VIMPAT SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Behavior and Ideation
• Dizziness and Ataxia
• Cardiac Rhythm and Conduction Abnormalities
• Syncope
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions

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 ompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

VIMPAT Tablet And Oral Solution In Adults

In the premarketing development of adjunctive therapy for partial-onset seizures, 1327 adult patients received VIMPAT tablets in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months. The monotherapy development program for partial-onset seizures included 425 adult patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.

Partial-Onset Seizures

Monotherapy Historical-Control Trial (Study 1)

In the monotherapy trial for partial-onset seizures, 16% of patients randomized to receive VIMPAT at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse reaction. The adverse reaction most commonly (≥1% on VIMPAT) leading to discontinuation was dizziness.

Adverse reactions that occurred in this study were generally similar to those that occurred in adjunctive placebo-controlled studies. One adverse reaction, insomnia, occurred at a rate of ≥2% and was not reported at a similar rate in previous studies. This adverse reaction has also been observed in postmarketing experience. Because this study did not include a placebo control group, causality could not be established.

Dizziness, headache, nausea, somnolence, and fatigue all occurred at lower incidences during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase.

Adjunctive Therapy Controlled Trials (Studies 2, 3, and 4)

In adjunctive therapy controlled clinical trials for partial-onset seizures, the rate of discontinuation as a result of an adverse reaction was 8% and 17% inpatients randomized to receive VIMPAT at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day (1.5 times greater than the maximum recommended dose), and 5% in patients randomized to receive placebo. The adverse reactions most commonly (>1% on VIMPAT and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and blurred vision.

Table 1 gives the incidence of adverse reactions that occurred in ≥2% of adult patients with partial-onset seizures in the VIMPAT total group and for which the incidence was greater than placebo.

Table 1: Adverse Reactions Incidence in Adjunctive Therapy Pooled, Placebo-Controlled Trials in Adult Patients with Partial-Onset Seizures (Studies 2, 3, and 4)

The overall adverse reaction rate was similar in male and female patients. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.

VIMPAT Tablet And Oral Solution In Pediatric Patients

Safety of VIMPAT was evaluated in clinical studies of pediatric patients 1 month to less than 17 years of age for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 847 patients 1 month to less than 17 years of age received VIMPAT oral solution or tablet, of whom 596 received VIMPAT for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 1 month to less than 17years of age were similar to those seen in adult patients.

Primary Generalized Tonic-Clonic Seizures In Patients (4 Years of Age and Older) Adjunctive Therapy Trial (Study 5)

In the adjunctive therapy placebo-controlled trial for primary generalized tonic-clonic seizures, adverse reactions that occurred in the study were generally similar to those that occurred in partial-onset seizure placebo-controlled studies. The most common adverse reactions (≥ 10% on VIMPAT)reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%), compared to 7%, 14%, 10%,and 6%, respectively, of patients who received placebo. Additionally, an adverse reaction not previously reported of myoclonic epilepsy was reported in3% of patients treated with VIMPAT compared to 1% of patients who received placebo. It is also noted that 2 patients receiving VIMPAT had acute worsening of seizures shortly after drug initiation, including one episode of status epilepticus, compared to no patients receiving placebo.

Laboratory Abnormalities

Abnormalities in liver function tests have occurred in controlled trials with VIMPAT in adult patients with partial-onset seizures who were taking 1 to 3concomitant anti-epileptic drugs. Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of placebo patients. Onecase of hepatitis with transaminases >20× ULN occurred in one healthy subject 10 days after VIMPAT treatment completion, along with nephritis(proteinuria and urine casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirub in was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT.

Other Adverse Reactions

The following is a list of adverse reactions reported by patients treated with VIMPAT in all clinical trials in adult patients, including controlled trials and long-term open-label extension trials. Adverse reactions addressed in other tables or sections are not listed here.

Blood and lymphatic system disorders: neutropenia, anemia

Cardiac disorders: palpitations

Ear and labyrinth disorders: tinnitus

Gastrointestinal disorders: constipation, dyspepsia, dry mouth, oral hypoaesthesia

General disorders and administration site conditions: irritability, pyrexia, feeling drunk

Injury, poisoning, and procedural complications: fall

Musculoskeletal and connective tissue disorders: muscle spasms

Nervous system disorders: paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome

Psychiatric disorders: confusional state, mood altered, depressed mood

VIMPAT Injection

Adult Patients (17 Years and Older)

Adverse reactions with intravenous administration to adult patients with partial-onset seizures generally were similar to those that occurred with the oral formulation, although intravenous administration was associated with local adverse reactions such as injection site pain or discomfort (2.5%), irritation(1%), and erythema (0.5%). One case of profound bradycardia (26 bpm: BP 100/60 mmHg) occurred in a patient during a 15-minute infusion of 150 mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued and the patient experienced a rapid recovery.

The safety of a 15-minute loading dose administration of VIMPAT Injection 200 mg to 400 mg followed by oral administration of VIMPAT given twice daily at the same total daily dose as the initial intravenous infusion was assessed in an open-label study in adult patients with partial-onset seizures. Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment. Treatment groups were as follows:

• Single dose of intravenous VIMPAT Injection 200 mg followed by oral VIMPAT 200 mg/day (100 mg every 12 hours)
• Single dose of intravenous VIMPAT Injection 300 mg followed by oral VIMPAT 300 mg/day (150 mg every 12 hours)
• Single dose of intravenous VIMPAT Injection 400 mg followed by oral VIMPAT 400 mg/day (200 mg every 12 hours).
• Table 2 gives the incidence of adverse reactions that occurred in ≥5% of adult patients in any VIMPAT dosing group.

Table 2: Adverse Reactions in a 15-minute Infusion Study in Adult Patients with Partial-Onset Seizures

Adverse reactions that occurred with infusion of VIMPAT 200 mg over 15-minutes followed by VIMPAT 100 mg administered orally twice per day were similar in frequency to those that occurred in 3-month adjunctive therapy controlled trials. Considering the difference in period of observations (1week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minuteadministration of VIMPAT Injection than with administration over a 30-to 60-minute period.

The adverse reactions associated with VIMPAT injection in adult patients with primary generalized tonic-clonic seizures are expected to be similar to those seen in adults with partial-onset seizures.

Pediatric Patients (1 Month To Less Than 17 Years Of Age)

The safety of VIMPAT injection was evaluated in a multicenter, open-label study of 103 pediatric patients 1 month to less than 17 years of age with epilepsy. Infusions were primarily administered over a 30 to 60 minute time period; infusion times less than 30 minutes were not adequately studied inpediatric patients. Although no serious or severe adverse reactions were noted at the time of infusion in this small study, the adverse reactions associated with VIMPAT injection in pediatric patients are expected to be similar to those noted in adults.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VIMPAT. Because these reactions are reported voluntarily from apopulation of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Aggression, agitation, hallucination, insomnia, psychotic disorder

Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Neurologic disorders: Dyskinesia, new or worsening seizures

SRC: NLM .