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Felbatol

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Felbatol

Felbatol

SIDE EFFECTS

To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.eov/medwatch .

The most common adverse reactions seen in association with Felbatol® (felbamate) in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse reactions seen in association with Felbatol® in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache.

The most common adverse reactions seen in association with Felbatol® in children during adjunctive therapy are anorexia, vomiting, insomnia, headache, and somnolence.

The dropout rate because of adverse experiences or intercurrent illnesses among adult felbamate patients was 12 percent (120/977). The dropout rate because of adverse experiences or intercurrent illnesses among pediatric felbamate patients was six percent (22/357). In adults, the body systems associated with causing these withdrawals in order of frequency were: digestive (4.3%), psychological (2.2%), whole body (1.7%), neurological (1.5%), and dermatological (1.5%). In children, the body systems associated with causing these withdrawals in order of frequency were: digestive (1.7%), neurological (1.4%), dermatological (1.4%), psychological (1.1%), and whole body (1.0%). In adults, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency were: anorexia (1.6%), nausea (1.4%), rash (1.2%), and weight decrease (1.1%). In children, specific events with an incidence of 1% or greater associated with causing these withdrawals, in order of frequency was rash (1.1%).

Incidence in Clinical Trials

The prescriber should be aware that the figures cited in the following table cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different investigators, treatments, and uses including the use of Felbatol® (felbamate) as adjunctive therapy where the incidence of adverse events may be higher due to drug interactions. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Adults
Incidence in Controlled Clinical Trials—Monotherapy Studies in Adults

The table that follows enumerates adverse events that occurred at an incidence of 2% or more among 58 adult patients who received Felbatol® monotherapy at dosages of 3600 mg/day in double-blind controlled trials. Table 3 presents reported adverse events that were classified using standard WHO-based dictionary terminology.

Table 3: Adults Treatment-Emergent Adverse Event Incidence in Controlled Monotherapy Trials

  Felbatol®*
(N=58)
Low Dose Valproate**
(N=50)
Body System Event % %
Body as a Whole
  Fatigue 6.9 4.0
  Weight Decrease 3.4 0
  Face Edema 3.4 0
Central Nervous System
  Insomnia 8.6 4.0
  Headache 6.9 18.0
  Anxiety 5.2 2.0
Dermatological
  Acne 3.4 0
  Rash 3.4 0
Digestive
  Dyspepsia 8.6 2.0
  Vomiting 8.6 2.0
  Constipation 6.9 2.0
  Diarrhea 5.2 0
  SGPT Increased 5.2 2.0
Metabolic/Nutritional
  Hypophosphatemia 3.4 0
Respiratory
  Upper Respiratory Tract Infection 8.6 4.0
  Rhinitis 6.9 0
Special Senses
  Diplopia 3.4 4.0
  Otitis Media 3.4 0
Urogenital
  Intramenstrual Bleeding 3.4 0
  Urinary Tract Infection 3.4 2.0
*3600 mg/day;
** 15 mg/kg/day

Incidence in Controlled Add-On Clinical Studies in Adults

Table 4 enumerates adverse events that occurred at an incidence of 2% or more among 114 adult patients who received Felbatol® adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day. Reported adverse events were classified using standard WHO-based dictionary terminology.

Many adverse experiences that occurred during adjunctive therapy may be a result of drug interactions. Adverse experiences during adjunctive therapy typically resolved with conversion to monotherapy, or with adjustment of the dosage of other antiepileptic drugs.

Table 4: Adults Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials

Body System/Event Felbatol® Placebo
(N=114) (N=43)
% %
Body as a Whole
  Fatigue 16.8 7.0
  Fever 2.6 4.7
  Chest Pain 2.6 0
Central Nervous System
  Headache 36.8 9.3
  Somnolence 19.3 7.0
  Dizziness 18.4 14.0
  Insomnia 17.5 7.0
  Nervousness 7.0 2.3
  Tremor 6.1 2.3
  Anxiety 5.3 4.7
  Gait Abnormal 5.3 0
  Depression 5.3 0
  Paraesthesia 3.5 2.3
  Ataxia 3.5 0
  Mouth Dry 2.6 0
  Stupor 2.6 0
Dermatological
  Rash 3.5 4.7
Digestive
  Nausea 34.2 2.3
  Anorexia 19.3 2.3
  Vomiting 16.7 4.7
  Dyspepsia 12.3 7.0
  Constipation 11.4 2.3
  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 7.0
  Sinusitis 3.5 0
  Pharyngitis 2.6 0
Special Senses
  Diplopia 6.1 0
  Taste Perversion 6.1 0
  Vision Abnormal 5.3 2.3

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 Felbatol® 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

Body System/Event Felbatol® Placebo
(N=31) (N=27)
% %
Body as a Whole
  Fever 22.6 11.1
  Fatigue 9.7 3.7
  Weight Decrease 6.5 0
  Pain 6.5 0
Central Nervous System
  Somnolence 48.4 11.1
  Insomnia 16.1 14.8
  Nervousness 16.1 18.5
  Gait Abnormal 9.7 0
  Headache 6.5 18.5
  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 7.4
Digestive
  Anorexia 54.8 14.8
  Vomiting 38.7 14.8
  Constipation 12.9 0
  Hiccup 9.7 3.7
  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 25.9
  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 Felbatol® (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 Felbatol® (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 Felbatol® 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 1/100-1/1000 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 Felbatol®.

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: GOT 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 Felbatol® (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-Schonlein 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 Abuse And Dependence

Abuse

Abuse potential was not evaluated in human studies.

Dependence

Rats administered felbamate orally at doses 8.3 times the recommended human dose 6 days each week for 5 consecutive weeks demonstrated no signs of physical dependence as measured by weight loss following drug withdrawal on day 7 of each week.

Read the Felbatol (felbamate) Side Effects Center for a complete guide to possible side effects

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 Felbatol® 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 Felbatol When Coadministered With Other AEDs

AED
Coadministered
AED
Concentration
Felbatol®
Concentration
Phenytoin
Valproate ↔**
Carbamazepine (CBZ)
*CBZ epoxide

Phenobarbital
*Not administered but an active metabolite of carbamazepine.
**No significant effect.

Specific Effects of Felbatol® on Other Antiepileptic Drugs

Phenytoin: Felbatol® causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state Cmin 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 Cmin 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 ofFelbatol® therapy resulted in phenytoin levels comparable to those prior to Felbatol® administration.

Carbamazepine: Felbatol® 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 (Cmin) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±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: Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16 micrograms/mL. The steady-state Cmin 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 Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day ofFelbatol®, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses ofFelbatol®.

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 (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week.

Effects of Other Antiepileptic Drugs on Felbatol®

Phenytoin: Phenytoin causes an approximate doubling of the clearance ofFelbatol® (felbamate) at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations ofFelbatol® as compared to the same dose ofFelbatol® given as monotherapy.

Carbamazepine: Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at steady-state and, therefore, the addition of Carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy.

Valproate: Available data suggest that there is no significant effect of valproate on the clearance of Felbatol® at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on Felbatol® (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 Felbatol®

The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was not affected when coadministered with antacids.

Effects of Erythromycin on Felbatol®

The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of Cmax, Cmin, AUC, Cl/kg or Tmax at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy.

Effects of Felbatol® on 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.

Drug/Laboratory Test Interactions

There are no known interactions of Felbatol® with commonly used laboratory tests.

Read the Felbatol Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/17/2012
This monograph has been modified to include the generic and brand name in many instances.

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