Extended-release Tablets

A total of 7% of Levetiracetam Extended-release Tablets-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 7% of Levetiracetam Extended-release Tablets-treated patients. Aggression was reported in 1% of Levetiracetam Extended-release Tablets-treated patients.

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

The number of patients exposed to Levetiracetam Extended-release Tablets was considerably smaller than the number of patients exposed to immediate-release Levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release Levetiracetam controlled trials will likely occur in patients receiving Levetiracetam Extended-release Tablets.

Immediate-Release Levetiracetam Tablets

A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with immediate-release Levetiracetam experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19% of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release Levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis suggested a worsening in aggressive behavior in patients treated with immediate-release Levetiracetam tablets in that study [ see Use in Specific Populations (8.4) ].

A total of 1.7% of adult patients treated with immediate-release Levetiracetam 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 patients treated with immediate-release Levetiracetam, compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with immediate-release Levetiracetam experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients.

One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release Levetiracetam experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and placebo-treated pediatric patients. In the controlled study that assessed the neurocognitive and behavioral effects of immediate-release Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% Levetiracetam-treated patients experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release Levetiracetam who experienced confusional state, compared to no placebo-treated patients [ see Use in Specific Populations (8.4) ].

Psychotic symptoms

Immediate-Release Levetiracetam tablets

One percent of Levetiracetam-treated adult patients experienced psychotic symptoms compared to 0.2% of placebo-treated patients.

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 pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.

5.2  Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Roweepra XR, 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 2 shows absolute and relative risk by indication for all evaluated AEDs.

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 Roweepra XR or any other AED must balance the risk of suicidal thoughts or behavior 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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.3  Somnolence and Fatigue

Levetiracetam Extended-release Tablets 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 Levetiracetam Extended-release Tablets to gauge whether it adversely affects their ability to drive or operate machinery.

Somnolence

Levetiracetam Extended-release Tablets

In the Levetiracetam Extended-release Tablets double-blind, controlled trial in patients experiencing partial onset seizures, 8% of Levetiracetam Extended-release Tablets-treated patients experienced somnolence compared to 3% of placebo-treated patients.

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

The number of patients exposed to Levetiracetam Extended-release Tablets was considerably smaller than the number of patients exposed to immediate-release Levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release Levetiracetam controlled trials will likely occur in patients receiving Levetiracetam Extended-release Tablets.

Immediate-Release Levetiracetam Tablets

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 3,000 mg/day. In a study where there was no titration, about 45% of patients receiving 4,000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the 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 in 0.9% of placebo-treated patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

Asthenia

Immediate-Release Levetiracetam Tablets

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.

5.4 Anaphylaxis and Angioedema

Roweepra XR 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 in patients treated 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, Roweepra XR should be discontinued and the patient should seek immediate medical attention. Roweepra XR 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 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 Extended-release Tablets 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  Coordination Difficulties

Coordination difficulties were not observed in the Levetiracetam Extended-release Tablets controlled trial, however, the number of patients exposed to Levetiracetam Extended-release Tablets was considerably smaller than the number of patients exposed to immediate-release Levetiracetam tablets in controlled trials. However, adverse reactions observed in the immediate-release Levetiracetam controlled trials may also occur in patients receiving Levetiracetam Extended-release Tablets.

Immediate-Release Levetiracetam Tablets

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-treated patients. A total of 0.4% of patients in controlled trials 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 Levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery.

5.7  Withdrawal Seizures

Antiepileptic drugs, including Roweepra XR, should be withdrawn gradually to minimize the potential of increased seizure frequency.

5.8  Hematologic Abnormalities

Roweepra XR can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in red blood cell (RBC) counts, hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cell (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.

In controlled trials of immediate-release Levetiracetam tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106 /mm3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release Levetiracetam-treated patients.

A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 109 /L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 109 /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.

In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release Levetiracetam, as compared to placebo. The mean decreases from baseline in the immediate-release Levetiracetam group were -0.4 × 109 /L and -0.3 × 109 /L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release Levetiracetam compared to a decrease of 4% in patients on placebo.

In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release Levetiracetam, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts.

In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release Levetiracetam-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X109 /L).

5.9  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.

The following adverse reactions are discussed in more details in other sections of 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) ]
• Coordination Difficulties [ see Warnings and Precautions (5.6) ]
• Hematologic Abnormalities [ see Warnings and Precautions (5.8)]

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.

Levetiracetam Extended-release Tablets

In the controlled clinical study in patients with partial onset seizures, the most common adverse reactions in patients receiving Levetiracetam Extended-release Tablets in combination with other AEDs, for events with rates greater than placebo, were irritability and somnolence.

Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving Levetiracetam Extended-release Tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam Extended-release Tablets or placebo was added to concurrent AED therapy.

Discontinuation or Dose Reduction in the Levetiracetam Extended-release Tablets Controlled Clinical Study

In the controlled clinical study, 5% of patients receiving Levetiracetam Extended-release Tablets and 3% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in Levetiracetam Extended-release Tablets-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash and respiratory failure. Each of these adverse reactions led to discontinuation in a Levetiracetam Extended-release Tablets-treated patient and no placebo-treated patients.

Immediate-Release Levetiracetam Tablets

Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the Levetiracetam Extended-release Tablets study seems somewhat different from that seen in partial onset seizure controlled studies for immediate-release Levetiracetam tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for Levetiracetam Extended-release Tablets are expected to be similar to those seen with immediate-release Levetiracetam tablets.

Adults

In controlled clinical studies of immediate-release Levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness.

Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving immediate-release Levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release Levetiracetam tablets or placebo was added to concurrent AED therapy.

Pediatric Patients 4 Years to <16 Years

In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial onset seizures, the adverse reactions most frequently reported with the use of immediate-release Levetiracetam in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-release Levetiracetam and were more common than in pediatric patients on placebo. In these studies, either immediate-release Levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

In controlled pediatric clinical studies in patients 4-16 years of age, 7% of patients treated with immediate-release Levetiracetam tablets and 9% of patients on placebo discontinued as a result of an adverse event.

In addition, the following adverse reactions were seen in other controlled studies of immediate-release Levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and blurred vision.

Comparison of Gender, Age and Race

There are insufficient data for Levetiracetam Extended-release Tablets to support a statement regarding the distribution of adverse reactions by gender, age and race.

6.2  Postmarketing Experience

The following adverse reactions have been identified during postapproval use of immediate-release Levetiracetam tablets. 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, anaphylasix, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with immediate-release Levetiracetam use; recovery was observed in majority of cases where immediate-release Levetiracetam was discontinued.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Psychiatric Reactions and Changes in Behavior

Advise patients that Roweepra XR may cause changes in behavior (e.g. irritability and aggression). In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of Levetiracetam, which include agitation, anger, anxiety, apathy, depression, hostility, and psychotic symptoms [ seeWarnings and Precautions (5.1) ].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including Roweepra XR, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider [ seeWarnings and Precautions (5.2) ].

Effects on Driving or Operating Machinery

Inform patients that Roweepra XR may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on Roweepra XR to gauge whether it adversely affects their ability to drive or operate machinery [ seeWarnings and Precautions (5.3) ].

Anaphylaxis and Angioedema

Advise patients to discontinue Roweepra XR and seek medical care if thet develop signs and symptoms of anaphylasix or angioedema [see Warnings and Precautions (5.4)].

Dermatological Adverse Reactions

Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their physician immediately if a rash develops [see Warnings and Precautions (5.5)].

Dosing and Administration

Patients should be instructed to only take Roweepra XR once daily and to swallow the tablets whole. They should not be chewed, broken, or crushed. Inform patients that they should not be concerned if they occasionally notice something that looks like swollen pieces of the original tablet in their stool.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Roweepra XR therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [ see Use in Specific Populations (8.1) ].

Manufactured for:

OWP Pharmaceuticals, Inc.

931 W. Hawthorne Lane

West Chicago, IL 60185

By:

Lotus Pharmaceutical Co., Ltd. Nantou Plant

No. 30 Chenggong 1st Rd., Sinsing Village, Nantou City,

Nantou County 54066, Taiwan

Rev. 05/2017

Applies to levetiracetam: intravenous solution, oral solution, oral tablet, oral tablet dispersible, oral tablet extended release

Nervous system

Very common (10% or more): Headache (14%), somnolence (14%)
Common (1% to 10%): Dizziness, ataxia, vertigo, paresthesia
Postmarketing reports: Choreoathetosis, dyskinesia[Ref]

Respiratory

Common (1% to 10%): Pharyngitis, rhinitis, increased cough, sinusitis[Ref]

Psychiatric

Common (1% to 10%): Depression, nervousness, amnesia, anxiety, hostility, emotional lability, irritability, mood swings, hypersomnia, insomnia, apathy, tearfulness, negativism
Frequency not reported: Suicidal ideation, delusional behavior[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea
Uncommon (0.1% to 1%): Nausea
Postmarketing reports: Pancreatitis[Ref]

Ocular

Common (1% to 10%): Diplopia[Ref]

Hematologic

Frequency not reported: Leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, decreases in total mean RBC count (0.03 x 1,000,000/mm2), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%)[Ref]

Dermatologic

Postmarketing reports: Erythema multiforme, leukopenia, neutropenia, pancytopenia (with bone marrow suppression in some cases), Stevens-Johnson syndrome (SJS), thrombocytopenia, toxic epidermal necrolysis (TEN), alopecia, angioedema[Ref]

Hepatic

Postmarketing reports: Abnormal liver function tests, hepatic failure, hepatitis[Ref]

Musculoskeletal

Common (1% to 10%): Neck pain[Ref]

Immunologic

Very common (10% or more): Infection (13%)
Common (1% to 10%): Influenza[Ref]

Metabolic

Common (1% to 10%): Anorexia
Postmarketing reports: Weight loss[Ref]

Other

Very common (10% or more): Asthenia (15%), fatigue (10%)
Common (1% to 10%): Pain, vertigo[Ref]

Cardiovascular

Very common (10% or more): Increased blood pressure in patients 1 month to less than 4 years of age (up to 17%)[Ref]

Hypersensitivity

Postmarketing reports: Anaphylaxis

Some side effects of Roweepra XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.