Gabapentin
FULL PRESCRIBING INFORMATION: CONTENTS*
- GABAPENTIN DESCRIPTION
- CLINICAL PHARMACOLOGY
- PHARMACOKINETICS AND DRUG METABOLISM
- INDICATIONS & USAGE
- GABAPENTIN CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- INFORMATION FOR PATIENTS
- LABORATORY TESTS
- DRUG INTERACTIONS
- DRUG & OR LABORATORY TEST INTERACTIONS
- CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
- PREGNANCY
- NURSING MOTHERS
- PEDIATRIC USE
- GERIATRIC USE
- GABAPENTIN ADVERSE REACTIONS
- DRUG ABUSE AND DEPENDENCE
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- STORAGE AND HANDLING
- SPL MEDGUIDE
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
FULL PRESCRIBING INFORMATION
GABAPENTIN DESCRIPTION
CLINICAL PHARMACOLOGY
Mechanism of ActionPHARMACOKINETICS AND DRUG METABOLISM
Oral Bioavailability:
Distribution:
Elimination:
Special Populations: Patients With Renal Insufficiency
DOSAGE AND ADMINISTRATION, TABLE 6
Special Populations:
Adult Patients With Renal Insufficiency:
DOSAGE AND ADMINISTRATION
Hemodialysis:
Dosage adjustment in patients undergoing hemodialysis is necessary (seeDOSAGE AND ADMINISTRATION).
Hepatic Disease:
Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment.
Age:
PRECAUTIONS: Geriatric use, andDOSAGE 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.
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 (seeDOSAGE 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
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
*Given in 3 divided doses (TID)StudyStudy DurationGabapentin (mg/day)*Target DosePatients Receiving GabapentinPatients Receiving Placebo18 weeks360011311627 weeks1800, 2400223111Total336227Each 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 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. Figures1and2show these changes for Studies 1 and 2.
Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1
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).
Figure 3. Proportion of Responders (patients withreduction in pain score) at Endpoint: Controlled PHN Studies
Epilepsy
The effectiveness of gabapentin 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, gabapentin 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 (theresponder 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
One study compared gabapentin 1200 mg/day divided TID with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin 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 gabapentin (N=101) with placebo (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 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 gabapentin 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 gabapentin 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 gabapentin 900 mg/day divided TID (N=111) and placebo (N=109). An additional gabapentin 1200 mg/day dosage group (N=52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo.
Analyses were also performed in each study to examine the effect of gabapentin 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 gabapentin 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, gabapentin; N=89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of gabapentin 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 (seeFigure 4).
Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in PatientsYears 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 gabapentin. 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 2535 mg/kg/day gabapentin (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 gabapentin group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (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.
INDICATIONS & USAGE
Postherpetic NeuralgiaEpilepsy
GABAPENTIN CONTRAINDICATIONS
WARNINGS
Suicidal Behavior and IdeationNeuropsychiatric Adverse Events-Pediatric Patients 3-12 years of age
Withdrawal Precipitated Seizure, Status Epilepticus
Tumorigenic Potential
PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility
Sudden and Unexplained Death in Patients With Epilepsy
PRECAUTIONS
INFORMATION FOR PATIENTS
Drug Interactions
PRECAUTIONS: Pregnancy
LABORATORY TESTS
DRUG INTERACTIONS
Phenytoin:
Carbamazepine:
Valproic Acid:
Phenobarbital:
Naproxen:
Hydrocodone:
Morphine:
PRECAUTIONS
Cimetidine:
Oral Contraceptive:
Antacid (Maalox
Effect of Probenecid:
DRUG & OR LABORATORY TEST INTERACTIONS
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
PREGNANCY
NURSING MOTHERS
PEDIATRIC USE
CLINICAL PHARMACOLOGY: Clinical Studies
GERIATRIC USE
CLINICAL PHARMACOLOGYADVERSE REACTIONSDOSAGE AND ADMINISTRATION
GABAPENTIN ADVERSE REACTIONS
Postherpetic NeuralgiaIncidence in Controlled Clinical Trials
TABLE 3
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Epilepsy
WARNINGS, Neuropsychiatric Adverse Events
Incidence in Controlled Clinical Trials
TABLE 4
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TABLE 5
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Other Adverse Events Observed During All Clinical Trials
Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)
Body As A Whole:
Cardiovascular System:
Digestive System:
salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.
Endocrine System:
Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic System:
's lymphoma, bleeding time increased.
Musculoskeletal System:
Nervous System:
Respiratory System:
Dermatological:
Urogenital System:
Special Senses:
Clinical trials in Pediatric Patients With Epilepsy
Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in adjunctive trials in adults are:
Body as a Whole:
dehydration, infectious mononucleosis
Digestive System:
hepatitis
Hemic and Lymphatic System:
coagulation defect
Nervous System:
aura disappeared, occipital neuralgia
Psychobiologic Function:
sleepwalking
Respiratory System:
pseudocroup, hoarseness
Clinical Trials in Adults With Neuropathic Pain of Various Etiologies
Safety information was obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain conditions for which efficacy has not been demonstrated. Adverse events reported by investigators were grouped into standardized categories using modified COSTART IV terminology. Listed below are all reported events except those already listed in Table 3 and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole:
Cardiovascular System:
Digestive System:
Endocrine System:
Infrequent: diabetes mellitus.
Hemic and Lymphatic System:
Metabolic and Nutritional:
Musculoskeletal:
Nervous System:
Respiratory System:
Skin and Appendages:
Special Senses:
Urogenital System:
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
DRUG ABUSE AND DEPENDENCE
OVERDOSAGE
DOSAGE & ADMINISTRATION
Postherpetic Neuralgia
Epilepsy
Patients >12 years of age:
Pediatric Patients Age 312 years:
CLINICAL PHARMACOLOGY, Pediatrics
Dosage in Renal Impairment
Dosage in Elderly
HOW SUPPLIED
STORAGE AND HANDLING
SPL MEDGUIDE
Gabapentin (gaba pentin) Tablets USPWhat is the most important information I should know about gabapentin?
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● thoughts about suicide or dying
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● attempts to commit suicide
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● new or worse depression
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● new or worse anxiety
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● feeling agitated or restless
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● panic attacks
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● trouble sleeping (insomnia)
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● new or worse irritability
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● acting aggressive, being angry, or violent
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● acting on dangerous impulses
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● an extreme increase in activity and talking (mania)
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● other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
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● Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
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● Keep all follow-up visits with your healthcare provider as scheduled.
What is gabapentin?
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● Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes after a herpes zoster infection) in adults.
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● Partial seizures when taken together with other medicines in adults and children 3 years of age and older.
Who should not take gabapentin?
What should I tell my healthcare provider before taking gabapentin?
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● have or have had kidney problems or are on hemodialysis
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● have or have had depression, mood problems, or suicidal thoughts or behavior
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● are pregnant or plan to become pregnant. It is not known if gabapentin can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking gabapentin. You and your healthcare provider will decide if you should take gabapentin while you are pregnant.
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● If you become pregnant while taking gabapentin, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
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● are breast-feeding or plan to breast-feed. Gabapentin can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take gabapentin.
How should I take gabapentin?
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● Take gabapentin exactly as prescribed. Your healthcare provider will tell you how much gabapentin to take.
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● Do not change your dose of gabapentin without talking to your healthcare provider. If you break a tablet in half the unused half of the tablet should be taken at your next scheduled dose. Half tablets not used within several days of breaking should be thrown away.
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● Gabapentin can be taken with or without food. If you take an antacid containing aluminum and magnesium, such as MaaloxMylantaGelusilGavisconor Di-Gelyou should wait at least 2 hours before taking your next dose of gabapentin.
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● If you take too much gabapentin, call your healthcare provider or your local Poison Control Center right away.
What should I avoid while taking gabapentin?
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● Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking gabapentin without first talking with your healthcare provider. Taking gabapentin with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
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● Do not drive, operate heavy machinery, or do other dangerous activities until you know how gabapentin affects you. Gabapentin can slow your thinking and motor skills.
What are the possible side effects of gabapentin?
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● SeeWhat is the most important information I should know about gabapentin?
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● The most common side effects of gabapentin include:
How should I store gabapentin?
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● Store Gabapentin Tablets USP between 59to 86(15to 30
www.glenmarkgenerics.com <%0A%09%09 >
What are the ingredients in gabapentin?
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
GabapentinGabapentin TABLET
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PLEASE, BE CAREFUL!
Be sure to consult your doctor before taking any medication!
