HELSINN EXHIBIT 2099
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`Page 1 of 35 [PR2025-00948
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`NDA 21-397
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`Page 3
`— N elll‘OIlwti‘Ii®‘(gabapentin)Cap‘sules
`Neurontin® (gabapent‘li\h)v,'l’"ébvlets
`Neurontin® (gabapentin) Oral Solution
`DESCRIPTION
`
`Neurontin® (gabapentin) Capsules, Neurontin® (gabapentin) Tablets, and Neurontin® (gabapentin) Oral
`Solution are supplied as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of
`gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg of gabapentin or an oral
`solution cont:ining 250 mg/5 mL of gabapentin. L
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`The inactive ingredients for the capsules-are lactose, cornstarch, and talc. The 100 mg capsule shell
`contains gelatin and titanium dioxide. The 300 mg éapéule shell contains gelatin, titanium dioxide, and
`yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and
`yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and t‘itanium dioxide.
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`The inactive ingredients for the tablets are poloxamer 407, ébpolyviddnum, comstarch, magnesium
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`stearate, hydroxypropy! cellulose, talc, candelilla wax and purified water. The imprinting ink for the
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`600 mg tablets contains synthetic black iron oxide, pharmaceutical shellac, pharmaceutical glaze,
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`propylene glycol, ammonium hydrox1de, 1sopropy] alcohol and n-butyl alcohol. The imprinting ink for
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`the 800 mg tablets contains synthetlc yellow iron oxide, synthetlc red i 1ron oxide, hydroxypropyl
`&‘hylcellu]ose propylene glycol, methanol, isopropyl alcohol and dexomzed water.
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`The inactive ingredients for the oral solutlon are glycenn xyhto] punfied water and artificial cool
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`strawberry anise flavor
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`Gabapentin is descnbed as 1-(ammomethy])cyclohexaneacetxc ac1d thh a molecular formula of
`CoH;;MNO; and a molecular wenght of 171.24. The structural forrnula of gabapentm is:
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`' CHgNHZ*
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`CH,CO,H
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`Gabapentin is a white to off-white crystalline solid with a pK,; of 37anda pKaz of 10.7. It is freely
`soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient
`(n-octanol/0.05M phosphate buffer) at pH 7.4 is -1.25.
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`CLINICAL PHARMACOLOGY
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`Mechanism of Action
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`The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of
`analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous
`stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents
`pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation
`models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection
`model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan
`footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat
`tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat
`irradiation test). The relevance of these models to human pain is not known.
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`The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test
`systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed
`anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal
`electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with
`genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known.
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`Gabapentin is strucfurally related to the neurotransmitter GABA (gamma-aminobutyfic acid) but it
`does not modify GABA, or GABAg racfioligand binding, it is not converted metabolically into GABA
`or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested
`in radioligand binding assays at concentrations up to 100 uM and did not exhibit affinity for a number
`of other conimon receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA),
`quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta
`adrenergic, adenosine Al or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2,
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`histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium
`channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites
`labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular
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`uptake of dopamine, noradrenaline, or serotonin.
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`In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat
`brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has
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`been identified as an auxiliary subunit of voltage-activated calcium charinels. However, functional
`correlates of gabapentin binding, if any, remain to be elucidated. . '
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`Pharmacokinetics and Drug Metabolism
`
`All pharmacological actions following gabapentin adrninistrati'onare due to the activity of the parent
`compound; gabapentin is not appreciably metabolized in humans:
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`Oral Bioavailability: Gabapentin bioavailability is not dose proportlonal i.e., as dose is mcreased
`bioavailability decreases. Bioavailability of gabapentin is approxxmately 60%, 47%, 34%, 33%, and
`27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food
`has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and
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`Canax)-
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`Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of
`distribution of gabapentin after 150 mg intravenous administration is 58+6 L (Mean +SD). In patients
`with epilepsy, steady-state predose (Cmin) concentrations of gabapcntm in cerebrospinal fluid were
`approximately 20% of the corresponding plasma concentratlons :
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`Elimination: Gabapentin is eliminated from the systemicci'r‘cillaticn’by renal excretion as unchanged
`drug. Gabapentin is not appreciably metabolized in humans.
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`Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing.
`Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to
`creatinine clearance (see Special Populations Patients With Renal Insufiicwncy, below). In elderly
`patients, and in panents with lmpaired renal function gabapentm plasma clearance is reduced.
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`Gabapentin can be removed from plasma by hemodlaly51s
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`Dosage adjustment in’ patlents w1th cornprormsed renal function or undergomg hemodialysis is
`recommended (see DOSAGE AND ADMlNlSTRATION Table 5)
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`Special Populations: Aa’ult Patzents With Renal Insufl‘ czency Subjects (N—60) with renal
`msufficwncy (mean creatmme clearance ranging from 13 114 mL/mm) were administered single
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`400 mg oral doses of gabapentm The mean gabapentm half llfe ranged from about 6. 5 hours (patients
`with creatinine clearance >60 mL/mm) to 52 hours: (creatminc Clearance <30 mL/min).and gabapentin
`renal clearance from about 90 mL/min (>60 mL/min group)-to about 10 mL/min (<30 mL/min). Mean
`plasma clearance (CL/F) decreased from approximately 190 mL/min- t0 20 mL/min.
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`Dosage adjustment in adult patients with compromised‘renal' function is necessary (see DOSAGE AND
`ADMINISTRATION). Pediatric patients with renal insufficiency have not been studied.
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`Hemodialysis: In a study in anuric subjects (N=11), the apparent elimination half-life of gabapentin on
`nondialysis days was about 132 hours; during dialysis the apparent l)xalf-life of gabapentin was reduced
`to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects.
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`Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
`ADMINISTRATION). ' -
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`Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients with
`hepatrc impairment. V
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`Age: The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of
`gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about
`125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr-adjusted for body surface
`area also declined with age; however, the decline in the renal clearance of gabapentin with age can
`largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in
`pat:ents who have age related compromised renal function. (See PRECAUTIONS, Gerxatnc Use, and
`DOSAGE AND ADMINISTRATION.)
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`Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of
`1 month and 12 years following a dose of approximately 10 mg/kg >Peak plasma concentrations were
`similar across the entire age group and occurred 2 to 3 hours postdose In general, pediatric subjects
`between 1 month and <5 years ‘of age achieved approxrmately 30% lower exposure (AUC) than that
`observed in those 5 years of age and older. Accordmgly, oral clearance normalized per body weight
`was higher in the younger children. Apparent oral- clearance of gabapentm was directly proportional to
`creatinine clearance. Gabapentin elimination half-life averaged 4. 7 hours and was similar across the
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`.age groups studied.
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`A population pharmacokinetic analysis was perforrrred m253ped1atne subjects between 1 month and
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`" 13 years of age._ Patients received 10 to 65 mg/kg/day given TID. ;A'pparent oral clearance (CL/F) was
`directly proportlonal to creatmme clearance and this relatlonshlp was similar following a single dose
`and at steady state. ngher ‘'oral clearance values were observed m cmldren <5 years of age compared to
`those observed in children 5 years of age and older, when normahzed per body weight. The clearance
`was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric
`patients 5 years of age and older were consistent with values ofiserv'vfed»in;adults after a single dose. The
`oral volume of distribution normalized per body weight was corrstarit‘ across the age range.
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`These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy
`ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma cbncentrations similar to those
`achieved in patients 5 years of age and older receiving gabapentin at 30'mg/kg/day.‘ (See DOSAGE
`AND ADMINISTRATION.)
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`Gender: Although no formal study has been conducted to compare the pharmacokinetics of gabapentin
`in men and women, it appears that the pharmacokinetic parameters for males and females are similar
`and there are no significant gender differences.
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`Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily
`renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic
`differences due to race are not expected.
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`Clinical Studies
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`Postherpetic Neuralgia
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`Neurontin® was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized,
`double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT)
`population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after
`healing of the herpes zoster skin rash. A
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`Table 1. Controlled PHN Studies: Duration, Dosages, and
`Number of Patients ‘
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`Study Study Gabapentin Patients Patients
`Duration (mg/day)® Receiving Receiving |.. -
`Target Dose Gabapentin Placebo
`1 8 weeks 3600 113 116
`2 7 weeks 1800, 2400 223 111
`Total 336 227
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`® Given in 3 divided doses (TID)
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`Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or
`8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated
`treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be
`titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In
`Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline
`and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale
`ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4
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`was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4).
`Analyses were conducted using the ITT population (all randomized patients who received at least one
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`dose of study medication).
`Both studies showed significant differences from placebo at all doses tested.
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`A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant
`differences were maintained to the end of treatment. Comparable treatment effects were observed in all
`active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence
`of efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2.
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`44— 4Week Dose Titration Period ———p-¢———4-Weoek Fixed Dose Period ——p
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`=O=Placebo
`&~ Gabapentin, 3600 mg/day
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`Mean Pain Score
`7]
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`= p<0.01
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`Baseline 1 2 3 4 s 6 7 8
`Wegks
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`Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT. Population): Study 1
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`<—3.Week Dose Titration Period—s<——— 4-Week Fixed Dose Period————b
`=O-Placebo
`-4~ Gabapentin, 1800 mg/day
`8 = Gabapentin, 2400 mg/day
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`1]
`2 -]
`c 5
`. B by -
`u -*r
`Q@
`& 3
`2.
`*p < 0.0
`l-
`0
`Baseline 1 2 3 4 5 ] 7
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`Weeks
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`Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
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`The proportion of responders (those patients reporting at least 50% improvement in endpoint pain
`score compared with baseline) was calculated for each study (Figure 3).
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`APPEARS THIS WAY
`ON ORIGINAL
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`** p<0.01
`*** p <0.001
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`35 A
`30 4
`25
`20 1
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`15 1
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`14%.
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`10 4 12%
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`Percentage of Responders at Endpoint
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`PBO GBP PBO GBP GBP
`3600 1800 ' 2400
`Study 1 Study 2
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`Figure 3. Proportion of Responders (patients with >50% reduction in pain score) at Endpoint:
`Controlled PHN Studies
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`Epilepsy
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`The effectiveness of Neurontin® as adjunctive therapy (added to other antiepileptic drugs) was
`established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and
`pediatric patients (3 years and older) with refractory partial seizures.
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`Evidence of effectiveness was obtained in three trials c_onduéted in 705 patients (age 12 years and
`above) and one trial conducted in 247 pediatric patients (3 to .112 years of age). The patients enrolled
`had a history of at least 4 partial seizures per month in spite of }eceiving one or more antiepileptic
`drugs at therapeutic levels and were observed on their estabvli.shed ahtiepileptic drug regimen during a
`12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at
`least 2 (or 4 in some studies) seizures per month, Neurontvivxrx® or placebo was then added on to the
`existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis
`of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to
`treatment (the “responder rate™) and a derived measure called response ratio, a measure of change
`defined as (T - B)/(T + B), where B is the patient’s baseline seizure frequency and T is the patient’s
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`seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero
`value indicates no change while complete elimination of seizures would give a value of -1; increased
`seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in
`seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients
`who received any doses of treatment) population in each study, unless otherwise indicated.
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`One study compared Neurontin® 1200 mg/day divided TID with placebo. Responder rate was 23%
`(14/61) in the Neurontin® group and 9% (6/66) in the placebo group; the difference between groups
`was statistically significant. Response ratio was also better in the Neurontin® group (-0.199) than in the
`placebo group (-0.044), a difference that also achieved statistical significance.
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`A second study compared primarily 1200 mg/day divided TID Neurontin® (N=101) with placebo
`(N=98). Additional smaller Neurontin® dosage groups (600 mg/day, N=53; 1800 mg/day, »=-54) were
`also studied for information regarding dose response. Responder rate was higher in the Neurontin®
`1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically
`significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo,
`but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the
`placebo rate. Response ratio was better in the Neurontin® 1200 mg/day group (-0.103) than in the
`placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better
`response was seen in the Neurontin® 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than
`in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to
`the placebo group.
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`A third study compared Neurontin® 900 mg/day divided TID (N=111) and placebo (N=109). An
`additional Neurontin® 1200 mg/day dosage group (N=52) provided dose-reéponse data. A stati’étically
`significant difference in responder rate was seen in the Neurontin® 900 mg/day group (22%) compared
`to that in the placebo group (10%). Response ratio was also statistically significantly superior in the
`Neurontin® 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response
`ratio in 1200 mg/day Neurontin® (-0.184) compared to placebo.
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`Analyses were also performed in each study to examine the effect of Neurontin® on preventing
`secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized
`tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled
`studies were included in these analyseé. There were several response ratio comparisons that showed a
`statistically significant advantage for Neurontin® compared to placebo and favorable trends for almost
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`all comparisons.
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`Analysis of responder rate using combined data from all three studies and all doses (N=162,
`Neurontin®; N=89, placebo) also showed a significant advantage for Neurontin® over placebo in
`reducing the frequency of secondarily generalized tonic-clonic seizures.
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`In two of the three controlled studies, more than one dose of Neurontin® was used. Within each study
`the results did not show a consistently increased response to dose. However, looking across studies, a
`trend toward increasing efficacy with increasing dose is evident (see Figure 4).
`
`22
`17— A |
`b a B STUDY 2
`g O
`g 12— O [ASTUDY b
`ks u |
`€ ;1 @ || OsTupyc
`a
`2=
`| | I |
`600 900 1200 1800
`daily dose (mq)
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`Figure 4. Responder Rate in Patients Receiving Neurontin® Expressed as a Difference From
`Placebo by Dose and Study: Adjunctive Therapy Studies in Patients 212 Years of Age
`With Partial Seizures )
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`In the figure, treatment effect magnitude, measured on the Y ai;is in terms of the difference in the
`proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in seizure
`frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis).
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`Although no formal analysis by gender has been performed, estimates of response (Response Ratio)
`derived from clinical trials (398 men, 307 women) indicate no important gender differences exist.
`There was no consistent patterri indicating that age had any effect on the response to Neurontin®. There
`were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy
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`among racial groups.
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`A fourth study in pediatric patients age 3 to 12 years compared 25 - 35 mg/kg/day Neurontin® (N=118)
`with placebo (N=127). For all paftia] seizures in the intent-to-treat population, the response ratio was
`statistically significantly better for the Neurontin® group (-0.146) than for the placebo group (-0.079).
`For the same population, the responder rate for Neurontin® (21%) was not significantly different from
`placebo (18%).
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`A'study in pediatfic patients age 1 month to 3 years compared 40 mg/kg/day Neurontin® (N=38) with
`placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least
`one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to
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`48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the
`occurrence of seizures. There were no statistically significant differences between treatments in either
`the response ratio or responder rate.
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`INDICATIONS AND USAGE
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`Postherpetic Neuralgia
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`Neurontin® (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
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`Epilepsy
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`Neurontin® (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with and
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`without secondary generalization in patients over 12 years of age with epilepsy. Neurontin® is also
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`indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 - 12 years. A
`CONTRAINDICATIONS
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`Neurontin® is contraindicated in patients who have demonstrated hypersensitivity to the drug or its
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`ingredients. ‘ '
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`WARNINGS
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`Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age
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`Gabapentin use in pediatric patients with epilepsy 3-12 years of age is associated with the occurrence
`of central nervous system related adverse events. The mbsf significant of these can be classified into
`the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including
`aggressive behaviors, 3) thought disorder, including concentration problems and change in school
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`performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-
`treated patients, most of the events were mild to moderate in intensity.
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`In controlled trials in pediatric patients 3-12 years of age, the incidence of these adverse events was:
`emotional lability 6% (gabapentin-treated patients) vs 1.3% (placébo-treated patients); hostility
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`5.2% vs 1.3%; hyperkinesia 4.7% vs 2.9%; and thought disorder 1.7% vs 0%. One of these events, a
`report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3%
`of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients
`reporting hostility and thought disorder. One placebo-treated pafient (0.4%) withdrew due to emotional
`lability.
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`Withdrawal Precipitated Seizure, Status Epilepticus
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`Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure
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`frequency.
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`In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus in
`paiients receiving Neurontin® was 0.6% (3 of 543) versus 0.5% in patients receiving placebo
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`(2 of 378). Among the 2074 patients >12 years of age treated with Neurontin® across all studies
`(controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior
`history of status epilepticus either before treatment or while on other medications. Because adequate
`historical data are not available, it is impossible to say whether or not treatment with Neurontin® is
`associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar
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`population not treated with Neurontin®.
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`Tumorigenic Potential
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`In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of
`pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See PRECAUTIONS:
`Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical significance of this finding is
`unknown. Clinical experience during gabapentin’s premarketmg development provides no direct means
`to assess its potential for inducing tumors in humans. ' ‘
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`In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in
`patients >12 years of age, new tumors were reported in 10 patlents (2 breast, 3 brain, 2 lung, 1 adrenal,
`1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and pre-existing tumors worsened in
`11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of
`Neurontin®. Without knowledge of the background incidence and recurrence in a similar population
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`not treated with Neurontin®, it is impossible to know whether the incidence seen in this cohort is or is
`not affected by treatment.
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`Sudden and Unexplained Death in Patients With Epilepsy
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`During the course of premarketihg development of Neurontin® 8 sudden and unexplained deaths were
`recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
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`Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at
`night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that
`expected in a healthy population matched for age and sex, it is within the range of estimates for the
`incidence of sudden unexplained deaths in patients with epilepsy not receiving Neurontin® (ranging
`from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to
`that in the Neurontin® program, to 0.005 for patients with refractory epilepsy). Consequently, whether
`these figures are reassuring or raise further concern depends on comparability of the populations
`reported upon to the Neurontin® cohort and the accuracy of the estimates provided.
`
`PRECAUTIONS
`
`Information for Patients .
`Patients should be instructed to take Neurontin® only as prescribed.
`
`Patients should be advised that Neurontin® may cause dizziness, somnolence and other symptoms and
`signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate
`other complex machinery until they have gained sufficient experience on Neurontin® to gauge whether
`or not it affects their mental and/or motor performance adversely.
`
`Patients who require concomitant treatment with morphine may experience increases in gabapentin
`concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence,
`and the dose of Neurontin® or morphine should be reduced appropriately (see Drug Interactions).
`
`Laboratory Tests
`
`Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary
`for the safe use of Neurontin®. The value of monitoring gabapentin blood concentrations has not been
`established. Neurontin® may be used in combination with other antiepileptic drugs without concern for
`alteration of the blood concentrations of gabapentin or of other antiepileptic drugs.
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`Drug Interactions
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`In vitro studies were conducted to investigéte the potential of gabapentin to inhibit the major
`cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2EI, and
`CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and
`human liver microsomal preparations. Only at the highest concentration tested (171 pg/mL; 1 mM) was
`a slight degree of inhibition (14%-30%) of isoform CYP2A6 observed. No inhibition of any of the
`other isoforms tested was observed at gabapentin concentrations up to 171 pg/mL (approximately
`
`15 times the Cp,x at 3600 mg/day).
`
`Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly
`coadministered antiepileptic drugs.
`
`The drug interaction data described in this section were obtained from studies inVolving healthy adults
`and adult patients with epilepsy.
`
`Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of Neurontin® in epileptic
`patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect
`on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on
`
`gabapentin pharmacokinetics.
`
`Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide
`concentrations were not affected by concomitant gabapentin (400 mg TID; N=12) administration.
`Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration.
`
`Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and during
`concomitant gabapentin administration (400 mg TID; N=17) were not different and neither were
`gabapentin pharmacokinetic parameters affected by valproic acid.
`
`Phenobarbital: Estimates of steady-state pharmacokinetic pargméters for phenobarbital or gabapentin
`(300 mg TID; N=12) are identical whether the drugs are administered alone or together.
`
`Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with Neurontin®
`
`(125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no
`effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for
`both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not
`
`known.
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`Page 15 of 35
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`Hydrocodone: Coadministration of Neurontin® (125 to 500 mg; N=48) decreases hydrocodone
`
`(10 mg; N=50) Crnax and AUC values in a dose-dependent manner relative to administration of
`hydrocodone alone; Crax and AUC values are 3% to 4% lower, respectively, after administration of
`125 mg Neurontin® and 21% to 22% lower, respectively, after administration of 500 mg Neurontin®.
`The mechanism for this interaction is unknown. Hydrocodone incr_eases gabapentin AUC values by
`14%. The magnitude of interaction at other doses is not known.
`
`Morphine: A literature article reported that when a 60-mg controlled release morphine capsule was
`administered 2 hours prior to a 600-mg Neurontin® capsule (N=12)_, mean gabapentin AUC increased
`by 44% compared to gabapentin administered without morphine (see PRECAUTIONS). Morphine
`pharmacokinetic parameter values were not affected by administration of Neurontin® 2 hours after
`morphine. The magnitude of interaction at other doses is not known. V
`
`Cimetidine: In the presence of cimetidine at 300 mg QID (N=12) the mean apparent oral clearance of
`gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine appeared to alter the
`renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small
`decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The
`
`effect of gabapentin on cimetidine was not evaluated.
`
`Oral Contracepfives: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of
`norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of
`norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration
`of gabapentin (400 mg TID; N=13). The Cpqx of norethindrone was 13% higher when it was
`coadministered with gabapentin; this interaction is not expected to be of clinical importance.
`
`Antacid (Maalox®): Maalox reduced the bioavailability of gabapentin (N=16) by about 20%. This
`decrease in bioavailabilityfwas about 5% when gabapentin was administered 2 hours after Maalox. It is
`recommended that gabapentin be taken at least 2 hours following Maalox administration.
`
`Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic
`parameters without and with probenecid were comparable. This indicates that gabapentin does not
`undergo renal tubular secretion by the pathway that is blocked by probenecxd
`
`Drug/Laboratory Tests Interactions
`
`Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for urinary
`protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid
`
`precipitation procedure is recommended to determine the presence of urine protein.
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