Rufinamide: Package Insert and Label Information

RUFINAMIDE- rufinamide tablet, film coated
Glenmark Pharmaceuticals Inc., USA

1 INDICATIONS AND USAGE

Rufinamide tablets are indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in pediatric patients 1 year of age and older and in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage Information

Pediatric patients (1 year to less than 17 years)

The recommended starting daily dose of rufinamide in pediatric patients with Lennox-Gastaut Syndrome is approximately 10 mg/kg administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day until a maximum daily dose of 45 mg/kg, not to exceed 3,200 mg, administered in two equally divided doses, is reached. It is not known whether doses lower than the target doses are effective.

Adults (17 years and older)

The recommended starting daily dose of rufinamide in adults with Lennox-Gastaut Syndrome is 400 mg per day to 800 mg per day administered in two equally divided doses. The dose should be increased by 400 mg to 800 mg every other day until a maximum daily dose of 3200 mg, administered in two equally divided doses, is reached. It is not known whether doses lower than 3,200 mg are effective.

2.2 Administration Information

Administer rufinamide with food. Rufinamide film-coated tablets can be administered whole, as half tablets or crushed.

2.3 Dosing in Patients Undergoing Hemodialysis

Hemodialysis may reduce exposure to a limited (about 30%) extent. Accordingly, adjusting the rufinamide dose during the dialysis process should be considered [see Clinical Pharmacology (12.3)].

2.4 Dosing in Patients with Hepatic Disease

Use of rufinamide in patients with hepatic impairment has not been studied. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7) ].

2.5 Dosing in Patients Taking Valproate

Patients taking valproate should begin rufinamide at a dose lower than 10 mg/kg per day in pediatric patients or 400 mg per day in adults [see Drug Interactions (7.2) ].

3 DOSAGE FORMS AND STRENGTHS

The 200 mg tablets are pink, film-coated, oblong-shaped tablets with functional scoring, embossed with ‘713’ and a ‘G’ on either side of a break line on one side and plain with a break line on the other side.
The 400 mg tablets are pink, film-coated, oblong-shaped tablets with functional scoring, embossed with ‘714’ and a ‘G’ on either side of a break line on one side and plain with a break line on the other side.

4 CONTRAINDICATIONS

Rufinamide is contraindicated in patients with Familial Short QT syndrome [see Warnings and Precautions (5.3) ].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including rufinamide, 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 1 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 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Absolute and Relative Risk of Suicidal Behavior and Ideation

Indication

Placebo Patients with Events Per 1,000 Patients

Drug Patients with Events Per 1,000 Patients

Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients

Risk Difference: Additional Drug Patients with Events Per 1,000 Patients

Epilepsy

1

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1

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 rufinamide 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, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.2 Central Nervous System Reactions

Use of rufinamide has been associated with central nervous system-related adverse reactions in the controlled clinical trial of patients 4 years or older with Lennox-Gastaut Syndrome. The most significant of these can be classified into two general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.

Somnolence was reported in 24% of rufinamide-treated patients compared to 13% of patients on placebo, and led to study discontinuation in 3% of rufinamide-treated patients compared to 0% of patients on placebo. Fatigue was reported in 10% of rufinamide-treated patients compared to 8% of patients on placebo patients. It led to study discontinuation in 1% of rufinamide-treated patients and 0% of patients on placebo patients.

Dizziness was reported in 2.7% of rufinamide-treated patients compared to 0% of patients on placebo, and did not lead to study discontinuation.

Ataxia and gait disturbance were reported in 5.4% and 1.4% of rufinamide-treated patients, respectively, compared to no patient on placebo. None of these reactions led to study discontinuation.

Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on rufinamide to gauge whether it adversely affects their ability to drive or operate machinery.

5.3 QT Shortening

Formal cardiac ECG studies demonstrated shortening of the QT interval (mean = 20 msec, for doses ≥ 2,400 mg twice daily) with rufinamide. In a placebo-controlled study of the QT interval, a higher percentage of rufinamide-treated subjects (46% at 2,400 mg, 46% at 3,200 mg, and 65% at 4,800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 to 10%).

Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7,200 mg per day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.

The degree of QT shortening induced by rufinamide is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.

Patients with Familial Short QT syndrome should not be treated with rufinamide. Caution should be used when administering rufinamide with other drugs that shorten the QT interval [see Contraindications (4) ].

5.4 Multi-organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including rufinamide. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or 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. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Because this disorder is variable in its expression, other organ systems not noted here may be involved.

All cases of DRESS identified in clinical trials with rufinamide occurred in pediatric patients less than 12 years of age, occurred within 4 weeks of treatment initiation, and resolved or improved with rufinamide discontinuation. DRESS has also been reported in adult and pediatric patients taking rufinamide in the postmarketing setting.

If DRESS is suspected, the patient should be evaluated immediately, rufinamide should be discontinued, and alternative treatment should be started.

5.5 Withdrawal of AEDs

As with all antiepileptic drugs, rufinamide should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, rufinamide discontinuation was achieved by reducing the dose by approximately 25% every 2 days.

5.6 Status Epilepticus

Estimates of the incidence of treatment emergent status epilepticus among patients treated with rufinamide are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1 %) rufinamide-treated patients had episodes that could be described as status epilepticus in the rufinamide-treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1,240 (0.9%) rufinamide-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients.

5.7 Leukopenia

Rufinamide has been shown to reduce white cell count. Leukopenia (white cell count <3 × 109 L) was more commonly observed in rufinamide-treated patients 43 of 1,171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials.

6 ADVERSE REACTIONS

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

Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
Central Nervous System Reactions [see Warnings and Precautions (5.2)]
QT Shortening [see Warnings and Precautions (5.3)]
Multi-organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]
Leukopenia [see Warnings and Precautions (5.7)]

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.

Adverse Reactions in Adult and Pediatric Patients ages 3 to 17 years of age

In the pooled, double-blind, adjunctive therapy studies in adult and pediatric patients ages 3 to 17 years of age, the most common (≥10%) adverse reactions in rufinamide-treated patients, in all doses studied (200 to 3,200 mg per day) with a higher frequency than in patients on placebo were: headache, dizziness, fatigue, somnolence, and nausea.

Table 2 lists adverse reactions that occurred in at least 3% of pediatric patients (ages 3 to less than 17 years) with epilepsy treated with rufinamide in controlled adjunctive studies and were numerically more common in patients treated with rufinamide than in patients on placebo.

At the target dose of 45 mg/kg per day for adjunctive therapy in pediatric patients (ages 3 to less than 17 years), the most common (≥3%) adverse reactions with an incidence greater than in placebo for rufinamide were somnolence, vomiting, and headache.

Table 2: Adverse Reactions in Pediatric Patients (Ages 3 to less than 17 years) in Pooled Double-Blind Adjunctive Trials

Adverse Reaction

Rufinamide
(N=187)
%
Placebo
(N=182)
%

Somnolence

17
9

Vomiting

17
7

Headache

16
8

Fatigue

9
8

Dizziness

8
6

Nausea

7
3

Influenza

5
4

Nasopharyngitis

5
3

Decreased Appetite

5
2

Rash

4
2

Ataxia

4
1

Diplopia

4
1

Bronchitis

3
2

Sinusitis

3
2

Psychomotor Hyperactivity

3
1

Upper Abdominal Pain

3
2

Aggression

3
2

Ear Infection

3
1

Disturbance in Attention

3
1

Pruritis

3
0

Table 3 lists adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with rufinamide (up to 3,200 mg per day) in adjunctive controlled studies and were numerically more common in patients treated with rufinamide than in patients on placebo. In these studies, either rufinamide or placebo was added to the current AED therapy.

At all doses studied of up to 3,200 mg per day given as adjunctive therapy in adults, the most common (≥3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for rufinamide were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia.

Table 3: Adverse Reactions in Adults in Pooled Double-Blind Adjunctive Trials

Adverse Reaction

Rufinamide

(N=823) %

Placebo

(N=376)%

Headache

27

26

Dizziness

19

12

Fatigue

16

10

Nausea

12

9

Somnolence

11

9

Diplopia

9

3

Tremor

6

5

Nystagmus

6

5

Blurred Vision

6

2

Vomiting

5

4

Ataxia

4

0

Upper Abdominal Pain

3

2

Anxiety

3

2

Constipation

3

2

Dyspepsia

3

2

Back Pain

3

1

Gait Disturbance

3

1

Vertigo

3

1

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