Neurontin® (gabapentin) Capsules
`Neurontin® (gabapentin) Tablets
`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 containing 250 mg/5 mL of gabapentin.
`The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule
`shell contains gelatin and titanium dioxide. The 300 mg capsule 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
`titanium dioxide.
`The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch,
`magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax and purified water.
`
`The inactive ingredients for the oral solution are glycerin, xylitol, purified water and artificial
`cool strawberry anise flavor.
`
`Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with a molecular formula of
`C9H17NO2 and a molecular weight of 171.24. The structural formula of gabapentin is:
`
`Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 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.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`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
`
`ARGENTUM Exhibit 1198
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
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`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.
`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.
`Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but
`it does not modify GABAA or GABAB radioligand 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 μM and did not
`exhibit affinity for a number of other common 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 A1 or A2,
`cholinergic muscarinic or nicotinic, dopamine D1 or D2, 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 uptake
`of dopamine, noradrenaline, or serotonin.
`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 been identified as an auxiliary subunit of voltage-activated calcium channels.
`However, functional correlates of gabapentin binding, if any, remain to be elucidated.
`Pharmacokinetics and Drug Metabolism
`
`All pharmacological actions following gabapentin administration are due to the activity of the
`parent compound; gabapentin is not appreciably metabolized in humans.
`Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is
`increased, bioavailability decreases. Bioavailability of gabapentin is approximately 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 Cmax).
`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 gabapentin in
`cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
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`Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as
`unchanged drug. Gabapentin is not appreciably metabolized in humans.
`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 Insufficiency,
`below). In elderly patients, and in patients with impaired renal function, gabapentin plasma
`clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
`Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is
`recommended (see DOSAGE AND ADMINISTRATION, Table 6).
`Special Populations: Adult Patients With Renal Insufficiency: Subjects (N=60) with renal
`insufficiency (mean creatinine clearance ranging from 13-114 mL/min) were administered single
`400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours
`(patients with creatinine clearance >60 mL/min) to 52 hours (creatinine 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 to
`20 mL/min.
`Dosage adjustment in adult patients with compromised renal function is necessary (see
`DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been
`studied.
`Hemodialysis: In a study in anuric adult subjects (N=11), the apparent elimination half-life of
`gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of
`gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin
`elimination in anuric subjects.
`Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND
`ADMINISTRATION).
`Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients
`with hepatic impairment.
`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 patients who have age related compromised renal function.
`(See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)
`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 approximately 30%
`lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral
`clearance normalized per body weight was higher in the younger children. Apparent oral
`clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination
`half-life averaged 4.7 hours and was similar across the age groups studied.
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`A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month
`and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance
`(CL/F) was directly proportional to creatinine clearance and this relationship was similar
`following a single dose and at steady state. Higher oral clearance values were observed in
`children <5 years of age compared to those observed in children 5 years of age and older, when
`normalized 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 observed in adults after a single dose. The oral volume of distribution normalized per
`body weight was constant across the age range.
`
`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 concentrations
`similar to those achieved in patients 5 years of age and older receiving gabapentin at 30
`mg/kg/day (see DOSAGE AND ADMINISTRATION).
`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.
`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.
`Clinical Studies
`
`Postherpetic Neuralgia
`
`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.
`
`TABLE 1. Controlled PHN Studies: Duration, Dosages, and
`Number of Patients
`Study
`Gabapentin
`(mg/day)a
`Duration
`Target Dose
`3600
`1800, 2400
`Total
`
`Patients
`Receiving
`Gabapentin
`113
`223
`336
`
`Patients
`Receiving
`Placebo
`116
`111
`227
`
`Study
`
`1
`2
`
`8 weeks
`7 weeks
`
`a Given in 3 divided doses (TID)
`
`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
`
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`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 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 dose of study medication).
`
`Both studies showed significant differences from placebo at all doses tested.
`
`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.
`
`4-Week Dose Titration Period
`
`4-Week Fixed Dose Period
`
`Placebo
`
`Gabapentin, 3600 mg/day
`
`**
`
`**
`
`**
`
`**
`
`**
`
`**
`
`**
`
`**
`
` ** p < 0.01
`
`10
`
`0123456789
`
`Baseline
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`Weeks
`
`Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
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`3-Week Dose Titration Period
`
`4-Week Fixed Dose Period
`
`Placebo
`Gabapentin, 1800 mg/day
`Gabapentin, 2400 mg/day
`
`**
`**
`
`**
`**
`
`**
`**
`
`**
`**
`
`**
`**
`
`**
`**
`
`**
`**
`
`**p < 0.01
`
`10
`
`9
`
`8
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
`
`0
`
`Mean Pain Score
`
`Baseline
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Weeks
`
`Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2
`
`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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`***
`34%
`
`***
`32%
`
`14%
`
`PBO
`
`GBP
`1800
`Study 2
`
`GBP
`2400
`
`**
`***
`
`p <0.01
`p <0.001
`
`**
`29%
`
`12%
`
`PBO
`
`GBP
`3600
`Study 1
`
`50
`
`45
`
`40
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`05
`
`Percentage of Responders at Endpoint
`
`Figure 3.
`
`Proportion of Responders (patients with (cid:116)50% reduction in pain score) at
`Endpoint: Controlled PHN Studies
`
`Epilepsy
`
`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.
`
`Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years
`and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients
`enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more
`antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic 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, Neurontin 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 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
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`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.
`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.
`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, N=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.
`
`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-response data. A
`statistically 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.
`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 analyses. There were several response ratio
`comparisons that showed a statistically significant advantage for Neurontin compared to placebo
`and favorable trends for almost all comparisons.
`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.
`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).
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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 (cid:116)12
`Years of Age with Partial Seizures
`In the figure, treatment effect magnitude, measured on the Y axis 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).
`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 pattern 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 among racial groups.
`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 partial 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%).
`A study in pediatric 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 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
`
`Postherpetic Neuralgia
`Neurontin (gabapentin) is indicated for the management of postherpetic neuralgia in adults.
`Epilepsy
`Neurontin (gabapentin) is indicated as adjunctive therapy in the treatment of partial seizures with
`and without secondary generalization in patients over 12 years of age with epilepsy. Neurontin is
`also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3
`– 12 years.
`
`CONTRAINDICATIONS
`Neurontin is contraindicated in patients who have demonstrated hypersensitivity to the drug or
`its ingredients.
`
`WARNINGS
`Suicidal Behavior and Ideation
`Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or
`behavior in patients taking these drugs for any indication. Patients treated with any AED for any
`indication should be monitored for the emergence or worsening of depression, suicidal thoughts
`or behavior, and/or any unusual changes in mood or behavior.
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
`different AEDs showed that patients randomized to one of the AEDs had approximately twice
`the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
`to patients randomized to placebo. In these trials, which had a median treatment duration of 12
`weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
`patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
`increase of approximately one case of suicidal thinking or behavior for every 530 patients
`treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
`patients, but the number is too small to allow any conclusion about drug effect on suicide.
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
`week after starting drug treatment with AEDs and persisted for the duration of treatment
`assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
`of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
`analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
`range of indications suggests that the risk applies to all AEDs used for any indication. The risk
`did not vary substantially by age (5-100 years) in the clinical trials analyzed.
`Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
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`Table 2
`Indication
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`Risk by indication for antiepileptic drugs in the pooled analysis
`Risk Difference:
`Placebo Patients Drug Patients
`Relative Risk:
`Incidence of Events in Additional Drug
`with Events Per with Events Per
`Patients with
`1000 Patients
`1000 Patients
`Drug
`Events Per 1000
`Patients/Incidence in
`Patients
`Placebo Patients
`3.5
`2.4
`1.5
`2.9
`1.9
`0.9
`1.8
`1.9
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`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.
`Anyone considering prescribing Neurontin or any other AED must balance the risk of suicidal
`thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
`which AEDs are prescribed are themselves associated with morbidity and mortality and an
`increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
`during treatment, the prescriber needs to consider whether the emergence of these symptoms in
`any given patient may be related to the illness being treated.
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
`thoughts and behavior and should be advised of the need to be alert for the emergence or
`worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
`or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
`concern should be reported immediately to healthcare providers.
`
`Neuropsychiatric Adverse Events—Pediatric Patients 3-12 years of age
`
`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 most 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 performance, and 4) hyperkinesia (primarily restlessness and
`hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate
`in intensity.
`
`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% (placebo-treated patients);
`hostility 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 patient
`(0.4%) withdrew due to emotional lability.
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`Withdrawal Precipitated Seizure, Status Epilepticus
`
`Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing
`seizure frequency.
`In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus
`in patients receiving Neurontin was 0.6% (3 of 543) versus 0.5% in patients receiving placebo (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 population not treated with Neurontin.
`Tumorigenic Potential
`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 premarketing
`development provides no direct means to assess its potential for inducing tumors in humans.
`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 patients (2 breast, 3 brain, 2 lung, 1
`adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting 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 not treated with Neurontin, it is impossible to know whether the incidence
`seen in this cohort is or is not affected by treatment.
`Sudden and Unexplained Death in Patients With Epilepsy
`During the course of premarketing development of Neurontin 8 sudden and unexplained deaths
`were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).
`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
`Inform patients of the availability of a Medication Guide, and instruct them to read the
`Medication Guide prior to taking Neurontin. Instruct patients to take Neurontin only as
`prescribed.
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`Patients, their caregivers, and families should be counseled that AEDs, including Neurontin, may
`increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert
`for the emergence or worsening of symptoms of depression, any unusual changes in mood or
`behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
`Behaviors of concern should be reported immediately to healthcare providers.
`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).
`Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED)
`Pregnancy Registry if they become pregnant. This registry is collecting information about the
`safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-
`888-233-2334 (see PRECAUTIONS, Pregnancy section).
`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.
`Drug Interactions
`In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
`cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, 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 (cid:80)g/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 (cid:80)g/mL (approximately 15 times the Cmax 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 phe