ADVERSE REACTIONS
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.
In all controlled and uncontrolled trials in patients with partial-onset seizures, 1327 patients have received VIMPAT of whom 1000 have been treated for longer than 6 months and 852 for longer than 12 months.
Clinical Trials Experience
Controlled Trials
Adverse reactions leading to discontinuation
In controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and 17% in patients randomized to receive VIMPAT at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo. The adverse events most commonly (>1% in the VIMPAT total group and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
Most common adverse reactions
Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult patients with partial-onset seizures in the total VIMPAT group and for which the incidence was greater than placebo. The majority of adverse events in the VIMPAT patients were reported with a maximum intensity of 'mild' or 'moderate'.
Table 2: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled Partial-Onset Seizure Trials (Events ≥2% of Patients in VIMPAT Total and More Frequent Than in the Placebo Group) System Organ Class/
Preferred Term | Placebo
N=364
% | VIMPAT
200 mg/day
N=270
% | VIMPAT
400 mg/day
N=471
% | VIMPAT
600 mg/day
N=203
% | VIMPAT
Total
N=944
% |
| Ear and labyrinth disorder |
| Vertigo | 1 | 5 | 3 | 4 | 4 |
| Eye disorders |
| Diplopia | 2 | 6 | 10 | 16 | 11 |
| Vision blurred | 3 | 2 | 9 | 16 | 8 |
| Gastrointestinal disorders |
| Nausea | 4 | 7 | 11 | 17 | 11 |
| Vomiting | 3 | 6 | 9 | 16 | 9 |
| Diarrhea | 3 | 3 | 5 | 4 | 4 |
| General disorders and administration site conditions |
| Fatigue | 6 | 7 | 7 | 15 | 9 |
| Gait disturbance | <1 | <1 | 2 | 4 | 2 |
| Asthenia | 1 | 2 | 2 | 4 | 2 |
| Injury, poisoning and procedural complications |
| Contusion | 3 | 3 | 4 | 2 | 3 |
| Skin laceration | 2 | 2 | 3 | 3 | 3 |
| Nervous system disorders |
| Dizziness | 8 | 16 | 30 | 53 | 31 |
| Headache | 9 | 11 | 14 | 12 | 13 |
| Ataxia | 2 | 4 | 7 | 15 | 8 |
| Somnolence | 5 | 5 | 8 | 8 | 7 |
| Tremor | 4 | 4 | 6 | 12 | 7 |
| Nystagmus | 4 | 2 | 5 | 10 | 5 |
| Balance disorder | 0 | 1 | 5 | 6 | 4 |
| Memory impairment | 2 | 1 | 2 | 6 | 2 |
| Psychiatric disorders |
| Depression | 1 | 2 | 2 | 2 | 2 |
| Skin and subcutaneous disorders |
| Pruritus | 1 | 3 | 2 | 3 | 2 |
Laboratory abnormalities
Abnormalities in liver function tests have been observed in controlled trials with VIMPAT in adult patients with partial-onset seizures who were taking 1 to 3 concomitant 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. One case of hepatitis with transaminases >20x ULN was observed 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, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT.
Other Adverse Reactions in Patients with Partial-Onset Seizures
The following is a list of treatment-emergent adverse events reported by patients treated with VIMPAT in all clinical trials in patients with partial-onset seizures, including controlled trials and long-term open-label extension trials. Events addressed in other tables or sections are not listed here. Events included in this list from the controlled trials occurred more frequently on drug than on placebo and were based on consideration of VIMPAT pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to VIMPAT. Events are further classified within system organ class.
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
Intravenous Adverse Reactions
Adverse reactions with intravenous administration generally appeared similar to those observed with the oral formulation, although intravenous administration was associated with local adverse events 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) was observed in a patient during a 15 minute infusion of 150mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued and the patient experienced a rapid recovery.
Comparison of Gender and Race
The overall adverse event rate was similar in male and female patients. Although there were few non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian patients were observed.
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