Gabapentin (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Gabapentin wasadministered orally to mice and rats in 2-year carcinogenicity studies. Noevidence of drug-related carcinogenicity was observed in mice treated at dosesup to 2000 mg/kg/day. At 2000 mg/kg, the plasma gabapentin exposure (AUC) inmice is approximately 2 times that in humans at the MRHD of 3600 mg/day. Inrats, increases in the incidence of pancreatic acinar cell adenoma andcarcinoma were found in male rats receiving the highest dose (2000 mg/kg), butnot at doses of 250 or 1000 mg/kg/day. At 1000 mg/kg, the plasma gabapentinexposure (AUC) in rats is approximately 5 times that in humans at the MRHD.

Studiesdesigned to investigate the mechanism of gabapentin-induced pancreaticcarcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in ratpancreatic acinar cells in vitro and, thus, may be acting as a tumorpromoter by enhancing mitogenic activity. It is not known whether gabapentinhas the ability to increase cell proliferation in other cell types or in otherspecies, including humans.

Gabapentin didnot demonstrate mutagenic or genotoxic potential in three in vitro andfour in vivo assays. It was negative in the Ames test and the invitro HGPRT forward mutation assay in Chinese hamster lung cells; it didnot produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomalaberration assay and in the in vivo micronucleus test in Chinese hamsterbone marrow; it was negative in the in vivo mouse micronucleus assay;and it did not induce unscheduled DNA synthesis in hepatocytes from rats givengabapentin.

No adverse effects on fertility or reproduction were observed in rats atdoses up to 2000 mg/kg. At 2000 mg/kg, the plasma gabapentin exposure (AUC) inrats is approximately 8 times that in humans at the MRHD.

14 CLINICAL STUDIES

14.1 Postherpetic Neuralgia

Gabapentin wasevaluated for the management of postherpetic neuralgia (PHN) in two randomized,double-blind, placebo-controlled, multicenter studies. The intent-to-treat(ITT) population consisted of a total of 563 patients with pain for more than 3months after healing of the herpes zoster skin rash (Table 6).

TABLE 6. Controlled PHN Studies: Duration, Dosages, and Number ofPatients

Study Study Duration Gabapentin (mg/day)a Target Dose Patients Receiving Gabapentin Patients Receiving Placebo
1 8 weeks 3600 113 116
2 7 weeks 1800, 2400 223 111
Total 336 227

a Given in 3 divided doses (TID)

Each studyincluded a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4weeks of fixed dose). Patients initiated treatment with titration to a maximumof 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600to 1200 mg/day increments at 3- to 7-day intervals to the target dose over 3 to4 weeks. Patients recorded their pain in a daily diary using an 11-pointnumeric 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.Analyses were conducted using the ITT population (all randomized patients whoreceived at least one dose of study medication).

Both studiesdemonstrated efficacy compared to placebo at all doses tested.

The reduction in weekly mean pain scores was seen by Week 1 in bothstudies, and were maintained to the end of treatment. Comparable treatmenteffects were observed in all active treatment arms.Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence ofefficacy across all doses. Figures 1 and 2 show pain intensity scores over timefor Studies 1 and 2.

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Figure 1. Weekly Mean Pain Scores (Observed Casesin ITT Population): Study 1

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Figure 2. Weekly Mean Pain Scores (Observed Casesin ITT Population): Study 2The proportion of responders (those patientsreporting at least 50% improvement in endpoint pain score compared withbaseline) was calculated for each study (Figure 3).

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Figure 3. Proportion of Responders (patients with ≥50%reduction in pain score) at Endpoint: Controlled PHN Studies

14.2 Epilepsy for Partial Onset Seizures (Adjunctive Therapy)

Theeffectiveness of gabapentin as adjunctive therapy (added to other antiepilepticdrugs) was established in multicenter placebo-controlled, double-blind,parallel-group clinical trials in adult and pediatric patients (3 years andolder) with refractory partial seizures.

Evidence ofeffectiveness was obtained in three trials conducted in 705 patients (age 12years and above) and one trial conducted in 247 pediatric patients (3 to 12years of age). The patients enrolled had a history of at least 4 partialseizures per month in spite of receiving one or more antiepileptic drugs attherapeutic levels and were observed on their established antiepileptic drugregimen during a 12-week baseline period (6 weeks in the study of pediatricpatients). In patients continuing to have at least 2 (or 4 in some studies)seizures per month, gabapentin or placebo was then added on to the existingtherapy during a 12-week treatment period. Effectiveness was assessed primarilyon the basis of the percent of patients with a 50% or greater reduction inseizure frequency from baseline to treatment (the “responder rate”) and aderived measure called response ratio, a measure of change defined as (T -B)/(T + B), in which B is the patient’s baseline seizure frequency and T is thepatient’s seizure frequency during treatment. Response ratio is distributedwithin the range -1 to +1. A zero value indicates no change while completeelimination of seizures would give a value of -1; increased seizure rates wouldgive positive values. A response ratio of -0.33 corresponds to a 50% reductionin seizure frequency. The results given below are for all partial seizures inthe intent-to-treat (all patients who received any doses of treatment)population in each study, unless otherwise indicated.

One studycompared gabapentin 1200 mg/day, in three divided doses with placebo. Responderrate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebogroup; the difference between groups was statistically significant. Responseratio was also better in the gabapentin group (-0.199) than in the placebogroup (-0.044), a difference that also achieved statistical significance.

A second studycompared primarily gabapentin 1200 mg/day, in three divided doses (N=101), withplacebo (N=98). Additional smaller gabapentin 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 gabapentin 1200 mg/day group (16%) than in theplacebo group (8%), but the difference was not statistically significant. Theresponder rate at 600 mg (17%) was also not significantly higher than in theplacebo, but the responder rate in the 1800 mg group (26%) was statisticallysignificantly superior to the placebo rate. Response ratio was better in thegabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); butthis difference was also not statistically significant (p = 0.224). A betterresponse was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/daygroup (-0.222) than in the 1200 mg/day group, with the 1800 mg/day groupachieving statistical significance compared to the placebo group.

A third studycompared gabapentin 900 mg/day, in three divided doses (N=111), and placebo(N=109). An additional gabapentin 1200 mg/day dosage group (N=52) provideddose-response data. A statistically significant difference in responder ratewas seen in the gabapentin 900 mg/day group (22%) compared to that in theplacebo group (10%). Response ratio was also statistically significantlysuperior in the gabapentin 900 mg/day group (-0.119) compared to that in theplacebo group (-0.027), as was response ratio in 1200 mg/day gabapentin(-0.184) compared to placebo.

Analyses werealso performed in each study to examine the effect of gabapentin on preventingsecondarily generalized tonic-clonic seizures. Patients who experienced asecondarily generalized tonic-clonic seizure in either the baseline or in thetreatment period in all three placebo-controlled studies were included in theseanalyses. There were several response ratio comparisons that showed astatistically significant advantage for gabapentin compared to placebo andfavorable trends for almost all comparisons.

Analysis ofresponder rate using combined data from all three studies and all doses (N=162,gabapentin; N=89, placebo) also showed a significant advantage for gabapentinover placebo in reducing the frequency of secondarily generalized tonic-clonicseizures.

In two of the three controlled studies, more than one dose of gabapentinwas used. Within each study, the results did not show a consistently increasedresponse to dose. However, looking across studies, a trend toward increasingefficacy with increasing dose is evident (see Figure 4).

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Figure 4.Responder Rate in Patients Receiving gabapentin Expressed as a Difference fromPlacebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥ 12 Years ofAge with Partial Seizures

In the figure,treatment effect magnitude, measured on the Y axis in terms of the differencein the proportion of gabapentin and placebo-assigned patients attaining a 50%or greater reduction in seizure frequency from baseline, is plotted against thedaily dose of gabapentin administered (X axis).

Although noformal analysis by gender has been performed, estimates of response (ResponseRatio) derived from clinical trials (398 men, 307 women) indicate no important genderdifferences exist. There was no consistent pattern indicating that age had anyeffect on the response to gabapentin. There were insufficient numbers ofpatients of races other than Caucasian to permit a comparison of efficacy amongracial groups.

A fourth studyin pediatric patients age 3 to 12 years compared 25 – 35 mg/kg/day gabapentin(N=118) with placebo (N=127). For all partial seizures in the intent-to-treatpopulation, the response ratio was statistically significantly better for thegabapentin group (-0.146) than for the placebo group (-0.079). For the samepopulation, the responder rate for gabapentin (21%) was not significantlydifferent from placebo (18%).

A study in pediatric patients age 1 month to 3 years compared 40mg/kg/day gabapentin (N=38) with placebo (N=38) in patients who were receivingat least one marketed antiepileptic drug and had at least one partial seizureduring the screening period (within 2 weeks prior to baseline). Patients had upto 48 hours of baseline and up to 72 hours of double-blind video EEG monitoringto record and count the occurrence of seizures. There were no statisticallysignificant differences between treatments in either the response ratio orresponder rate.

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