RUFINAMIDE Drug Interactions: What You Need to Know

INTERACTIONS

• Patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) ( 7.2 )
• Hormonal contraceptives may be less effective with rufinamide; use additional non-hormonal forms of contraception ( 7.3 )

7.1 Effects of Rufinamide on other AEDs Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide C avss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population.

Table

6 summarizes the drug-drug interactions of rufinamide with other AEDs.

Table

6: Summary of drug-drug interactions of rufinamide with other antiepileptic drugs AED Co- administered Influence of Rufinamide on AED concentration a) Influence of AED on Rufinamide concentration Carbamazepine Decrease by 7 to 13% b) Decrease by 19 to 26% Dependent on dose of carbamazepine Lamotrigine Decrease by 7 to 13% b)

No Effect Phenobarbital

Increase by 8 to 13% b) Decrease by 25 to 46% c), d) Independent of dose or concentration of phenobarbital Phenytoin Increase by 7 to 21% b) Decrease by 25 to 46% c),d) Independent of dose or concentration of phenytoin Topiramate No Effect No Effect Valproate No Effect Increase by <16 to 70% c) Dependent on concentration of valproate Primidone Not Investigated Decrease by 25 to 46% c), d) Independent of dose or concentration of primidone Benzodiazepines e)

Not Investigated No

Effect a) Predictions are based on rufinamide concentrations at the maximum recommended dose of rufinamide. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of rufinamide, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on rufinamide clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on rufinamide clearance. Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (C avss 15 mcg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction.

7.2 Effects of other AEDs on Rufinamide Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital, appear to increase the clearance of rufinamide (see Table 6). Given that the majority of clearance of rufinamide is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred, were likely to be more marked in the pediatric population.

Valproate

Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) [ see Dosage and Administration (2.5 ), Clinical Pharmacology ( 12.3 )].

7.3 Effects of Rufinamide on Hormonal Contraceptives Female patients of childbearing age should be warned that the concurrent use of rufinamide with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using rufinamide [ see Use in Specific Populations ( 8.3 ), Clinical Pharmacology ( 12.3 ) and Patient Counseling Information ( 17 ) ].

Drug Interactions

Based on in vitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Drugs that are substrates of CYP 2E1 (e.g., chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied. Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In pediatric patients, valproate administration may lead to elevated levels of rufinamide by up to 70% [ see Drug Interactions ( 7.2 )] . Based on in vivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP 3A4.

• Co-administration and pre-treatment of rufinamide (400 mg twice daily) and triazolam resulted in a 37% decrease in AUC and a 23% decrease in C max of triazolam, a CYP 3A4 substrate.
• Co-administration of rufinamide (800 mg twice daily for 14 days) and Ortho-Novum 1/35 ® resulted in a mean decrease in the ethinyl estradiol AUC 0 to 24 of 22% and C max by 31% and norethindrone AUC 0 to 24 by 14% and C max by 18%, respectively. The clinical significance of this decrease is unknown [see Drug Interactions ( 7.3 ) and Use in Specific Populations ( 8.3 )] . Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broad-spectrum inducers such as carbamazepine and phenobarbital may have minor effects on rufinamide metabolism via this mechanism. Drugs that are inhibitors of carboxylesterases may decrease metabolism of rufinamide.

Rufinamide oral suspension is contraindicated in patients with Familial Short QT syndrome [see Warnings and Precautions ( 5.3 )] . Rufinamide oral suspension is contraindicated in patients with Familial Short QT syndrome ( 4 )

AND PRECAUTIONS Monitor patients for new or worsening depression, suicidal thoughts/behavior, and unusual changes in mood or behavior ( 5.1 ) Central nervous system reactions can occur ( 5.2 ) Use caution when administering rufinamide tablets with other drugs that shorten the QT interval ( 5.3 ) Discontinue rufinamide tablet if multi-organ hypersensitivity reaction occurs ( 5.4 ) Withdraw rufinamide tablet gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus ( 5.5 )

5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including rufinamide tablets, 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 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 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 tablets 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 tablets 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 tablet-treated patients compared to 13% of patients on placebo, and led to study discontinuation in 3% of rufinamide tablet-treated patients compared to 0% of patients on placebo. Fatigue was reported in 10% of rufinamide tablet-treated patients compared to 8% of patients on placebo patients. It led to study discontinuation in 1% of rufinamide tablet-treated patients and 0% of patients on placebo patients. Dizziness was reported in 2.7% of rufinamide tablet-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 tablet-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 tablet 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 &gt;2400 mg twice daily) with rufinamide tablets. In a placebo-controlled study of the QT interval, a higher percentage of rufinamide tablet-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at T max 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 7200 mg per day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias. The degree of QT shortening induced by rufinamide tablets 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 tablets. Caution should be used when administering rufinamide tablet 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 tablets. 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 tablets occurred in pediatric patients less than 12 years of age, occurred within 4 weeks of treatment initiation, and resolved or improved with rufinamide tablet discontinuation. DRESS has also been reported in adult and pediatric patients taking rufinamide tablets in the postmarketing setting. If DRESS is suspected, the patient should be evaluated immediately, rufinamide tablets should be discontinued, and alternative treatment should be started.

5.5 Withdrawal of AEDs As with all antiepileptic drugs, rufinamide tablets 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 tablets 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 tablets are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1%) rufinamide tablet-treated patients had episodes that could be described as status epilepticus in the rufinamide tablet-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 1240 (0.9%) rufinamide tablet-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 tablet has been shown to reduce white cell count. Leukopenia (white cell count &lt; 3X10 9 L) was more commonly observed in rufinamide tablet-treated patients 43 of 1171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials.