Felbamate (Page 4 of 6)

Drug Laboratory Test Interactions:

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

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity studies were conducted in mice and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30, and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high-dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats receiving felbamate. The relevance of these findings to humans is unknown.

As a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and 1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m2 basis, of the dose levels shown to be carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors.

Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames Salmonella /microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid exchange assay in CHO cells, and bone marrow cytogenetics assay.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total daily dose on a mg/m2 basis.

Pregnancy:

Pregnancy Category C. The incidence of malformations was not increased compared to control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m2 basis.

Placental transfer of felbamate occurs in rat pups. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

To provide information regarding the effects of in utero exposure to felbamate, physicians are advised to recommend that pregnant patients taking felbamate enroll in the NAAED 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/.

Labor and Delivery:

The effect of felbamate on labor and delivery in humans is unknown.

Nursing Mothers:

Felbamate has been detected in human milk. The effect on the nursing infant is unknown (see Pregnancy section).

Pediatric Use:

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

Geriatric Use:

No systematic studies in geriatric patients have been conducted. Clinical studies of felbamate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

The most common adverse reactions seen in association with felbamate 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 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 felbamate 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

Felbamate* (N=58)

Low Dose Valproate** (N=50)

Body System Event

%

%

Body as a Whole Fatigue Weight Decrease Face Edema

6.93.43.4

4.000

Central Nervous System Insomnia Headache Anxiety

8.66.95.2

4.018.02.0

Dermatological Acne Rash

3.43.4

00

Digestive Dyspepsia Vomiting Constipation Diarrhea SGPT Increased

8.68.66.95.25.2

2.02.02.002.0

Metabolic/Nutritional Hypophosphatemia

3.4

0

Respiratory Upper Respiratory Tract Infection Rhinitis

8.66.9

4.00

Special Senses Diplopia Otitis Media

3.43.4

4.00

Urogenital Intramenstrual Bleeding Urinary Tract Infection

3.43.4

02.0

*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 felbamate 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

Felbamate

Placebo

(N=114)

(N=43)

Body System/Event

%

%

Body as a Whole Fatigue Fever Chest Pain

16.82.62.6

7.04.70

Central Nervous System Headache Somnolence Dizziness Insomnia Nervousness Tremor Anxiety Gait Abnormal Depression Paraesthesia Ataxia Mouth Dry Stupor

36.819.318.417.57.06.15.35.35.33.53.52.62.6

9.37.014.07.02.32.34.7002.3000

Dermatological Rash

3.5

4.7

Digestive Nausea Anorexia Vomiting Dyspepsia Constipation Diarrhea Abdominal Pain SGPT Increased

34.219.316.712.311.45.35.33.5

2.32.34.77.02.32.300

Musculoskeletal Myalgia

2.6

0

Respiratory Upper Respiratory Tract Infection Sinusitis Pharyngitis

5.33.52.6

7.000

Special Senses Diplopia Taste Perversion Vision Abnormal

6.16.15.3

002.3

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 Fatigue Weight Decrease Pain

22.69.76.56.5

11.13.700

Central Nervous System Somnolence Insomnia Nervousness Gait Abnormal Headache Thinking Abnormal Ataxia Urinary Incontinence Emotional Lability Miosis

48.416.116.19.76.56.56.56.56.56.5

11.114.818.5018.53.73.77.400

Dermatological Rash

9.7

7.4

Digestive Anorexia Vomiting Constipation Hiccup Nausea Dyspepsia

54.838.712.99.76.56.5

14.814.803.703.7

Hematologic Purpura Leukopenia

12.96.5

7.40

Respiratory Upper Respiratory Tract Infection Pharyngitis Coughing

45.29.76.5

25.93.70

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 1/100-1/1000 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.

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