Felbamate Drug Information

Chest Pain 2.6 0 Central Nervous System Headache 36.8 9.3 Somnolence 19.3

7 Dizziness 18.4 14 Insomnia 17.5 7 Nervousness 7

Tremor 6.1 2.3 Anxiety 5.3 4.7 Gait Abnormal 5.3 0 Depression 5.3

0 Paraesthesia 3.5

Ataxia 3.5 0 Mouth Dry 2.6 0 Stupor 2.6 0 Dermatological Rash

3.5

Digestive Nausea 34.2 2.3 Anorexia 19.3 2.3 Vomiting 16.7 4.7 Dyspepsia 12.3

7 Constipation 11.4

Diarrhea 5.3 2.3 Abdominal Pain 5.3 0

SGPT Increased 3.5 0 Musculoskeletal Myalgia 2.6 0 Respiratory Upper Respiratory Tract Infection 5.3 7 Sinusitis 3.5 0 Pharyngitis 2.6 0 Special Senses Diplopia 6.1 0 Taste Perversion 6.1 0 Vision Abnormal 5.3

Children Incidence in a Controlled Add-On Trial in Children with Lennox-Gastaut Syndrome

Table 5 enumerates adverse events that occurred more than once among 31 pediatric patients who received felbamate up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology. Table 5 Children Treatment-Emergent Adverse Event Incidence in Controlled Add-On Lennox-Gastaut Trials Felbamate Placebo (N=31) (N=27) Body System/Event % % Body as a Whole Fever 22.6

Fatigue 9.7 3.7 Weight Decrease 6.5 0 Pain 6.5 0 Central Nervous

System Somnolence 48.4

Thinking Abnormal 6.5 3.7 Ataxia 6.5 3.7 Urinary Incontinence 6.5 7.4 Emotional

Lability 6.5 0 Miosis 6.5 0 Dermatological Rash 9.7

Nausea 6.5 0 Dyspepsia 6.5 3.7 Hematologic Purpura 12.9 7.4 Leukopenia 6.5

0 Respiratory Upper Respiratory Tract Infection 45.2

Pharyngitis 9.7 3.7 Coughing 6.5 0 Special Senses Otitis Media 9.7 0

Other Events Observed in Association with the Administration of Felbamate In the paragraphs that follow, the adverse clinical events, other than those in the preceding tables, that occurred in a total of 977 adults and 357 children exposed to felbamate and that are reasonably associated with its use are presented. They are listed in order of decreasing frequency. Because the reports cite events observed in open-label and uncontrolled studies, the role of felbamate in their causation cannot be reliably determined.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=1334) exposed to felbamate. Body as a Whole : Frequent: Weight increase, asthenia, malaise, influenza-like symptoms; Rare: anaphylactoid reaction, chest pain substernal.

Cardiovascular : Frequent: Palpitation, tachycardia; Rare: supraventricular tachycardia. Central Nervous System : Frequent: Agitation, psychological disturbance, aggressive reaction: Infrequent: hallucination, euphoria, suicide attempt, migraine. Digestive : Frequent: SGOT increased; Infrequent: esophagitis, appetite increased; Rare: GGT elevated.

Hematologic : Infrequent: Lymphadenopathy, leukopenia, leukocytosis, thrombocytopenia, granulocytopenia; Rare: antinuclear factor test positive, qualitative platelet disorder, agranulocytosis. Metabolic/Nutritional : Infrequent: Hypokalemia, hyponatremia, LDH increased, alkaline phosphatase increased, hypophosphatemia; Rare: creatinine phosphokinase increased. Musculoskeletal : Infrequent: Dystonia.

Dermatological : Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous membrane swelling, Stevens-Johnson Syndrome. Special Senses : Rare: Photosensitivity allergic reaction. Postmarketing Adverse Event Reports Voluntary reports of adverse events in patients taking felbamate (usually in conjunction with other drugs) have been received since market introduction and may have no causal relationship with the drug(s). These include the following by body system: Body as a Whole : neoplasm, sepsis, L.E. syndrome, SIDS, sudden death, edema, hypothermia, rigors, hyperpyrexia.

Cardiovascular : atrial fibrillation, atrial arrhythmia, cardiac arrest, torsade de pointes, cardiac failure, hypotension, hypertension, flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia, bradycardia, Henoch-Schönlein purpura (vasculitis). Central & Peripheral Nervous System : delusion, paralysis, mononeuritis, cerebrovascular disorder, cerebral edema, coma, manic reaction, encephalopathy, paranoid reaction, nystagmus, choreoathetosis, extrapyramidal disorder, confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory depression, apathy, concentration impaired. Dermatological : abnormal body odor, sweating, lichen planus, livedo reticularis, alopecia, toxic epidermal necrolysis. Digestive : (Refer to WARNINGS ) hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia, pancreatitis, hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding, acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative stomatitis, glossitis, dysphagia, jaundice, gastric ulcer, gastric dilatation, gastroesophageal reflux.

Fetal Disorders : fetal death, microcephaly, genital malformation, anencephaly, encephalocele. Hematologic : (Refer to WARNINGS ) increased and decreased prothrombin time, anemia, hypochromic anemia, aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean corpuscular volume (mcv) with and without anemia, coagulation disorder, embolism-limb, disseminated intravascular coagulation, eosinophilia, hemolytic anemia, leukemia, including myelogenous leukemia, and lymphoma, including T-cell and B-cell lymphoproliferative disorders. Metabolic/Nutritional : hypernatremia, hypoglycemia, SIADH, hypomagnesemia, dehydration, hyperglycemia, hypocalcemia.

Musculoskeletal : arthralgia, muscle weakness, involuntary muscle contraction, rhabdomyolysis. Respiratory : dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis, pleural effusion, respiratory insufficiency, pulmonary hemorrhage, asthma. Special Senses : hemianopsia, decreased hearing, conjunctivitis.

Urogenital : menstrual disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary retention, nephrosis, vaginal hemorrhage, abnormal renal function, dysuria, placental disorder.

Drug Interactions The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy. Use in Conjunction with Other Antiepileptic Drugs (see DOSAGE AND ADMINISTRATION ) The addition of felbamate to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2: Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs AED Coadministered AED Concentration Felbamate Concentration Phenytoin ↑ ↓ Valproate ↑ ↔ No significant effect.

Carbamazepine (CBZ) Not administered but an active metabolite of carbamazepine. CBZ epoxide ↓ ↑ ↓ Phenobarbital ↑ ↓ Specific Effects of Felbamate on Other Antiepileptic Drugs Phenytoin Felbamate causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (C min ) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state C min increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered.

Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin C min to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects. In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of felbamate therapy resulted in phenytoin levels comparable to those prior to felbamate oral suspension administration. Carbamazepine Felbamate causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration.

In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (C min ) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state C min decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state C min concentrations increased 57% from 1±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate. In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.

Valproate Felbamate causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (C min ) valproate plasma concentration was 63±16 micrograms/mL. The steady-state C min increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate C min to 96±25 micrograms/mL. Corresponding values for free valproate C min concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day felbamate, respectively.

The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of felbamate, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of felbamate. Phenobarbital Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations.

In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (C min ) phenobarbital concentration was 14.2 micrograms/mL. The steady-state C min concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week. Effects of Other Antiepileptic Drugs on Felbamate Phenytoin Phenytoin causes an approximate doubling of the clearance of felbamate at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of felbamate as compared to the same dose of felbamate given as monotherapy. Carbamazepine Carbamazepine causes an approximate 50% increase in the clearance of felbamate at steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of felbamate as compared to the same dose of felbamate given as monotherapy.

Valproate Available data suggest that there is no significant effect of valproate on the clearance of felbamate at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on felbamate plasma concentrations. Phenobarbital It appears that phenobarbital may reduce plasma felbamate concentrations.

Steady-state plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day. Effects of Antacids on Felbamate The rate and extent of absorption of a 2400 mg dose of felbamate as monotherapy given as tablets was not affected when coadministered with antacids. Effects of Erythromycin on Felbamate The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of C max, C min, AUC, Cl/kg or T max at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy.

Effects of Felbamate Low-Dose Combination Oral Contraceptives A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen containing 30 µg ethinyl estradiol and 75 µg gestodene for at least 3 months received 2400 mg/day of felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles. Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate treatment.

Pregnancy Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see Pregnancy section).

Pediatric Use The safety and effectiveness of felbamate in children other than those with Lennox-Gastaut syndrome has not been established.

Felbamate oral suspension, USP is contraindicated in patients with known hypersensitivity to felbamate oral suspension, its ingredients, or known sensitivity to other carbamates. It should not be used in patients with a history of any blood dyscrasia or hepatic dysfunction.

Four subjects inadvertently received felbamate as adjunctive therapy in dosages ranging from 5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting 12,000 mg of felbamate in a 12-hour period.

The only adverse experiences reported were mild gastric distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported. General supportive measures should be employed if overdosage occurs.

It is not known if felbamate is dialyzable.