Source: Health Products and Food Branch (CA) Revision Year: 2022
Patients who are hypersensitive to BRIVLERA (brivaracetam) or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.
As with all AEDs, BRIVLERA (brivaracetam) should be withdrawn gradually to minimize the potential of increased seizure frequency and status epilepticus (see 4.2 Recommended Dose and Dosage Adjustment).
See 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and 16 NON-CLINICAL TOXICOLOGY, Genotoxicity for discussion on animal data.
BRIVLERA treatment has been associated with somnolence, dizziness, fatigue, and disturbance in coordination. Patients should be monitored for such signs and symptoms and advised not to drive a car or to operate other potentially hazardous machines until they are familiar with the effects of BRIVLERA on their ability to perform such activities (see 7 WARNINGS AND PRECAUTIONS, Neurologic and 8 ADVERSE REACTIONS).
BRIVLERA can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies in adults, a total of 1.8% of BRIVLERA-treated patients and 1.1% of placebo-treated patients had at least one clinically significant decreased white blood cell count (<3.0 × 109/L), and 0.3% of BRIVLERA-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 × 109/L).
There are limited clinical data on the use of BRIVLERA in adult patients with pre-existing hepatic impairment, and no clinical data in the pediatric population with hepatic impairme nt. Dose decreases are recommended. In adults, a 25 mg twice daily (50 mg per day) starting dose should be considered. A maximum dose of 75 mg twice daily (150 mg per day) is recommended for all stages of hepatic impairment. For dosing recommendations for pediatric patients, see 4 DOSAGE AND ADMINISTRATION (see also 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency).
Bronchospasm and Angioedema: BRIVLERA can cause hypersensitivity reactions. Rare cases of bronchospasm and angioedema have been reported in patients taking BRIVLERA. If a patient develops hypersensitivity reactions after treatment with BRIVLERA, the drug should be discontinued and an alternative considered.
Serious Dermatologic Reactions: Multi-organ hypersensitivity syndrome (also known as Drug Reaction Eosinophilia and Systemic Symptoms or DRESS), is a serious condition sometimes induced by antiepileptic drugs. Typically, although not exclusively, DRESS initially presents with fever and rash, then with other organ system involvement that may or may not include eosinophilia, lymphadenopathy, hepatitis, nephritis, and/or myocarditis. Because DRESS is variable in its expression, other organ system signs and symptoms not noted here may also occur. Organ involvement may be more severe than skin involvement. If any of these hypersensitivity reactions are suspected and an alternative cause cannot be established, BRIVLERA should be discontinued and alternative treatment started.
BRIVLERA causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, malaise, hypersomnia, sedation, and lethargy). In the Phase 3 controlled adjunctive epilepsy trials in adults, these events were reported in 25% of patients randomized to receive BRIVLERA at least 50 mg/day (20% at 50 mg/day, 26% at 100 mg/day, and 27% at 200 mg/day) compared to 14% of placebo-treated patients. The risk is greatest early in treatment but can occur at any time (see 8 ADVERSE REACTIONS).
BRIVLERA causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination). In the Phase 3 controlled adjunctive epilepsy trials in adults, these events were reported in 16% of patients randomized to receive BRIVLERA at least 50 mg/day (16% at 50 mg/day, 14% at 100 mg/day, and 18% at 200 mg/day) compared to 10% of placebotreated patients. The risk is greatest early in treatment but can occur at any time (see 8 ADVERSE REACTIONS).
BRIVLERA causes both psychotic and non-psychotic adverse reactions which are not dosedependent. In the Phase 3 controlled adjunctive epilepsy trials in adults, psychiatric events were reported in approximately 13% of patients randomized to receive BRIVLERA at least 50 mg/day compared to 8% of placebo-treated patients. Non-psychotic events (e.g., irritability, anxiety, nervousness, aggression, anger, agitation, restlessness, depression, altered mood, affect lability, psychomotor hyperactivity, etc.) occurred in 12% of the patients treated with BRIVLERA at least 50 mg/day compared to 7% of placebo-treated patients. A total of 1.7% of adult patients treated with BRIVLERA discontinued treatment due to psychiatric events (e.g., aggression, irritability, depression) compared to 1.3% of patients who received placebo. In the Phase 3 controlled epilepsy studies in adults, irritability, depression, and anxiety symptoms occurred in 2% of BRIVLERA-treated patients and 1% of placebo-treated patients.
While psychiatric events observed in open-label pediatric trials were generally similar to those observed in adults, irritability and aggression were approximately double the incidence rates seen in adults, and the most frequent terms in pediatrics. Psychomotor hyperactivity was also reported at notably higher rates than in adults.
There have been post-marketing reports of psychotic disorder and related events (e.g., hallucinations, delusions, paranoia). Some cases were resolved following BRIVLERA dose reduction or discontinuation (see 8.5 Post-Market Adverse Reactions, Psychosis/Psychotic Disorder).
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.
All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.
There were 43,892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.
There are limited clinical data on the use of BRIVLERA in patients with pre-existing renal impairment as these patients were excluded from pre-market clinical studies of epilepsy. Based on a single-dose pharmacokinetic study, dose adjustments are not required for patients with impaired renal function. Based on data in adults, no dose adjustment is necessary in pediatric patients with impaired renal function.
There are no data in patients with end-stage renal disease undergoing dialysis. Thus, BRIVLERA is not recommended in this population (see 4.2 Recommended Dose and Dosage Adjustment, Patients with Renal Impairment and 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).
Women of Childbearing Potential / Contraception: In a drug-drug interaction study, BRIVLERA 100 mg/day did not significantly influence the pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol and 0.15 mg levonorgestrel). In another study, BRIVLERA 400 mg/day (twice the recommended daily dose) reduced exposure to oral contraceptives by 27% for estrogen and 23% for progestin (see 9.4 Drug-Drug Interactions, Drug-Drug Interaction Studies with Other Drugs, Oral Contraceptives).
Physicians should discuss family planning and contraception with women of childbearing potential taking BRIVLERA (see 7.1.1 Pregnant Women).
No human data on the effect of BRIVLERA on fertility are available. In rats, there was no effect on fertility with brivaracetam at doses associated with systemic exposures up to 6 and 13 times that at the 200 mg/day human dose, in male and female rats, respectively (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
Pregnant Women: There is a limited amount of data from the use of BRIVLERA in pregnant women. BRIVLERA was used as adjunctive therapy in clinical studies in non-pregnant individuals, and when used with carbamazepine, it induced a dose-related increase in the concentration of an active metabolite, carbamazepine-epoxide (see 9.4 Drug-Drug Interactions, Drug-Interaction Studies with Antiepileptic Drugs (AEDs), Carbamazepine). The clinical significance of this increase in carbamazepine-epoxide in pregnant women is unknown.
Animal studies did not detect any teratogenic potential of brivaracetam in either the rat or the rabbit, however embryo-fetal and maternal toxicity was seen in rabbits with systemic exposure (AUC) at the no-effect dose about 8 times that at the 200 mg/day human dose. In rats, brivaracetam has been shown to readily cross the placenta (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology). There are no data on human placental transfer. The potential risk for humans is unknown.
BRIVLERA should not be used during pregnancy unless clinically necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus). If a woman decides to become pregnant, the use of BRIVLERA should be carefully re-evaluated.
Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking BRIVLERA enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Labour and Delivery: The effect of BRIVLERA on labour and delivery in humans is unknown.
It is not known whether BRIVLERA is excreted in human milk. Studies in rats have shown that brivaracetam is readily excreted in breast milk. If BRIVLERA is to be co-administered with carbamazepine, the amount of carbamazepine epoxide in breast milk can increase (see 9.4 Drug-Drug Interactions, Drug-Interaction Studies with Antiepileptic Drugs (AEDs), Carbamazepine).
Because many drugs are excreted into human milk, a decision should be made as to whe ther to discontinue nursing or to discontinue BRIVLERA, taking into account the benefit of the drug to the mother.
Pediatrics (<18 years of age): The efficacy of BRIVLERA has been established in adolescents and children ≥4 years of age using evidence from adequate and well-controlled studies of BRIVLERA in adults with partial-onset seizures; and pharmacokinetic data from adult and pediatric patients. The extrapolation approach was based on achieving similar systemic exposure of BRIVLERA in this patient population compared to adults taking similar recommended doses.
The safety has been established using safety data from clinical studies in 161 pediatric patients aged 4-17 with partial onset seizures (see 8.2.1 Clinical Trial Adverse Reactions – Pediatrics; 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics, and 14 CLINICAL TRIALS). The safety and efficacy in pediatric patients less than 4 years have not been established.
The long-term safety, including effects on growth, maturation, and behavioural development, in patients under 18 years of age has not been systematically evaluated. See 8.2.1 Clinical Trial Adverse Reactions – Pediatrics.
Safety of BRIVLERA solution for injection in pediatric patients has not been established.
Geriatrics (≥65 years of age): There were insufficient numbers of patients 65 years of age and older in the double-blind, placebo-controlled epilepsy studies in adults (n=29) to adequately assess the safety and efficacy of BRIVLERA in this population. No BRIVLERA dose adjustment based on age is necessary (see 4 DOSAGE AND ADMINISTRATION and 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics).
In pooled placebo-controlled adjunctive therapy studies involving 1558 adult patients with partial-onset seizures (1099 patients treated with BRIVLERA (brivaracetam) and 459 treated with placebo), 68.3% of patients treated with BRIVLERA and 62.1% of patients treated with placebo experienced adverse events.
Safety of BRIVLERA in pediatric patients was evaluated in two open-label, safety and pharmacokinetic trials in patients 1month to less than 17 years of age. Across the two studies, a total of 161 patients with partial onset seizures, aged 4 years to less than 17 years, have received BRIVLERA oral solution or tablet, of whom 109 received BRIVLERA for at least 12 months.
The most frequently reported adverse events (>10%) in controlled adult trials with BRIVLERA treatment were: somnolence (14.3%) and dizziness (11.0%). They were usually mild to moderate in intensity. Somnolence and fatigue were reported at a higher incidence with increasing dose. The types of adverse events reported during the first 7 days of treatment were similar to those reported for the overall treatment period. The most common adverse events requiring clinical intervention (dose adjustment/interruption or requiring additional therapy) were cough (1.5%), nausea (1.0%), and fatigue (0.8%).
In pooled placebo-controlled adjunctive therapy studies in adults, the discontinuation rate due to adverse events was 6.0%, 7.4%, and 6.8% for patients randomized to receive BRIVLERA at the recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, and 3.5% in patients randomized to receive placebo. The adverse reactions most commonly leading to discontinuation were dizziness (0.8%), depression (0.5%), and fatigue (0.5%).
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Table 3. Incidence of Treatment-Emergent Adverse Events in Double-Blind, PlaceboControlled, Phase 3 Partial-Onset Seizure Studies in Adults (Events ≥1% of Patients in Any BRIVLERA Group and More Frequent Than in the Placebo Group):
| System Organ Class/ Preferred Term | Placebo (N=459)% | BRIVLERA 50 mg/day (N=200)% | BRIVLERA 100 mg/day (N=353)% | BRIVLERA 200 mg/day (N=250)% |
|---|---|---|---|---|
| Ear and labyrinth disorders | ||||
| Vertigo | 2 | 2 | 3 | 2 |
| Eye disorders | ||||
| Vision blurred | <1 | 2 | <1 | 2 |
| Diplopia | <1 | 2 | <1 | <1 |
| Conjunctivitis | 0 | 1 | <1 | <1 |
| Eye pain | 0 | 1 | 0 | <1 |
| Visual impairment | 0 | <1 | 1 | 0 |
| Gastrointestinal disorders | ||||
| Nausea | 2 | 4 | 4 | 4 |
| Diarrhea | 3 | 4 | 2 | 3 |
| Vomiting | <1 | 5 | 1 | 1 |
| Constipation | <1 | 3 | 1 | 2 |
| Abdominal pain upper | <1 | 3 | 1 | 1 |
| Toothache | 1 | 2 | <1 | 2 |
| Abdominal discomfort | <1 | 0 | 1 | 0 |
| Gastritis | <1 | 0 | 1 | 0 |
| General disorders and administration site conditions | ||||
| Fatigue | 4 | 7 | 8 | 12 |
| Irritability | 1 | 5 | 3 | 3 |
| Gait disturbance | <1 | 1 | <1 | <1 |
| Chest pain | <1 | 1 | 0 | 0 |
| Infections and infestations | ||||
| Nasopharyngitis | 3 | 3 | 3 | 4 |
| Upper respiratory tract infection | 2 | <1 | 2 | 2 |
| Influenza | 1 | 2 | 2 | <1 |
| Viral infection | <1 | 1 | 1 | <1 |
| Bacteriuria | <1 | <1 | <1 | 2 |
| Oral herpes | 0 | 2 | 0 | <1 |
| Injury, poisoning and procedural complications | ||||
| Fall | 1 | 2 | 1 | 1 |
| Excoriation | 1 | 2 | <1 | <1 |
| Head injury | <1 | 2 | <1 | <1 |
| Investigations | ||||
| Weight decreased | <1 | 2 | <1 | 1 |
| Gamma-glutamyltransferase increased | 1 | 2 | <1 | 1 |
| Weight increased | <1 | 2 | <1 | <1 |
| Blood cholesterol increased | 0 | 1 | <1 | 0 |
| Blood triglycerides increased | <1 | 1 | <1 | 0 |
| Neutrophil count decreased | <1 | 1 | 0 | <1 |
| Urine analysis abnormal | <1 | 1 | 0 | <1 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | <1 | 3 | <1 | 2 |
| Hyponatremia | <1 | 0 | 1 | 2 |
| Dyslipidemia | <1 | 0 | 1 | 1 |
| Musculoskeletal disorders | ||||
| Myalgia | 1 | 3 | 1 | <1 |
| Back pain | <1 | 3 | 1 | <1 |
| Pain in extremity | 1 | 3 | <1 | <1 |
| Muscle spasms | 0 | 1 | <1 | <1 |
| Arthralgia | <1 | 1 | <1 | <1 |
| Nervous system disorders | ||||
| Somnolence | 9 | 12 | 16 | 17 |
| Dizziness | 7 | 12 | 9 | 14 |
| Headache | 10 | 16 | 7 | 8 |
| Convulsion | 2 | 3 | 3 | 1 |
| Tremor | 1 | 2 | <1 | 2 |
| Balance disorder | <1 | 2 | <1 | 1 |
| Memory impairment | 1 | 2 | <1 | 1 |
| Paresthesia | 1 | 2 | 1 | <1 |
| Ataxia | <1 | 2 | <1 | <1 |
| Disturbance in attention | <1 | <1 | 1 | <1 |
| Amnesia | 0 | 1 | <1 | <1 |
| Hypoesthesia | <1 | 1 | <1 | <1 |
| Migraine | <1 | 0 | <1 | 1 |
| Sedation | 0 | 0 | 0 | 2 |
| Psychomotor hyperactivity | 0 | 1 | <1 | 0 |
| Psychiatric disorders | ||||
| Insomnia | 2 | 5 | 2 | 2 |
| Anxiety | 1 | 2 | 1 | 3 |
| Depression | 1 | 5 | 1 | 1 |
| Nervousness | <1 | 2 | <1 | <1 |
| Agitation | 0 | 1 | <1 | 0 |
| Depressed mood | <1 | 1 | <1 | <1 |
| Mood swings | 0 | <1 | 0 | 1 |
| Restlessness | 0 | 0 | 1 | 0 |
| Sleep disorder | <1 | 1 | <1 | 0 |
| Renal and urinary disorders | ||||
| Hematuria | 0 | 1 | <1 | <1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 2 | 2 | 3 | 2 |
| Dyspnea | 0 | 2 | <1 | <1 |
| Oropharyngeal pain | <1 | 1 | <1 | 0 |
| Reproductive system and breast disorders | ||||
| Dysmenorrhea | <1 | <1 | <1 | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Rash | 1 | 2 | 1 | <1 |
| Pruritis | <1 | 2 | <1 | 2 |
| Eczema | 0 | <1 | 0 | 2 |
There was a dose-related increase in the incidences of somnolence and fatigue across the therapeutic range of BRIVLERA (50 mg/day to 200 mg/day). Somnolence was reported at a higher frequency with increasing BRIVLERA dose, ranging from 11.5% in the BRIVLERA 50 mg/day group to 16.8% in the BRIVLERA 200 mg/day group. Fatigue was also reported at a slightly higher incidence with increasing BRIVLERA dose, ranging from 7.0% in the BRIVLERA 50 mg/day group to 11.6% in the BRIVLERA 200 mg/day group.
The following is a description of treatment-emergent adverse events reported by patients treated with BRIVLERA in clinical trials in adult 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.
In the short-term clinical studies of BRIVLERA in adult epilepsy patients, there were no cases of completed suicide and suicide attempt, however both have been reported in open-label extension studies (<0.1% and 0.5%, respectively). See 8.2.1 Clinical Trial Adverse Reactions – Pediatrics.
Adverse reactions with intravenous administration were generally similar to those observed with oral administration. Intravenous administration was associated with infusion site pain in 2.8% of patients.
No significant gender differences were noted in the incidence of adverse reactions. Although the majority of patients were Caucasian (approximately 74% of patients were Caucasian and 26% were non-Caucasian), no differences in the incidences of adverse reactions compared to non-Caucasian patients were observed.
In an open-label cross-over human abuse potential study in 44 subjects, aged 18-55 years, single doses of BRIVLERA 50 mg, 200 mg and 1000 mg were compared to placebo and alprazolam (1.5 mg and 3 mg). All subjects had a history or were current users of central nervous system depressants. BRIVLERA showed fewer sedative, euphoric, stimulant, dizziness, and negative effects as compared to alprazolam; however, BRIVLERA was not significantly different from alprazolam on some measures of balance and positive effects at the supratherapeutic doses (200 mg and 1000 mg).
Somnolence, euphoric mood, dizziness, and fatigue were the most commonly reported adverse events in this study. Overall, 1000 mg BRIVLERA was associated with the highest incidence of euphoric mood (66%), followed by the other BRIVLERA doses (40% at 200 mg, 32% at 50 mg), while the incidence of euphoric mood following alprazolam was lower (17% at both 1.5 mg and 3.0 mg doses). Sedative effects were observed in healthy subjects in the single ascending dose and multiple ascending dose studies; however, no euphoria or stimulant-like effects were observed using controlled pharmacodynamic measures (e.g., ARCI, VAS).
In the overall BRIVLERA adult clinical program, the incidence of euphoric mood and feeling drunk was 0.5% in patient populations but higher (19.9%) in Phase 1 studies. The common adverse events associated with abuse were dizziness, somnolence, fatigue and asthenia.
There was no evidence of physical dependence potential or a withdrawal syndrome with BRIVLERA in a pooled review of placebo-controlled adjunctive therapy studies in adults. However, psychological dependence cannot be excluded because of reports of euphoric type effects even at therapeutic doses.
The safety profile of BRIVLERA observed in children was generally consistent with the safety profile observed in adults, with higher rates found regarding some psychiatric/behaviour disorder events (see 7 WARNINGS AND PRECAUTIONS, Psychiatric).
The long-term safety, including effects on growth, maturation and behavioural development in patients under 18 years of age has not been systematically evaluated.
There are limited safety data from open-label studies in children from 1 month to <4 years of age. Limited data are available on neurodevelopment in children <4 years of age. No clinical data are available in neonates.
In the open label, uncontrolled, long-term studies, suicidal ideation was reported in 4.7% of pediatric patients (more common in adolescents) compared with 2.4% of adults.
Other adverse events reported by <1% of patients with partial-onset seizures in the total BRIVLERA group in placebo-controlled clinical studies in adults that occurred more frequently or had greater severity than in the placebo group were:
Blood and lymphatic system disorders: neutropenia
Psychiatric disorders: aggression, psychotic disorder
Events included in this list above from the controlled studies are included based on consideration of BRIVLERA pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to BRIVLERA.
There have been post-marketing reports of psychotic disorder and related events (e.g., hallucinations, paranoia, delusions, acute psychosis, psychotic behaviour) in patients receiving BRIVLERA with or without concomitant medications. These events have been reported in all age groups, including pediatrics and geriatrics. Most patients were taking daily doses of BRIVLERA 50-200 mg. In some cases, BRIVLERA dose reduction or discontinuation led to resolution of the event.
In a pharmacokinetic and pharmacodynamic interaction study in 18 healthy male subjects, aged 21-47 years, BRIVLERA (single dose 200 mg) was co-administered with ethanol (continuous intravenous infusion to achieve a blood alcohol concentration of 60 mg/100 mL during 5 hours). Although there was no significant pharmacokinetic interaction between BRIVLERA and ethanol, BRIVLERA significantly increased alcohol-induced impairment of subjects' psychomotor function, attention, and memory. Co-administration of BRIVLERA and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale (VAS) alertness, and a larger increase from baseline in body sway and in saccadic reaction time compared with BRIVLERA alone or ethanol alone. Use of alcohol during BRIVLERA therapy is not recommended.
In vitro, brivaracetam did not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4. Brivaracetam weakly inhibited CYP2C19 and would not be expected to cause significant interaction with substrates of CYP2C19 in humans. Brivaracetam was an inhibitor of epoxide hydrolase (IC50 = 8.2 μmol/L), suggesting that brivaracetam can inhibit the enzyme in vivo.
Brivaracetam at concentrations up to 10 μmol/L caused little or no change of mRNA expression of CYP1A2, 2B6, 2C9, 2C19, 3A4, and epoxide hydrolase. It is unlikely that brivaracetam will induce these enzymes in vivo.
Brivaracetam was not a substrate of P-gp, MRP1, or MRP2. Brivaracetam did not inhibit or weakly inhibited BCRP, BSEP, MATE1, MATE2/K, MRP2, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or P-gp, suggesting that brivaracetam is unlikely to inhibit these transporters in vivo.
Potential interactions between BRIVLERA (brivaracetam) (25 mg twice daily to 100 mg twice daily) and other AEDs were investigated in a pooled analysis of plasma drug concentrations (n=1771 subjects) and in a population pharmacokinetics analysis (n=1248 subjects) from all Phase 2 and 3 studies in adults, and in a population exposure-response analysis of placebocontrolled, Phase 3 studies in adjunctive therapy in the treatment of adults with partial-onset seizures (n=1549 subjects).
The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Table 4. Established or Potential Drug-Drug Interactions:
| [Proper/Common name] | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Carbamazepine | CT | Co-administration of carbamazepine and BRIVLERA results: - in 26% decrease in plasma concentration of BRIVLERA - in increase of carbamazepineepoxide.* See also Carbamazepine section below. | No dosage adjustment required. Prescribers should take caution upon initiation and during uptitration of either BRIVLERA or carbamazepine in the presence of steady-state levels of the other. Monitor patients for possible symptoms, adverse events, or tolerability issues. Prescribers should take into account other concomitant drugs that can affect plasma levels of carbamazepine and/or carbamazepine epoxide. |
| Clobazam | CT | No data | No dosage adjustment required. |
| Clonazepam | CT | No data | No dosage adjustment required. |
| Lacosamide | CT | No data | No dosage adjustment required. |
| Lamotrigine | CT | None | No dosage adjustment required. |
| Levetiracetam | CT | None | No dosage adjustment required. |
| Oxcarbazepine | CT | None | No dosage adjustment required. |
| Phenobarbital | CT | Co-administration of phenobarbital and BRIVLERA results in 19% decrease in plasma concentration of BRIVLERA. | No dosage adjustment required. |
| Phenytoin | CT | Co-administration of phenytoin and BRIVLERA results: in 21% decrease in plasma concentration of BRIVLERA in up to 20% increase in plasma concentration of phenytoin** | No dose adjustment required. |
| Topiramate | CT | None | No dosage adjustment required. |
| Valproic acid | CT | None | No dosage adjustment required. |
Legend: CT = Clinical Trial;
* Brivaracetam is a reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. The carbamazepine-epoxide plasma concentration increased up to 198% at a BRIVLERA dose of 100 mg twice daily.
** At a supratherapeutic dose of 400 mg/day brivaracetam, there was a 20% increase in phenytoin plasma concentration.
Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase resulting in increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine.
In a Phase 1, single-centre, open-label, bilateral pharmacokinetic interaction study with carbamazepine, 14 young healthy male subjects were titrated to carbamazepine 600 mg/day during 35 days and received BRIVLERA 400 mg/day during the last 10 days. Plasma concentrations were collected at single dose and steady-state for brivaracetam and over time for carbamazepine and carbamazepine epoxide. Carbamazepine 600 mg/day decreased the brivaracetam (200 mg single dose) AUC by 29% and Cmax by 13% on Study Day 22. No further effect was seen on Day 35 after multiple dose administration of brivaracetam and carbamazepine. No brivaracetam dose adjustment was deemed necessary. Brivaracetam 400 mg/day did not significantly alter carbamazepine exposure (AUCτ) and Cmax, but resulted in a 2.6-fold increase in exposure to the metabolite, carbamazepine-epoxide.
In two Phase 1, single-centre, open-label, unilateral metabolic interaction studies, 18 male and female adult subjects with epilepsy being chronically treated with stable dosages of carbamazepine alone or in combination with valproate, were titrated in weekly increments with BRIVLERA 100 mg/day, 200 mg/day, and 400 mg/day, respectively. Trough plasma samples were obtained for determination of each substance including carbamazepine epoxide and carbamazepine diol. Following brivaracetam 200 mg/day, the increase from baseline in carbamazepine-epoxide was 1.98-fold (with carbamazepine alone) and 1.78-fold (in combination with valproate) indicating that valproate does not appear to further increase epoxide levels in the presence of brivaracetam.
In controlled epilepsy adjunctive therapy studies of BRIVLERA in adults, a total of 722 patients took varying daily doses of carbamazepine (median [range] daily dose of carbamazepine was 800 mg [200-1400 mg]). In these studies, carbamazepine-epoxide plasma concentration increased by a mean of 1.37-, 1.62- and 1.98-fold from baseline, at BRIVLERA doses of 50 mg/day, 100 mg/day and 200 mg/day, respectively. In these studies, there was no correlation between carbamazepine-epoxide levels and symptoms which are recognized as being among the more common symptoms of carbamazepine-epoxide toxicity, namely ataxia, diplopia, dizziness, nystagmus and somnolence. However, prescribers should take caution upon initiation and during up-titration of either BRIVLERA or carbamazepine in the presence of steady-state levels of the other and to monitor patients for possible symptoms, adverse events, or tolerability issues. Prescribers should also take into account the patients' other concomitant drugs that can affect plasma levels of carbamazepine and/or carbamazepine epoxide.
In a two-way crossover pharmacokinetic interaction study in 28 healthy female volunteers, 19 to 39 years of age, co-administration of BRIVLERA 100 mg/day with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not significantly influence the pharmacokinetics of brivaracetam, ethinylestradiol, or levonorgestrel.
In another two-way crossover pharmacokinetic interaction study in 24 healthy female volunteers, 20 to 40 years of age, co-administration of BRIVLERA 400 mg/day (twice the recommended maximum daily dose) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) reduced ethinylestradiol and levonorgestrel AUCs by 27% and 23%, respectively. This interaction is not expected to be clinically significant.
Studies with lower dose oral contraceptives have not been conducted.
In 2 two-way crossover pharmacokinetic interaction studies in two groups of 26 healthy adult male volunteers, a single 150 mg dose of BRIVLERA was co-administered with the strong CYP450 inducer and pan-inducer affecting among others CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, rifampin (600 mg/day for 5 days), or with the CYP2C8 and CYP2C9 inhibitor, gemfibrozil (1200 mg/day for 7 days). Gemfibrozil did not influence brivaracetam pharmacokinetics whereas rifampin resulted in a 45% decrease in AUC and half-life of brivaracetam. The dose of BRIVLERA should be adjusted when rifampin treatment is initiated or discontinued. There are no data on the effects of BRIVLERA on rifampin or gemfibrozil pharmacokinetics.
In a pooling of Phase 2 and 3 adult studies in epilepsy, BRIVLERA did not influence pregabalin plasma concentrations. There are no data on the effects of pregabalin on brivaracetam pharmacokinetics.
BRIVLERA is completely absorbed after oral administration. Food does not affect the extent of absorption.
Interactions with herbal products have not been evaluated.
Interactions with laboratory tests have not been evaluated.
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