NDA 020189/S-027
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`FDA Approved Labeling Text dated 8/27/2012
`Page 1
`1
`FELBATOL® (felbamate)
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`Tablets 400 mg and 600 mg, Oral Suspension 600 mg/5 mL
`3
`
` IN-00431-18 Rev. 7/11
`4
`
`5
`Before Prescribing Felbatol® (felbamate), the physician should be thoroughly familiar with the
`6
`
` details of this prescribing information.
`7
`
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`FELBATOL® SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A
`9 COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT, PARENT, OR GUARDIAN
`
`10
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`HAS BEEN PROVIDED THE FELBATOL WRITTEN ACKNOWLEDGEMENT (SEE
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` PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM).
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`
`13
`WARNING
`14
`1. APLASTIC ANEMIA
`15
`THE USE OF FELBATOL® (felbamate) IS ASSOCIATED WITH A MARKED INCREASE IN THE
`16
`INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBATOL® SHOULD ONLY BE USED
`17
`IN PATIENTS WHOSE EPILEPSY IS SO SEVERE THAT THE RISK OF APLASTIC ANEMIA IS
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`DEEMED ACCEPTABLE IN LIGHT OF THE BENEFITS CONFERRED BY ITS USE (SEE
`19
`INDICATIONS). ORDINARILY, A PATIENT SHOULD NOT BE PLACED ON AND/OR
`
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`CONTINUED ON FELBATOL® WITHOUT CONSIDERATION OF APPROPRIATE EXPERT
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`HEMATOLOGIC CONSULTATION.
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`
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`AMONG FELBATOL® TREATED PATIENTS, APLASTIC ANEMIA (PANCYTOPENIA IN THE
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`PRESENCE OF A BONE MARROW LARGELY DEPLETED OF HEMATOPOIETIC PRECURSORS)
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`OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A 100 FOLD GREATER THAN THAT
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`SEEN IN THE UNTREATED POPULATION (I.E., 2 TO 5 PER MILLION PERSONS PER YEAR).
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`THE RISK OF DEATH IN PATIENTS WITH APLASTIC ANEMIA GENERALLY VARIES AS A
`28
`FUNCTION OF ITS SEVERITY AND ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL
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`CASE FATALITY RATE ARE IN THE RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70%
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`HAVE BEEN REPORTED IN THE PAST.
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`
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`THERE ARE TOO FEW FELBATOL® ASSOCIATED CASES, AND TOO LITTLE KNOWN ABOUT
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`THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S INCIDENCE OR ITS CASE
`34
`
`FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY, THAT MIGHT CONCEIVABLY BE
`35
`USED TO PREDICT WHO IS AT GREATER OR LESSER RISK.
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`
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`IN MANAGING PATIENTS ON FELBATOL®, IT SHOULD BE BORNE IN MIND THAT THE
`38
`CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A
`39
`PATIENT HAS BEEN ON FELBATOL® FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC
`40
`ANEMIA AMONG FELBATOL® EXPOSED PATIENTS FOR WHOM DATA ARE AVAILABLE
`41
`HAS RANGED FROM 5 TO 30 WEEKS). HOWEVER, THE INJURY TO BONE MARROW STEM
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`CELLS THAT IS HELD TO BE ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR
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`WEEKS TO MONTHS EARLIER. ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED
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`FROM FELBATOL® REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND
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`UNKNOWN, PERIOD AFTERWARDS.
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`
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`IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC ANEMIA
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`CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE TO ASSUME
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`THAT A PATIENT WHO HAS BEEN ON FELBATOL® WITHOUT SIGNS OF HEMATOLOGIC
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`ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.
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`Reference ID: 3180666
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 1
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` NDA 020189/S-027
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`FDA Approved Labeling Text dated 8/27/2012
`Page 2
`IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBATOL® AFFECTS THE
`INCIDENCE OF APLASTIC ANEMIA.
`
`
`IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC DRUGS
`AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
`
`APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL OR
`LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF
`INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING CANNOT
`BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT, IT WILL, IN
`SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES BEFORE THE
`SYNDROME DECLARES ITSELF CLINICALLY. FELBATOL® SHOULD BE DISCONTINUED IF
`ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
`
`
`2. HEPATIC FAILURE
`EVALUATION OF POSTMARKETING EXPERIENCE SUGGESTS THAT ACUTE LIVER
`
`FAILURE IS ASSOCIATED WITH THE USE OF FELBATOL®. THE REPORTED RATE IN THE
`U.S. HAS BEEN ABOUT 6 CASES OF LIVER FAILURE LEADING TO DEATH OR TRANSPLANT
`PER 75,000 PATIENT YEARS OF USE. THIS RATE IS AN UNDERESTIMATE BECAUSE OF
`UNDER REPORTING, AND THE TRUE RATE COULD BE CONSIDERABLY GREATER THAN
`THIS. FOR EXAMPLE, IF THE REPORTING RATE IS 10%, THE TRUE RATE WOULD BE ONE
`CASE PER 1,250 PATIENT YEARS OF USE.
`
`OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR LIVER
`TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND
`SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC
`DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER
`INITIATION OF FELBATOL®. ALTHOUGH SOME REPORTS DESCRIBED DARK URINE AND
`NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND
`GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY
`PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
`
`IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC FAILURE
`CHANGES WITH DURATION OF EXPOSURE.
`
`
`
`
`
`IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF FELBATOL® AFFECTS THE
`
`INCIDENCE OF HEPATIC FAILURE.
`
`
`
`IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC DRUGS
`AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
`
`FELBATOL® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC
`DYSFUNCTION.
`
`TREATMENT WITH FELBATOL® SHOULD BE INITIATED ONLY IN INDIVIDUALS WITHOUT
`ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM TRANSAMINASES. IT HAS
`NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE TESTING WILL PREVENT
`SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT EARLY DETECTION OF DRUG­
`INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE WITHDRAWAL OF THE SUSPECT
`DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY. THERE IS NO INFORMATION
`AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS CAN PROGRESS FROM
`
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`Reference ID: 3180666
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 2
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`FDA Approved Labeling Text dated 8/27/2012
`Page 3
`102
`NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER DRUGS KNOWN TO BE
`103
`HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G., FROM NORMAL ENZYMES
`104
`TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY, MONITORING OF SERUM
`105
`TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND
`106
`PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE MONITORING THE
`107
`GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE SCHEDULE FOR
`108
`MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
`109
`
`110
`FELBATOL® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR SERUM ALT LEVELS
`111
`BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF NORMAL, OR IF CLINICAL SIGNS
`112
`AND SYMPTOMS SUGGEST LIVER FAILURE (SEE PRECAUTIONS ). PATIENTS WHO
`113
`DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON FELBATOL® AND ARE
`114
`WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT
`115
`
`INCREASED RISK FOR LIVER INJURY IF FELBATOL® IS REINTRODUCED. ACCORDINGLY,
`116
`SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
`117
`
`118 DESCRIPTION
`
`119
`Felbatol® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL
`120
`
`suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate.
`121
`
`122
`Felbamate is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble
`123
`in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl
`124
`sulfoxide. The molecular weight is 238.24; felbamate's molecular formula is C H N O ; its
`
`11
` 14
`2
`4
`125
`structural formula is:
`126
`
`
`
`
`127
`128
`
`129
`The inactive ingredients for Felbatol® (felbamate) Tablets 400 mg and 600 mg are starch,
`130 microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6,
`131 D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for
`
`132
`Felbatol® (felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose,
`133
`carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium,
`134
`propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water.
`135
`
`136 CLINICAL PHARMACOLOGY
`137 Mechanism of Action:
`
`138
`The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test
`139
`systems designed to detect anticonvulsant activity, felbamate has properties in common with other
`140 marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the
`
`141
`subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also
`142
`exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of
`143
`glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock­
`144
`induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of
`145
`efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced
`146
`seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of
`
`147
`potential efficacy in absence seizures.
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`Reference ID: 3180666
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 3
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`
`149
`Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor
`150
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`binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of
`151
`the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the
`152
`strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is
`153
`not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory
`
`
`154
`amino acid agonists NMDA, kainate, or quisqualate in vitro.
`155
`
`156
`The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock­
`157
`induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6)
`158
`activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites
`159
`did not contribute significantly to the anticonvulsant action of felbamate.
`160
`
`161
`Pharmacokinetics:
`
`162
`The numbers in the pharmacokinetic section are mean ± standard deviation.
`163
`
`164
`Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of
`1000 mg 14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been
`165
`166 measured. The tablet and suspension were each shown to be bioequivalent to the capsule used in clinical
`167
`
` trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of
`168
`food on absorption of the tablet; the effect of food on absorption of the suspension has not been evaluated.
`169
`
`170
`Following oral administration, felbamate is the predominant plasma species (about 90% of plasma
`171
`radioactivity). About 40-50% of absorbed dose appears unchanged in urine, and an additional 40% is
`172
`present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2­
`173
`hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.
`
`174
`
`175
`Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10
`176
`and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on
`
`177
`the albumin concentration.
`
`178
`
`179
`Felbamate is excreted with a terminal half-life of 20-23 hours, which is unaltered after multiple doses.
`180
`Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is
`181
`30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate
`182
`
` Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100-800 mg
`183
`single doses and 1200-3600 mg daily doses. Cmin (trough) blood levels are also dose proportional.
`184 Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21
`185 micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at
`186
`
`doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose
`187
`
`proportional steady-state peak plasma concentrations in children age 4-12 over a range of 15, 30, and 45
`188 mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL.
`
`189
`
`190
`The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but
`191
`plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects
`192
`of felbamate kinetics on hepatic functional impairment have not been evaluated.
`193
`
`194 Renal Impairment:
`195
` Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy
`
`196
`individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 hours
`197
`prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal
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`Reference ID: 3180666
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 4
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`FDA Approved Labeling Text dated 8/27/2012
`Page 5
` function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal
`function.
`
`Pharmacodynamics:
`
`Typical Physiologic Responses:
`1.Cardiovascular:
`
`In adults, there is no effect of felbamate on blood pressure. Small but statistically significant mean
`increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean
`increases of up to 5 bpm were not clinically significant. In children, no clinically relevant changes in
`
`blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate.
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`209
`2. Other Physiologic Effects:
`210
`The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in
`211
`respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in
`212
`body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were
`213 mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean
`214
`changes were not statistically significant. These mean reductions in adults and children were
`215
`approximately 5% of the mean weights at baseline.
`216
`
`217 CLINICAL STUDIES
`
`218
`The results of controlled clinical trials established the efficacy of Felbatol® (felbamate) as monotherapy
`
`219
`and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and
`
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`in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
`221
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`222
`Felbatol® Monotherapy Trials in Adults
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`223
`Felbatol® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as
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`224 monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy
`
`
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`225
`trial. Both trials were conducted according to an identical study design. During a 56-day baseline period,
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`226
`all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at
`227
`a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure
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`frequencies were 12.4 per 28 days in the Felbatol® group and 21.3 per 28 days in the low-dose valproate
`229
`group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol®
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`group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with
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`Felbatol® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study
`
`
`232
`endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative
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`to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day
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`seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or
`235
`(4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each
`236
`treatment group who met escape criteria.
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`In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the
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`Felbatol® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the
`
`240
`percentage of patients who met escape criteria was 14% (3/21) in the Felbatol® group and 90% (19/21) in
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`241
`the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape
`242
`criteria was statistically significant (P<.001) in favor of Felbatol®. These two studies by design were
`243
`intended to demonstrate the effectiveness of Felbatol® monotherapy. The studies were not designed or
`244
`intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at
`245
`the maximally effective dose.
`246
`
`247
`Felbatol® Adjunctive Therapy Trials in Adults
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`IPR2014-01126
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`248 A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods.
`249
`Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at
`250
`therapeutic levels were administered Felbatol® (felbamate) as add-on therapy at a starting dosage of 1400
`251 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56
`252
`patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with
`
`253
`Felbatol® had fewer seizures than patients treated with placebo for each treatment sequence. There was a
`254
`23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol®.
`255
`
`256
`Felbatol® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in
`257
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`patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of
`258
`intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization,
`259
`seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or
`260 more than one generalized seizure per day, and a minimum average of one partial or generalized tonic­
`261
`clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was
`262
`time to fourth seizure after randomization to treatment with Felbatol® or placebo. Thirteen (46%) of 28
`263
`patients in the Felbatol® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth
`264
`seizure. The median times to fourth seizure were greater than 28 days in the Felbatol® group and 5 days
`
`265
`in the placebo group. The difference between Felbatol® and placebo in time to fourth seizure was
`266
`statistically significant (P=.002) in favor of Felbatol®.
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`267
`
`268
`Felbatol® Adjunctive Therapy Trial in Children with Lennox-Gastaut Syndrome
`269
`In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol® 45
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`270 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with
`271
`this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving
`272
`therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average
`273
`of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was
`274
`valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the
`275
`Felbatol® group and 716 per month in the placebo group. Statistically significant differences in the effect
`276
`on seizure frequency favored Felbatol® over placebo for total seizures (26% reduction vs. 5% increase,
`277
`P<.001), atonic seizures (44% reduction vs. 7% reduction, P=.002), and generalized tonic-clonic seizures
`278
`(40% reduction vs. 12% increase, P=.017). Parent/guardian global evaluations based on impressions of
`279
`quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control
`280
`significantly (P<.001) favored Felbatol® over placebo.
`281
`
`282 When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and
`283 monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122
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`284 males and 142 females.
`285
`
`286
`INDICATIONS AND USAGE
`
`287
`
`288
`Felbatol® is not indicated as a first line antiepileptic treatment (see Warnings). Felbatol® is
`289
`recommended for use only in those patients who respond inadequately to alternative treatments and
`290 whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed
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`291
`acceptable in light of the benefits conferred by its use.
`
`292
`
`293
`If these criteria are met and the patient has been fully advised of the risk, and has provided written
`294
`acknowledgement, Felbatol® can be considered for either monotherapy or adjunctive therapy in the
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`295
`treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive
`296
`therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in
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`297
`children.
`298
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`Reference ID: 3180666
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 6
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`299 CONTRAINDICATIONS
`
`300
`Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, its ingredients, or
`301
`known sensitivity to other carbamates. It should not be used in patients with a history of any blood
`302
`dyscrasia or hepatic dysfunction.
`303
`
`304 WARNINGS
`
`305
`See Boxed Warning regarding aplastic anemia and hepatic failure.
`306 Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure
`
`307
`frequency.
`
`308
`
`309
`Suicidal Behavior and Ideation
`310 Antiepileptic drugs (AEDs) including Felbatol ®, increase the risk of suicidal thoughts or behavior in
`311
`patients taking these drugs for any indication. Patients treated with any AED for any indication should be
`312 monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any
`313
`unusual changes in mood or behavior.
`314
`
`315
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different
`316 AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted
`317
`Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to
`318
`placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate
`319
`of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%
`
`320
`among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal
`321
`thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in
`
`322
`the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about
`323
`drug effect on suicide.
`324
`
`325
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
`326
`starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most
`327
`trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior
`328
`beyond 24 weeks could not be assessed.
`
`329
`
`330
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
`331
`finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
`332
`suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by
`
`
`333
`age (5-100 years) in the clinical trials analyzed.
`334
`
`335
`Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
` Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`
`Placebo Patients
`
`Drug Patients with
`Relative Risk:
`with Events
`Events Per
`
`Incidence of
`Per 1000 Patients
`1000 Patients
`
`Events in Drug
`
`Patients/Incidence
`in Placebo Patients
`3.5
`1.5
`1.9
`1.8
`
`1.0
`5.7
`1.0
`2.4
`
`Epilepsy
`
`Psychiatric
`Other
`
`Total
`
`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.
`
`3.4
`8.5
`1.8
`4.3
`
`Indication
`
`336
`337
`338
`339
`
`
`
`Reference ID: 3180666
`
`Risk Difference:
`
`Additional Drug
`
`Patients with
`
`
`Events Per 1000
`Patients
`2.4
`2.9
`0.9
`1.9
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 7
`
`

`
`Information for Patients: Patients should be informed that the use of Felbatol® is associated with
`aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term.
`
` NDA 020189/S-027
`
`FDA Approved Labeling Text dated 8/27/2012
`Page 8
`340
`
`341 Anyone considering prescribing Felbatol or any other AED must balance the risk of suicidal thoughts or
`
`342
`behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are
`343
`prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal
`344
`thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber
`345
`needs to consider whether the emergence of these symptoms in any given patient may be related to the
`
`346
`illness being treated.
`347
`
`348
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
`349
`thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the
`350
`signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of
`
`351
`suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported
`352
`immediately to healthcare providers.
`353
`
`354
`PRECAUTIONS
`
`355 Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal
`356
`dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with
`357
`
`diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction (see
`358 DOSAGE AND ADMINISTRATION).
`359
`360
`361
`362
`363
`364
`365
`366
`Patients should be instructed to read the Medication Guide supplied as required by law when
`367
`Felbatol® is dispensed. The complete text of the Medication Guide is reprinted at the end of this
`
`368
`document.
`369
`
`370 Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is
`371
`not known with any degree of reliability, but patients on Felbatol® may be at more than a 100 fold greater
`372
`risk for developing the syndrome than the general population.
`373
`
`374
` The long term outlook for patients with aplastic anemia is variable. Although many patients are
`
`375
`apparently cured, others require repeated transfusions and other treatments for relapses, and some,
`376
`although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g.,
`
`377
`leukemia).
`378
`
`379 At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented
`
`
`380
`effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any
`381
`blood dyscrasia should not receive Felbatol®.
`382
`
`383
`Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia
`384
`(fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any
`
`385
`such signs or symptoms appear.
`386
`
`387 Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is
`388
`
` not known with any degree of reliability but patients on Felbatol® are at a greater risk for developing
`389
`hepatic failure than the general population.
`
`
`
`The physician should obtain written acknowledgement prior to initiation of Felbatol® therapy (see
`PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section).
`
`
`
`Reference ID: 3180666
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2002 page 8
`
`

`
` NDA 020189/S-027
`
`FDA Approved Labeling Text dated 8/27/2012
`Page 9
`390
`
`391 At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a
`
`
`392
`history of hepatic dysfunction should not be started on Felbatol®.
`393
`
`394
`Patients should be advised to follow their physician's directives for liver function testing both before
`395
`starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®.
`
`396
`
`397
`Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal
`398
`complaints, malaise, etc.) and to report them to their doctor immediately if they should occur.
`
`399
`
`400
`Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy,
`
`401
`frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy.
`
`402 While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, there is no
`403
`evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia
`404
`occurs. (see Boxed Warnings). Complete pretreatment blood counts, including platelets and reticulocytes
`405
`should be obtained as a baseline. If any hematologic abnormalities are detected during the course of
`406
`treatment, immediate consultation with a hematologist is advised. Felbatol® should be discontinued if
`407
`any evidence of bone marrow depression occurs.
`408
`
`409
`See Box Warnings for recommended monitoring of serum transaminases. If significant, confirmed liver
`410
`abnormalities are detected during the course of Felbatol® treatment, Felbatol® should be discontinued
`411
`immediately with continued liver function monitoring until values return to normal. (see
`
`412
`PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM ).
`413
`
`414
`Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled
`415
`that AEDs, including Felbatol®, may increase the risk of suicidal thoughts and behavior and
`416
`should be advised of the need to be alert for the emergence or worsening of symptoms of
`417
`depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
`418
`behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to
`419
`healthcare providers.
`420
`
`421
`Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug
`422
`(NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information
`423
`about the safety of antiepile