Living with Advanced MS? Watch this video to learn more.

Gabapentin Tablets

Pronunciation

Dosage Form: tablet

Indications and Usage for Gabapentin Tablets

 
Gabapentin Tablets USP are indicated for:
Management ofpostherpeticneuralgiain adults
Adjunctivetherapyin thetreatment ofpartial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy

Gabapentin Tablets Dosage and Administration

Gabapentin Tablets are given orally with or without food. Patients should beinformed that, should they break the scored 600 mg or800 mgtablet in orderto administerahalf-tablet, theyshould take theunused half-tablet asthenext dose. Half-tablets not used within 28 daysofbreakingthe scored tablet should bediscarded.

If Gabapentin Tablets doseis reduced, discontinued, orsubstituted with an alternativemedication, this should bedone graduallyoveraminimum of1 week (alonger periodmay beneeded at the discretion oftheprescriber).

Postherpetic Neuralgia

In adults with postherpeticneuralgia, gabapentin tablet therapymay beinitiated on Day1 as a single300 mgdose, on Day2 as 600 mg/day (300mgtwo times aday), and on Day3 as 900 mg/day (300 mgthreetimes aday). Thedose can subsequentlybetitrated up as needed for pain reliefto adoseof1800 mg/day (600 mgthreetimes aday). In clinical studies, efficacy was demonstrated overa rangeofdoses from 1800 mg/dayto 3600 mg/day with comparable effects across thedose range; however, in these clinical studies, the additional benefit ofusingdoses greaterthan 1800 mg/day was not demonstrated.

Epilepsy with Partial OnsetSeizures

Gabapentin Tablets are recommended for add-on therapyin patients 3 years of age and older. Effectiveness in pediatricpatients belowthe age of3 years has not been established.

Patients 12 years ofageand above:Thestarting doseis 300 mgthreetimes aday. The effectivedoseof Gabapentin Tablets is 300 mgto 600 mgthreetimes aday. Dosages up to 2400 mg/dayhavebeen well tolerated in long-term clinical studies. Doses of3600 mg/dayhave also been administered toasmall numberofpatients fora relativelyshort duration, and havebeen well tolerated. Gabapentin Tablets should be administered threetimes adayusing600 mgor 800 mgtablets. The maximum timebetween dosesshould not exceed 12 hours.

Pediatric Patients Age3 to 11 years:Thestartingdose rangeis 10 mg/kg/dayto 15 mg/kg/day, given in threedivided doses, and the effectivedose reached byupward titration overaperiod of approximately3 days. The effectivedose of Gabapentin Tablets in patients 3 to 4 years of ageis 40 mg/kg/day, given in threedivided doses. The effectivedoseof Gabapentin Tablets in patients 5 to 11 years of ageis 25 mg/kg/dayto 35 mg/kg/day, given in threedivided doses. Gabapentin may be administered as the oral solution, capsule, ortablet, orusing combinations ofthese formulations. Dosages up to 50 mg/kg/dayhave been well tolerated in along-term clinical study. Themaximum timeinterval between doses should not exceed 12 hours.

It is not necessaryto monitor gabapentin plasma concentrations to optimize Gabapentin Tablets therapy. Further, becausethere areno significant pharmacokineticinteractions among Gabapentin Tablets and other commonlyused antiepilepticdrugs, the addition of Gabapentin Tablets does not altertheplasmalevels ofthesedrugs appreciably.

If Gabapentin Tablets are discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should bedonegraduallyoveraminimum of1 week.

Patients with Renal Impairment

Dosage adjustment in patients 12 years of age andolder with compromised renal function or undergoinghemodialysis is recommended, as follows (seedosing recommendations above for effectivedoses in each indication):

Table 1: Gabapentin Tablets Dosage Based on Renal Function
*
a For patients withcreatinineclearance<15 mL/min,reduce daily dose in proportion tocreatinineclearance(e.g., patients withacreatinineclearance of 7.5 mL/min shouldreceive one-half the daily dose that patients witha creatinineclearance of 15 mL/minreceive).
b Patients on hemodialysis shouldreceive maintenance doses based onestimates ofcreatinineclearanceasindicated in the upper portion of the tableanda supplemental post-hemodialysis doseadministeredaftereach 4 hours of hemodialysisas indicated in the lower portion of the table.

Renal Function Creatinine Clearance (mL/min)

Total Daily Dose Range (mg/day)

Dose Regimen (mg)

≥ 60

900 to 3600

300 TID

400 TID

600 TID

800 TID

1200 TID

>30 to 59

400 to 1400

200 BID

300 BID

400 BID

500 BID

700 BID

>15 to 29

200 to 700

200 QD

300 QD

400 QD

500 QD

700 QD

15*

100 to 300

100 QD

125 QD

150 QD

200 QD

300 QD

Post-Hemodialysis Supplemental Dose (mg)

Hemodialysis

125b

150b

200b

250b

350b

TID= Three timesa day; BID = Two timesa day;QD= Single daily dose

Creatinine clearance (CLCr)is difficult to measurein outpatients. In patients with stable renal

function, creatinine clearance can be reasonably well estimated usingthe equation ofCockcroft

and Gault:

Theuseof gabapentin in patients less than 12 years of age with compromised renal function has not been studied.

Dosagein Elderly

Because elderlypatients aremorelikelyto have decreased renal function, careshould betaken in doseselection, and doseshould be adjusted basedon creatinine clearance values in these patients.

Dosage Forms and Strengths

 
Tablets:

Gabapentin Tablets, 600 mg are available as white, oval shaped tablets, debossed “4443”, with a partial score on one side and “600” on the other side

Gabapentin Tablets, 800 mg are available as white, oval shaped tablets, debossed “4444”, with a partial score on one side and “800” on the other side

Contraindications

Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings and Precautions

Drug Reaction with Eosinophilia and SystemicSymptoms (DRESS)/Multiorgan Hypersensitivity

DrugReaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin. Someofthese reactionshavebeen fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with otherorgan system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophiliais often present. Thisdisorderis variablein its expression, and other organ systems not noted heremay beinvolved.

It is important to notethat earlymanifestations of hypersensitivity, such as fever or lymphadenopathy, may bepresent even though rash is not evident. Ifsuch signs or symptoms are present, thepatient should be evaluated immediately. Gabapentin should bediscontinued if an alternative etiology forthesigns or symptoms cannot be established.

Effects on Driving andOperating Heavy Machinery

Patients taking gabapentin should not drive until theyhavegained sufficient experienceto assess whether gabapentin impairs their abilityto drive. Driving performancestudies conducted with aprodrugofgabapentin (gabapentin enacarbil tablet, extended release)indicate that gabapentin may causesignificant drivingimpairment.Prescribers andpatients should be awarethat patients’ abilityto assess theirown driving competence, as well as their abilityto assess thedegreeofsomnolence caused by gabapentin, can beimperfect. Theduration of drivingimpairment afterstartingtherapy with gabapentin is unknown. Whetherthe impairment is related to somnolence[see Warnings and Precautions (5.3)]orother effects of gabapentin is unknown.

Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.3)], patients should be advised not to operate complexmachineryuntil theyhave gained sufficient experienceon gabapentin to assess whether gabapentin impairs their abilityto perform such tasks.

Somnolence/Sedation and Dizziness

Duringthe controlled epilepsytrials in patients olderthan 12 years of age receivingdoses of gabapentin up to 1800 mgdaily, somnolence,dizziness, and ataxia were reported at a greater ratein patients receiving gabapentin comparedto placebo: i.e., 19%indrug versus 9%in placebo forsomnolence,17%in drug versus 7% in placebo fordizziness, and 13%in drug versus 6%in placebo for ataxia. In thesetrials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients olderthan 12 years of age, with 1.2%, 0.8% and 0.6%discontinuing forthese events, respectively.

Duringthe controlled trials in patients with post-herpeticneuralgia, somnolence and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3600 mg perday: i.e.,21%in gabapentin -treated patients versus 5%in placebo-treated patients forsomnolence and 28%in gabapentin-treatedpatients versus 8%in placebo-treated patients fordizziness. Dizziness and somnolence were amongthemost common adverse reactions leading to discontinuation of gabapentin.

Withdrawal Precipitated Seizure, Status Epilepticus

Antiepilepticdrugs should not be abruptlydiscontinued becauseofthepossibilityofincreasing seizure frequency.

In theplacebo-controlled epilepsystudies in patients >12 years of age, theincidenceofstatus epilepticus in patients receiving gabapentin was 0.6% (3 of543)vs. 0.5%in patients receivingplacebo (2 of 378). Amongthe2074 patients >12 years of agetreated with gabapentin across all epilepsystudies (controlled and uncontrolled), 31 (1.5%)had status epilepticus. Ofthese, 14patients had no priorhistory ofstatus epilepticus eitherbeforetreatment or whileon othermedications. Because adequatehistorical data arenot available, it is impossible to say whether ornot treatment with gabapentin is associated with ahigherorlower rateof status epilepticus than would be expected to occurin asimilarpopulation not treated with gabapentin.

SuicidalBehaviorand Ideation

Antiepilepticdrugs (AEDs), including gabapentin, increasethe risk ofsuicidal thoughts or behaviorin patients takingthese drugs for anyindication. Patients treated with any AED for any indication should bemonitored forthe emergenceor worseningof depression, suicidal thoughts orbehavior, and/or any unusual changes in moodorbehavior.

Pooled analyses of199 placebo-controlled clinicaltrials (mono- and adjunctivetherapy)of11 different AEDs showed that patients randomized to oneofthe AEDs had approximatelytwice the risk (adjusted RelativeRisk 1.8, 95% CI:1.2, 2.7)ofsuicidal thinkingorbehavior compared to patients randomized to placebo. In thesetrials, which had amedian treatment duration of12 weeks, the estimated incidence rateofsuicidal behaviororideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increaseof approximatelyone case ofsuicidal thinkingor behavior for every530 patients treated. There were foursuicides in drug-treated patients in thetrials and nonein placebo-treated patients, but thenumberis too small to allow any conclusion about drug effect on suicide.

Theincreased risk ofsuicidal thoughts or behavior with AEDs was observed as early as one week afterstartingdrug treatment with AEDs andpersisted forthedurationoftreatment assessed. Becausemost trials included in the analysis did not extend beyond 24 weeks, the risk ofsuicidal thoughts or behaviorbeyond 24 weeks could not be assessed.

The risk ofsuicidal thoughts orbehavior was generally consistent among drugs in the data analyzed. The findingofincreased risk with AEDs ofvaryingmechanisms of action and across a rangeofindications suggests that the risk applies to all AEDs used for any indication. The risk did not varysubstantially by age (5 to 100 years)in the clinical trials analyzed. Table2 shows absolute and relative risk byindication for all evaluated AEDs.

Table 2: Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo Patients with Events Per 1000 Patients

Drug Patients with Events Per 1000 Patients

Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients

Risk Difference: Additional Drug Patients with Events Per 1000 Patients

Epilepsy

1

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

The relative risk forsuicidal thoughts orbehavior was higherin clinical trials for epilepsythan in clinical trials forpsychiatricorother conditions, but the absolute risk differences weresimilar for the epilepsy and psychiatricindications.

Anyone considering prescribing gabapentin or anyother AEDmust balancethe risk of suicidal thoughts orbehavior with the risk ofuntreated illness. Epilepsy and manyotherillnesses for which AEDs areprescribed arethemselves associated with morbidity and mortality and an increased risk ofsuicidalthoughts and behavior. Should suicidal thoughts and behavior emerge duringtreatment, theprescriberneeds to consider whetherthe emergence ofthese symptoms in any given patient maybe related to theillness beingtreated.

Patients, their caregivers, and families should beinformed that AEDs increasethe risk ofsuicidal thoughts and behavior and should be advised oftheneed to be alert forthe emergenceor worseningofthesigns and symptoms ofdepression, anyunusual changes in mood orbehavior, orthe emergenceofsuicidal thoughts, behavior, orthoughts about self-harm. Behaviors of concern should be reported immediatelyto healthcare providers.

Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age)

Gabapentin usein pediatricpatients with epilepsy3 to 12 years of ageis associated with the occurrenceof central nervous system related adverse reactions. Themost significant ofthese can be classified into the following categories: 1) emotional lability (primarilybehavioral problems), 2)hostility, including aggressivebehaviors, 3)thought disorder, including concentration problems and changein school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Amongthegabapentin-treated patients, most ofthe reactions weremild to moderatein intensity.

In controlled clinical epilepsytrials in pediatricpatients 3 to 12 years of age,theincidence ofthese adverse reactions was: emotional lability6% (gabapentin-treated patients)vs. 1.3% (placebo‑ treated patients); hostility5.2%vs. 1.3%; hyperkinesia4.7%vs. 2.9%; and thought disorder 1.7%vs. 0%. Oneofthese reactions, a report ofhostility, was considered serious. Discontinuation ofgabapentin treatment occurredin 1.3%ofpatients reporting emotional lability and hyperkinesia and 0.9%of gabapentin-treatedpatients reportinghostility and thought disorder. Oneplacebo-treated patient (0.4%) withdrewdueto emotional lability.

Tumorigenic Potential

In an oral carcinogenicitystudy, gabapentin increased theincidenceof pancreatic acinar cell tumors in rats [seeNonclinical Toxicology (13.1)]. The clinical significanceofthis findingis unknown. Clinical experienceduring gabapentin’spremarketing development provides no direct means to assess its potential forinducingtumors in humans.

In clinical studies in adjunctivetherapyin epilepsy comprising2085 patient-years of exposurein patients >12 years of age, newtumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinomain situ), andpreexistingtumors worsened in 11 patients (9 brain, 1 breast, 1 prostate)duringorup to 2 years following discontinuation of gabapentin. Without knowledge ofthebackground incidence and recurrencein asimilarpopulation not treated with gabapentin, it is impossibleto know whethertheincidence seen in this cohort is oris not affected bytreatment.

Sudden and Unexplained Death in Patients with Epilepsy

Duringthe courseofpremarketing development of gabapentin, 8 sudden and unexplained deaths were recorded amonga cohort of2203 epilepsy patients treated (2103 patient-years of exposure) with gabapentin.

Someofthese could represent seizure-related deaths in which theseizure was not observed, e.g., at night. This represents an incidenceof0.0038 deaths per patient-year. Although this rate exceeds that expected inahealthypopulation matched for age and sex, it is within the rangeof estimates fortheincidenceofsudden unexplained deaths in patients with epilepsynot receiving gabapentin (ranging from 0.0005 forthe general population of epileptics to 0.003 fora clinical trial population similarto that in the gabapentin program, to 0.005 forpatients with refractory epilepsy). Consequently, whetherthese figures are reassuringor raise further concern depends on comparabilityofthe populations reported upon to the gabapentin cohort and the accuracy ofthe estimatesprovided.

Laboratory Tests

Clinical trials datado not indicatethat routinemonitoringof clinical laboratoryparameters is necessary forthe safeuseof gabapentin. The valueofmonitoring gabapentin blood concentrations has not been established. Gabapentin maybeused in combination with other antiepilepticdrugs without concern for alterationoftheblood concentrations ofgabapentin or of other antiepilepticdrugs.

Adverse Reactions

The following serious adverse reactions arediscussed in greaterdetail in othersections:

DrugReaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity[see Warnings and Precautions (5.1)]
Somnolence/Sedation and Dizziness [see Warnings and Precautions (5.3)]
Withdrawal PrecipitatedSeizure, Status Epilepticus [see Warnings and Precautions (5.4)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
Neuropsychiatric AdverseReactions (PediatricPatients 3 to 12 Years of Age)[see Warnings and Precautions (5.5)]
Sudden and Unexplained Death in Patients with Epilepsy[see Warnings and Precautions (5.8)]

Clinical Trials Experience

Because clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in the clinical trials ofadrug cannot be directly compared to ratesin the clinical trials of anotherdrug and maynot reflect the rates observed in practice.

Postherpetic Neuralgia

Themost commonlyobserved adverse reactions associated with theuseof gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, weredizziness, somnolence, and peripheral edema.

In the2 controlled studies in postherpeticneuralgia, 16%ofthe336 patients who received gabapentin and 9%ofthe227 patients who received placebo discontinued treatment because of an adverse reaction. The adverse reactions thatmost frequently led to withdrawal in gabapentin-treated patients weredizziness, somnolence, and nausea.

IncidenceinControlled Clinical Trials

Table3 lists treatment-emergent signs and symptoms that occurred in at least 1%of gabapentin-treated patients with postherpeticneuralgiaparticipatinginplacebo-controlled trials and that werenumericallymore frequent in the gabapentin group than in theplacebo group. Adverse reactions wereusuallymild to moderatein intensity.

Table 3: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Postherpetic Neuralgia (Reactions in at least 1% of Gabapentin-Treated Patients and Numerically More Frequent Than in the Placebo Group)
*
Reported as blurred vision

Body System/

Preferred Term

Gabapentin

N=336

%

Placebo

N=227

%

Body as a Whole

Asthenia

6

5

Infection

5

4

Accidental injury

3

1

Digestive System

Diarrhea

6

3

Dry mouth

5

1

Constipation

4

2

Nausea

4

3

Vomiting

3

2

Metabolic and Nutritional Disorders

Peripheral edema

8

2

Weight gain

2

0

Hyperglycemia

1

0

Nervous System

Dizziness

28

8

Somnolence

21

5

Ataxia

3

0

Thinking abnormal

3

0

Abnormal gait

2

0

Incoordination

2

0

Respiratory System

Pharyngitis

1

0

Special Senses

Amblyopia*

3

1

Conjunctivitis

1

0

Diplopia

1

0

Otitis media

1

0

Other reactions in more than 1%ofpatients but equallyormore frequent intheplacebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.

There wereno clinicallyimportant differences between men and women inthe types and incidenceof adverse reactions. Becausethere were fewpatients whose race was reported as other than white, there areinsufficient datato supportastatement regardingthe distribution of adverse reactions by race.

 
Epilepsy

Themost commonlyobserved adverse reactions associated with theuseof gabapentin in combination with other antiepilepticdrugs in patients >12 years of age, notseen at an equivalent frequency amongplacebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. Themost commonlyobserved adverse reactions reported with theuseof gabapentin in combination with other antiepilepticdrugs in pediatricpatients 3 to 12 years of age, not seen at an equal frequency amongplacebo-treated patients, were viral infection, fever, nausea and/orvomiting,somnolence, and hostility[see Warnings and Precautions (5.4)].

Approximately 7%ofthe2074 patients >12 years of age and approximately7%ofthe449 pediatricpatients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with withdrawal in patients >12 years of age weresomnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/orvomiting (0.6%), and dizziness (0.6%). The adverse reactions most commonly associated with withdrawal in pediatricpatients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).

Incidencein Controlled AdjunctiveClinical Trials

Table4 lists treatment-emergent signs and symptoms that occurred in at least 1%of gabapentin-treated patients >12 years of age with epilepsy participating in placebo-controlled trials and werenumericallymore common in the gabapentin group. Inthesestudies, either gabapentin orplacebo was added to the patient’s current antiepilepticdrugtherapy. Adverse reactions wereusually mild to moderatein intensity.

Table : Treatment-Emergent Adverse Reaction Incidence in Controlled Add-On Trials In Patients >12 years of age (Reactions in at least 1% of gabapentin patients and numerically more frequent than in the placebo group)

*
Plus backgroundantiepileptic drug therapy
Amblyopia was often describedas blurred vision.

Body System/

Adverse Reaction

Gabapentin*

N=543

%

Placebo*

N=378

%

Body As A Whole

Fatigue

11

5

Weight Increase

3

2

Back Pain

2

1

Peripheral Edema

2

1

Cardiovascular

Vasodilatation

1

0

Digestive System

Dyspepsia

2

1

Mouth or Throat Dry

2

1

Constipation

2

1

Dental Abnormalities

2

0

Nervous System

Somnolence

19

9

Dizziness

17

7

Ataxia

13

6

Nystagmus

8

4

Tremor

7

3

Dysarthria

2

1

Amnesia

2

0

Depression

2

1

Thinking Abnormal

2

1

Coordination Abnormal

1

0

Respiratory System

Pharyngitis

3

2

Coughing

2

1

Skin and Appendages

Abrasion

1

0

Urogenital System

Impotence

2

1

Special Senses

Diplopia

6

2

Amblyopia

4

1

Theoverall incidence of adverse reactions and the types of adverse reactions seen weresimilaramongmen and women treated with gabapentin. Theincidenceof adverse reactions increased slightly with increasing agein patients treated with either gabapentin orplacebo. Becauseonly3% ofpatients (28/921)in placebo-controlled studies wereidentified as nonwhite (black orother), there areinsufficient datato support astatement regarding thedistribution of adverse reactions by race.

Table5 lists treatment-emergent signs and symptoms that occurred in at least 2%of gabapentin-treated patients, age3 to 12 years of age with epilepsy participatingin placebo-controlled trials, and which werenumericallymore common in the gabapentin group. Adverse reactions were usuallymild to moderate in intensity.

Table 5: Treatment-Emergent Adverse Reaction Incidence in Pediatric Patients Age 3 to 12 Years in a Controlled Add-On Trial (Reactions in at least 2% of gabapentin patients and numerically more frequent than in the placebo group)
*
Plus background antiepileptic drug therapy

Body System/

Adverse Reaction

Gabapentina*

N=119

%

Placeboa*

N=128

%

Body As A Whole

Viral Infection

11

3

Fever

10

3

Weight Increase

3

1

Fatigue

3

2

Digestive System

Nausea and/or Vomiting

8

7

Nervous System

Somnolence

8

5

Hostility

8

2

Emotional Lability

4

2

Dizziness

3

2

Hyperkinesia

3

1

Respiratory System

Bronchitis

3

1

Respiratory Infection

3

1

Other reactions in more than 2%ofpediatricpatients 3 to 12 years of age but equallyormore frequent in theplacebogroup included: pharyngitis, upper respiratoryinfection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of gabapentin.Becausethese reactions are reportedvoluntarily froma populationofuncertain size, it is not always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure.

General disorders and administration site conditions: fever

Hepatobiliarydisorders: jaundice

Investigations: blood glucose fluctuation, elevated creatinekinase, elevatedliver function tests

Metabolism and nutrition disorders: hyponatremia

Nervous system disorders: movement disorder

Musculoskeletal and connectivetissuedisorders: rhabdomyolysis

Reproductive system andbreast disorders: breast enlargement

Skin andsubcutaneoustissuedisorders: angioedema, erythemamultiforme,Stevens-Johnson syndrome.

Adverse reactions followingthe abruptdiscontinuationof gabapentinhave alsobeen reported. Themost frequently reported reactions were anxiety, insomnia, nausea, pain, and sweating.

Drug Interactions

Other Antiepileptic Drugs

Gabapentin is not appreciablymetabolized nordoes it interfere with themetabolism of commonly coadministered antiepilepticdrugs [seeClinical Pharmacology (12.3)].

Hydrocodone

Coadministration of gabapentin (125 to 500mg)decreases hydrocodoneCmaxand AUC values in adose-dependent manner. TheCmaxand AUC values are3%to 4%lower, respectively, after administration of125 mg gabapentinand 21%to 22%lower, respectively, after administration of500 mg gabapentin . Hydrocodoneincreases gabapentin AUC values by 14%[seeClinical Pharmacology (12.3)].

Morphine

Aliterature article reported that when a60 mg controlled-releasemorphine capsule wasadministered 2 hours priorto a600 mg gabapentin capsule (N=12), mean gabapentin AUC increased by44% compared to gabapentin administered without morphine[see Patient Counseling Information (17)]. Morphinepharmacokineticparametervalues werenot affected by administration of gabapentin 2 hours aftermorphine. Themagnitudeofinteraction at other doses is not known.

Maalox®(aluminumhydroxide, magnesiumhydroxide)

Themean bioavailabilityofgabapentin was reduced by about 20% with concomitant useof an antacid (Maalox®) containingmagnesium and aluminum hydroxides. It is recommended that gabapentin betaken at least 2 hours following Maalox administration [seeClinical Pharmacology (12.3)].

Drug/Laboratory Test Interactions

Because falsepositive readings were reported with the Ames N-Multistix SG®dipstick test for urinaryprotein when gabapentin was added to other antiepilepticdrugs, themorespecific sulfosalicylic acid precipitation procedureis recommended to determine thepresenceof urine protein.

USE IN SPECIFIC POPULATIONS

Pregnancy

PregnancyCategoryC: There areno adequate and well-controlled studies inpregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentallytoxic when administered to pregnant animals at doses similarto orlowerthan thoseused clinically. Gabapentin should beused during pregnancy onlyifthepotential benefit justifies the potential risk to the fetus.

When pregnant mice received oral doses of gabapentin (500, 1000, or3000mg/kg/day)during theperiod oforganogenesis, embryo-fetal toxicity (increased incidences ofskeletal variations) was observed at thetwohighest doses. Theno-effectdose for embryo-fetal developmental toxicityin mice was 500mg/kg/dayor approximately½ ofthemaximum recommended human dose (MRHD)of3600 mg/kgon abodysurface area (mg/m2)basis.

In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day), during pregnancy, adverse effect on offspring development (increased incidencesof hydroureter and/or hydronephrosis) wereobserved at all doses. The lowest effect dose fordevelopmental toxicityin ratsis approximately equal to theMRHDon amg/m2basis.

When pregnant rabbits weretreated with gabapentin duringtheperiod oforganogenesis, an increasein embryo-fetalmortality was observed at all doses tested (60, 300, or1500 mg/kg). The lowest effect dose for embryo-fetal developmentaltoxicityin rabbits is less than theMRHDon a mg/m2basis.

Inapublished study,gabapentin (400 mg/kg/day) was administered byintraperitoneal injection to neonatal miceduringthe first postnatal week, a period of synaptogenesis in rodents (correspondingto the last trimesterofpregnancy in humans). Gabapentin caused amarked decreasein neuronal synapse formation in brains ofintact mice and abnormal neuronal synapse formation in amousemodel of synaptic repair. Gabapentin has been shownin vitro to interfere with activityofthe α2δ subunit ofvoltage-activated calcium channels, a receptorinvolved in neuronal synaptogenesis. The clinical significanceofthese findings is unknown.

To provideinformation regardingthe effects ofinutero exposureto gabapentin, physicians are advised to recommend that pregnant patients taking gabapentin enroll in the North American Antiepileptic Drug (NAAED)PregnancyRegistry. This can bedone by callingthetoll freenumber1-888-233-2334, and must bedone bypatients themselves. Information on the registry can also be found at the websitehttp://www.aedpregnancyregistry.org/.

Nursing Mothers

Gabapentin is secreted into human milk followingoral administration. Anursed infant could be exposed to amaximum doseof approximately1 mg/kg/dayofgabapentin. Becausethe effect on thenursinginfant is unknown, gabapentin should beused in women who arenursingonlyif thebenefits clearlyoutweigh the risks.

Pediatric Use

Safety and effectivenessof gabapentin in themanagement ofpostherpeticneuralgiain pediatricpatients have not been established.

Effectiveness as adjunctivetherapyin thetreatment ofpartial seizures in pediatricpatients below the ageof3 years has not been established [seeClinical Studies (14.2)].

Geriatric Use

Thetotal numberofpatients treated with gabapentin in controlled clinical trials in patients with postherpeticneuralgia was 336, of which 102 (30%) were65 to 74 years of age, and 168 (50%) were75 years of age and older. There wasalargertreatment effect in patients 75 years of age and older compared with youngerpatients who received thesamedosage. Since gabapentin is almost exclusively eliminated by renal excretion, thelargertreatment effect observed in patients ≥75 years may bea consequenceofincreased gabapentin exposure fora given dosethat results from an age-related decreasein renal function. However, other factors cannot be excluded. The types andincidenceof adverse reactions weresimilar across age groups except for peripheral edema and ataxia, which tended to increasein incidence with age.

Clinical studies of gabapentin in epilepsydidnot includesufficient numbers ofsubjects aged 65 and overto determine whetherthey respondeddifferently from youngersubjects. Other reported clinical experiencehas not identified differences in responses between the elderly and youngerpatients. In general, doseselection for an elderlypatient should be cautious, usually starting at thelow end ofthedosing range, reflectingthe greater frequencyofdecreased hepatic, renal, or cardiac function, and of concomitant diseaseorother drugtherapy.

This drugis known to besubstantially excreted bythekidney, and the risk oftoxic reactions to this drugmaybegreaterin patients with impaired renal function. Because elderly patients are morelikelyto havedecreased renal function, careshould betaken in dose selection, and dose should be adjusted basedon creatinine clearance values in thesepatients [see Dosageand Administration (2.4), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

Renal Impairment

Dosage adjustment in adult patients with compromised renal function is necessary[see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)]. Pediatricpatients with renal insufficiencyhavenot been studied.

Dosage adjustment in patients undergoing hemodialysis is necessary[see Dosageand Administration (2.3)andClinical Pharmacology (12.3)].

Drug Abuse and Dependence

Controlled Substance

Gabapentin is not ascheduled drug.

Abuse

Gabapentin does not exhibit affinity forbenzodiazepine, opiate (mu, delta orkappa), or cannabinoid 1 receptorsites. Asmall numberof postmarketing cases report gabapentin misuse and abuse. Theseindividuals were takinghigher than recommended dosesofgabapentin for unapproved uses. Most oftheindividuals described in these reports hada historyofpoly-substance abuseorused gabapentin to relieve symptoms of withdrawal from othersubstances. When prescribing gabapentin carefully evaluatepatients forahistory ofdrug abuse and observe them forsigns and symptoms of gabapentin misuseor abuse (e.g. development oftolerance, self-dose escalation, and drug-seekingbehavior).

Dependence

There are rarepostmarketing reports ofindividuals experiencing withdrawal symptoms shortly afterdiscontinuinghigherthan recommended doses of gabapentin used to treat illnesses for which thedrugis not approved. Such symptoms included agitation, disorientation and confusion aftersuddenlydiscontinuing gabapentin that resolved after restarting gabapentin. Most ofthese individuals had ahistoryofpoly-substance abuseorused gabapentin to relieve symptoms of withdrawal from othersubstances. The dependence and abuse potential of gabapentin has not been evaluated in humanstudies.

Overdosage

Alethaldoseof gabapentin wasnotidentified inmice and rats receivingsingleoraldoses as high as8000 mg/kg.Signsof acutetoxicity in animalsincluded ataxia,laboredbreathing,ptosis, sedation, hypoactivity, or excitation.

Acuteoraloverdosesof gabapentin upto49gramshavebeen reported. Inthese cases,double vision,slurredspeech,drowsiness,lethargy anddiarrhea, wereobserved. Allpatients recovered with supportive care.

Gabapentin canbe removed by hemodialysis. Althoughhemodialysishasnotbeenperformedin the fewoverdose cases reported,itmaybeindicated bythepatient’s clinicalstateorinpatients with significant renal impairment.

Ifoverexposureoccurs, call yourpoison control center at 1-800-222-1222.

Gabapentin Tablets Description

Gabapentin Tablets USP are an anticonvulsant for oral administration. Gabapentin, USP is described as 1-(aminomethyl)cyclohexaneacetic acid. Gabapentin, USP 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. The structural formula of gabapentin, USP is:

C9H17NO2 M.W. 171.24

Each Gabapentin Tablet USP, for oral administration, contains 600 mg or 800 mg of gabapentin, USP and contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose and polyethylene glycol.

Gabapentin Tablets - Clinical Pharmacology

Mechanism of Action

Theprecisemechanisms by whichgabapentin produces its analgesic and antiepileptic actions are unknown.

In animal models of analgesia,gabapentin prevents allodynia (pain-relatedbehaviorin response to anormallyinnocuousstimulus) and hyperalgesia (exaggerated responseto painful stimuli). Gabapentin prevents pain-related responses in several models ofneuropathicpain in rats and mice (e.g., spinal nerveligation models, spinal cord injurymodel, acuteherpes zosterinfection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, latephaseof formalin test), but does not alterimmediatepain-related behaviors (rat tail flick test, formalin footpad acutephase). The relevance ofthesemodels to human pain is not known.

Gabapentin exhibits antiseizure activityin mice and rats in both themaximal electroshock and pentylenetetrazoleseizuremodels and otherpreclinical models (e.g., strains with genetic epilepsy, etc.). The relevanceofthesemodels to human epilepsyis not known.

Gabapentin is structurally related to theneurotransmitter gamma-aminobutyric acid (GABA)but has no effect on GABA binding, uptakeor degradation. Gabapentin did not exhibit affinity fora numberofother common receptorion channel, ortransporterproteins. In vitro studies have shown that gabapentin binds with high-affinitytothe α2δsubunit ofvoltage-activated calcium channels; however, the relationship ofthis bindingto thetherapeutic effectsofgabapentin is unknown.

Pharmacokinetics

All pharmacological actions following gabapentin administration areduetothe activityofthe parent compound; gabapentin is not appreciablymetabolized in humans.

Oral Bioavailability

Gabapentin bioavailabilityis not doseproportional; i.e., as doseis increased, bioavailability decreases. Bioavailabilityofgabapentin is approximately60%, 47%, 34%,33%, and 27% following900, 1200, 2400, 3600, and 4800 mg/daygiven in 3 divided doses, respectively. Food has onlyaslight effect on the rate and extent of absorption ofgabapentin (14%increasein AUC and Cmax).

Distribution

Less than3%ofgabapentin circulates bound to plasmaprotein. The apparent volumeof distribution of gabapentin after150 mgintravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations ofgabapentin in cerebrospinal fluid were approximately20%ofthe correspondingplasma concentrations.

Elimination

Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciablymetabolized in humans.

Gabapentin elimination half-lifeis 5 to 7 hours and is unaltered bydoseor followingmultiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance aredirectly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearanceis reduced. Gabapentin can be removed from plasma by hemodialysis.

 
Special Populations

Adult Patients WithRenal Insufficiency

Subjects (N=60) with renal insufficiency (mean creatinine clearance ranging from 13 to 114 mL/min) were administered single400 mgoral 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 about10 mL/min (<30 mL/min). Mean plasma clearance (CL/F)decreased from approximately190 mL/min to 20 mL/min.

 
Dosage adjustment in adult patients with compromised renal function is necessary[see Dosage and Administration (2.3)and Usein Specific Populations (8.6)].Pediatricpatients with renal insufficiencyhavenot been studied.

Hemodialysis

Inastudyin anuric adultsubjects (N=11), the apparent elimination half-lifeof gabapentin on nondialysis days was about 132 hours; duringdialysis the apparent half-lifeofgabapentin was reduced to 3.8 hours. Hemodialysis thus has asignificant effect on gabapentin elimination in anuricsubjects.

Dosage adjustment in patients undergoing hemodialysis is necessary[see Dosageand Administration (2.3)and Usein Specific Populations (8.6)].

Hepatic Disease

Becausegabapentin is not metabolized, no study was performed in patients with hepatic impairment.

Age

The effect of age was studied in subjects 20 to 80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as ageincreased, from about 225 mL/min in thoseunder30 years of ageto about 125 mL/min in thoseover70 years of age.Renal clearance (CLr) and CLr adjusted for bodysurface area also declined with age; however, thedeclinein the renal clearance of gabapentin with age can largelybe explained bythedeclinein renal function. Reduction of gabapentin dosemay be required in patients who have age related compromised renal function. [see Dosageand Administration (2.3)and UseinSpecific Populations (8.4)]

Pediatric

Gabapentin pharmacokinetics weredetermined in48 pediatricsubjects between the ages of1 month and 12 years followingadoseof approximately10 mg/kg. Peak plasma concentrations weresimilar across the entire age group and occurred 2 to 3 hours postdose. Ingeneral, pediatric subjects between 1 month and <5 years of age achieved approximately30%lower exposure (AUC)than that observed in those5 years of age and older. Accordingly,oral clearance normalized perbody weight was higherin the younger children. Apparent oral clearanceof gabapentin was directlyproportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the agegroups studied.

Apopulation pharmacokinetic analysis was performed in 253 pediatricsubjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given threetimes aday. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar followingasingledose and at steadystate. Higheroral clearance values wereobserved in children <5 years of age compared to thoseobserved in children 5 years of age and older, when normalized perbody weight. The clearance was highlyvariablein infants <1 yearof age. The normalized CL/Fvaluesobserved in pediatricpatients 5 years of age and older were consistent with values observed in adults afterasingledose. Theoral volumeofdistribution normalized per body weight was constant across the age range.

Thesepharmacokinetic dataindicatethat the effectivedailydosein pediatricpatients with epilepsy ages 3 and 4 years should be40 mg/kg/dayto achieve averageplasma concentrations similarto those achievedin patients 5 years of age and older receiving gabapentin at 30 mg/kg/day[see Dosageand Administration (2.2)].

Gender

Although no formal studyhas been conducted to comparethepharmacokinetics of gabapentin in men and women, it appears that thepharmacokineticparameters formales and females are similar and there areno significantgenderdifferences.

Race

Pharmacokineticdifferences dueto race havenotbeen studied. Because gabapentin is primarily renally excreted and there areno important racial differences in creatinine clearance, pharmacokineticdifferences dueto race arenot expected.

Drug Interactions

 
In Vitro Studies

In vitro studies were conducted to investigatethepotential ofgabapentin to inhibit themajor cytochromeP450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19,CYP2D6, CYP2E1, and CYP3A4)that mediate drug and xenobioticmetabolism usingisoform selectivemarker substrates and human livermicrosomal preparations. Only at thehighest concentration tested (171 mcg/mL; 1 mM) was aslight degreeofinhibition (14% to 30%)ofisoform CYP2A6 observed. No inhibition of anyoftheotherisoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately15 times theCmaxat 3600 mg/day).

In Vivo Studies

Thedruginteraction datadescribed in this section wereobtained from studies involvinghealthy adults and adult patients with epilepsy.

Phenytoin

Inasingle (400 mg) andmultipledose (400 mgthreetimes a day)studyof gabapentin in epilepticpatients (N=8)maintained on phenytoin monotherapy for at least2 months, gabapentin had no effect on thesteady-statetrough plasma concentrations ofphenytoin and phenytoin had no effect on gabapentin pharmacokinetics.

Carbamazepine

Steady-statetrough plasma carbamazepine and carbamazepine10, 11 epoxide concentrations werenot affected by concomitant gabapentin (400mgthreetimes aday; N=12) administration. Likewise, gabapentin pharmacokinetics wereunaltered by carbamazepine administration.

Valproic Acid

Themean steady-statetrough serum valproic acid concentrations priorto and during concomitant gabapentin administration (400 mgthreetimes a day; N=17) werenot different and neither were gabapentin pharmacokineticparameters affected byvalproic acid.

Phenobarbital

Estimates ofsteady-statepharmacokinetic parameters forphenobarbital orgabapentin (300 mg threetimes aday; N=12) areidentical whetherthedrugs are administered aloneortogether.

Naproxen

Coadministration (N=18)ofnaproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increasethe amount of gabapentin absorbed by12%to 15%. Gabapentin had no effect on naproxen pharmacokineticparameters. These doses arelowerthan thetherapeuticdoses for both drugs. Themagnitudeofinteraction within the recommended dose ranges of either drugis not known.

Hydrocodone

Coadministration of gabapentin (125 to 500mg; N=48)decreases hydrocodone (10 mg; N=50)Cmaxand AUC values in adose-dependentmanner relativeto administration of hydrocodone alone; Cmaxand AUC values are3% to 4%lower, respectively, after administration of125 mg gabapentin and 21%to 22%lower, respectively, after administration of500 mg gabapentin. Themechanism forthis interaction is unknown. Hydrocodoneincreases gabapentin AUC values by14%. Themagnitudeofinteraction at otherdoses is not known.

Morphine

Aliterature article reported that when a60 mg controlled-releasemorphine capsule was administered 2 hours priorto a600 mg gabapentin capsule (N=12), mean gabapentin AUC increased by44% compared to gabapentin administered without morphine.Morphine pharmacokinetic parametervalues werenot affected by administration of gabapentin 2 hours aftermorphine. Themagnitudeofinteraction at otherdoses is not known.

Cimetidine

In the presence of cimetidine at 300 mg QID (N=12), themean apparent oral clearanceof gabapentin fell by14% and creatinine clearance fell by10%. Thus, cimetidine appeared to alter the renal excretion ofboth gabapentin and creatinine, an endogenous markerof renal function. This small decreasein excretion of gabapentin by cimetidineis not expected to beof clinical importance. The effect of gabapentin on cimetidine was not evaluated.

Oral Contraceptive

Based on AUC and half-life, multiple-dosepharmacokineticprofiles ofnorethindrone and ethinyl estradiol following administration oftablets containing2.5 mgofnorethindrone acetate and 50 mcgof ethinyl estradiol weresimilar with and without coadministration of gabapentin (400 mgthreetimes aday; N=13). TheCmaxofnorethindrone was 13%higher when it was coadministered with gabapentin; this interaction is not expected to beof clinical importance.

Antacid (Maalox®)(aluminumhydroxide, magnesiumhydroxide)

Antacid (Maalox®) containingmagnesium and aluminum hydroxides reduced themean bioavailabilityof gabapentin (N=16) by about 20%. This decreasein bioavailability was about 10% when gabapentin was administered 2 hours afterMaalox. It is recommended that gabapentin betaken at least 2 hours following Maalox administration.

Probenecid

Probenecid is ablocker of renal tubular secretion. Gabapentin pharmacokineticparameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubularsecretion bythepathwaythat is blocked by probenecid.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gabapentin was administered orallyto mice and rats in 2-year carcinogenicitystudies. No evidence ofdrug-related carcinogenicity was observed in micetreated at doses up to 2000 mg/kg/day. At 2000 mg/kg, theplasmagabapentin exposure (AUC)in miceis approximately2 times that in humans at theMRHDof3600 mg/day. In rats, increases in theincidenceof pancreatic acinar cell adenoma and carcinoma were found in male rats receivingthehighest dose (2000 mg/kg), but not atdoses of250 or1000 mg/kg/day. At 1000 mg/kg, theplasma gabapentin exposure (AUC)in rats is approximately5 times that in humans at theMRHD.

Studies designed to investigatethemechanism of gabapentin-induced pancreatic carcinogenesis in rats indicatethat gabapentin stimulates DNAsynthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as atumorpromoter by enhancingmitogenic activity. It is not known whether gabapentin has the abilityto increase cellproliferation in other cell types orin other species, includinghumans.

Gabapentin did not demonstratemutagenicorgenotoxicpotential inthreein vitro and fourin vivo assays. It was negativein the Ames test and thein vitro HGPRT forward mutation assayin Chinesehamsterlung cells; it did not producesignificant increases in chromosomal aberrations in thein vitro Chinesehamsterlung cell assay; it was negativein thein vivo chromosomal aberration assay and in thein vivo micronucleus test in Chinesehamsterbonemarrow; it was negativein thein vivo mousemicronucleus assay; and it did not induceunscheduled DNA synthesis in hepatocytes from rats given gabapentin.

No adverse effects on fertilityor reproduction wereobserved in rats at doses up to 2000 mg/kg. At 2000 mg/kg, theplasmagabapentin exposure (AUC)in rats is approximately8 times that in humans at theMRHD.

Clinical Studies

Postherpetic Neuralgia

Gabapentin was evaluated forthe management ofpostherpeticneuralgia (PHN)in tworandomized, double-blind, placebo-controlled, multicenterstudies. Theintent-to-treat (ITT) population consisted ofatotal of563 patients with pain formorethan 3 months afterhealing of theherpes zosterskin rash (Table6).

Table 6: Controlled PHN Studies: Duration, Dosages, and Number of Patients
*
Given in 3 divided doses (TID)

Study

Study Duration

Gabapentin (mg/day)*Target Dose

 
Patients Receiving Gabapentin

Patients ReceivingPlacebo

1

8 weeks

3600

113

116

2

7 weeks

1800, 2400

223

111

Total

336

227

Each studyincluded a 7-or8-week double-blind phase (3 or4 weeks oftitration and 4 weeks of fixed dose). Patients initiated treatment with titration to amaximum of900mg/day gabapentin over3 days. Dosages werethen to betitrated in 600 to 1200 mg/dayincrements at 3-to 7-day intervals to thetarget doseover3 to 4 weeks. Patients recorded their pain in adailydiaryusing an 11-point numericpain rating scale ranging from 0 (no pain)to 10 (worst possiblepain). A mean pain scoreduring baselineof at least 4 was required for randomization. Analyses were conducted usingthe ITTpopulation (all randomized patients who received at least onedoseof studymedication).

Both studies demonstrated efficacy compared to placebo at all doses tested.

The reduction in weeklymean pain scores was seen by Week 1 in both studies, and were maintained to the end oftreatment. Comparabletreatment effects wereobserved in all active treatment arms. Pharmacokinetic/pharmacodynamicmodelingprovided confirmatory evidence of efficacy across all doses. Figures 1 and 2 showpain intensityscores overtime forStudies 1 and 2.

Figure1. WeeklyMeanPain Scores (Observed Cases in ITTPopulation): Study1

Figure2. WeeklyMeanPain Scores (Observed Cases in ITTPopulation): Study2

Theproportion of responders (thosepatients reporting at least 50%improvement in endpoint pain score compared with baseline) was calculated for each study (Figure3).

 
Figure3. Proportion of Responders (patients with ≥50% reduction in pain score) at Endpoint: Controlled PHNStudies

Epilepsy

The effectiveness of gabapentin as adjunctivetherapy (added to other antiepilepticdrugs) was established in multicenterplacebo-controlled,double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures.

Evidenceof effectiveness was obtained in three trials conducted in 705 patients (age12 years and above) and onetrial conducted in 247 pediatricpatients (3 to 12 yearsof age). Thepatients enrolled had ahistory of at least 4 partial seizurespermonth in spiteof receivingone ormore antiepilepticdrugs at therapeuticlevels and were observed on their established antiepilepticdrug regimen duringa12-week baselineperiod (6 weeks in thestudyofpediatricpatients). In patients continuingto have at least 2 (or4 in somestudies)seizures permonth, gabapentin orplacebo was then added on to the existingtherapyduringa12-week treatment period. Effectiveness was assessed primarilyon thebasis ofthepercent of patients with a50%or greater reduction in seizure frequency from baselineto treatment (the “responder rate”) and a derived measure called response ratio, ameasureof change defined as (T- B)/(T+ B), in whichB is thepatient’s baselineseizure frequency and Tis the patient’s seizure frequencyduringtreatment. Response ratio is distributed withinthe range -1 to +1. A zero valueindicates no change while complete elimination ofseizures would givea valueof -1; increased seizure rates would givepositive values. A response ratioof -0.33 corresponds to a50% reduction in seizure frequency. The results given below are for all partial seizures in theintent-to-treat (all patients who received any doses oftreatment)population in each study, unless otherwiseindicated.

Onestudy compared gabapentin 1200 mg/day, in threedivided doses, with placebo. Responder rate was 23% (14/61)in the gabapentin group and 9% (6/66)in theplacebo group; thedifference between groups was statisticallysignificant. Response ratio was also betterin the gabapentin group (-0.199)than in theplacebo group (-0.044),adifferencethat also achieved statistical significance.

Asecond study compared primarily gabapentin 1200 mg/day, in threedivided doses (N=101), with placebo (N=98). Additional smaller gabapentin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were also studied forinformation regardingdose response. Responder rate was higherin the gabapentin 1200 mg/day group (16%)than in theplacebo group (8%), but thedifference was not statisticallysignificant. The responder rate at 600 mg (17%) was also not significantlyhigherthan in theplacebo, but the responder ratein the1800 mg group (26%) was statisticallysignificantlysuperiorto theplacebo rate.Response ratio was betterin the gabapentin 1200 mg/daygroup (-0.103)than in theplacebo group (-0.022); but this difference was also not statisticallysignificant (p =0.224). A better response was seen in the gabapentin 600 mg/daygroup (-0.105) and 1800 mg/day group (-0.222)than in the1200 mg/day group, with the1800 mg/day group achievingstatistical significance compared to the placebo group.

Athird study compared gabapentin 900 mg/day, in threedivided doses (N=111), and placebo (N=109). An additional gabapentin 1200 mg/daydosage group (N=52)provided dose-responsedata.Astatisticallysignificant differencein responder rate was seen in the gabapentin 900 mg/daygroup (22%) compared to that in theplacebo group (10%). Response ratio was also statisticallysignificantlysuperiorin the gabapentin 900mg/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 studyto examinethe effect of gabapentin on preventingsecondarilygeneralized tonic-clonic seizures. Patients who experiencedasecondarily generalized tonic-clonicseizurein eitherthebaselineorin thetreatment period in all three placebo-controlled studies wereincluded in these analyses. There were several response ratio comparisons that showedastatisticallysignificant advantage for gabapentin compared to placebo and favorabletrends for almost all comparisons.

Analysis of responder rateusing combined data from all threestudies and all doses (N=162, gabapentin; N=89, placebo) also showedasignificant advantage for gabapentin over placebo in reducingthe frequency ofsecondarily generalized tonic-clonicseizures.

In two ofthethree controlled studies, morethan onedoseof gabapentin was used. Within each study, the results did not showa consistentlyincreased responseto dose. However, looking across studies, atrend toward increasing efficacy with increasingdoseis evident (see Figure4).

Figure4. ResponderRatein Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive TherapyStudies in Patients ≥12 Years of Age with Partial Seizures

In the figure, treatment effect magnitude, measured on theY axis in termsofthedifferencein the proportion of gabapentin and placebo-assigned patients attaininga50%or greater reduction in seizure frequency from baseline, is plotted against thedailydose of gabapentin administered (X axis).

Although no formal analysis by genderhas beenperformed, estimates of response (Response Ratio)derived from clinical trials (398 men, 307 women)indicateno important gender differences exist. There was no consistent patternindicatingthat agehad any effect on the responseto gabapentin. There wereinsufficient numbers ofpatients of races otherthan Caucasian to permit a comparison of efficacy among racial groups.

A fourth studyin pediatricpatients age3 to 12 years compared 25 to35 mg/kg/day gabapentin(N=118) with placebo (N=127). For all partial seizures in theintent-to-treat population, the response ratio was statisticallysignificantlybetter forthe gabapentin group (-0.146)than for theplacebo group (-0.079). Forthe samepopulation, the responder rate for gabapentin (21%) was not significantlydifferent from placebo (18%).

Astudyin pediatricpatients age1 month to 3 years compared 40 mg/kg/day gabapentin(N=38) with placebo (N=38)in patients who were receiving at least onemarketed antiepileptic drug and had at least onepartial seizureduringthescreening period (within2 weeks priorto baseline). Patients had upto 48 hours ofbaseline and up to 72 hours ofdouble-blind video EEG monitoringto record and count theoccurrenceof seizures. There wereno statisticallysignificant differences between treatments in eitherthe response ratio or responder rate.

How Supplied/Storage and Handling

Gabapentin Tablets USP, 600 mg are available as white, oval shaped tablets, debossed “4443”, with a partial score on one side and “600” on the other side containing 600 mg gabapentin, USP.

NDC 0093-4443-01 600 mg packaged in bottles of 100 tablets

NDC 0093-4443-05 600 mg packaged in bottles of 500 tablets

NDC 0093-4443-10 600 mg packaged in bottles of 1000 tablets

Gabapentin Tablets USP, 800 mg are available as white, oval shaped tablets, debossed “4444”, with a partial score on one side and “800” on the other side containing 800 mg gabapentin, USP.

NDC 0093-4444-01 800 mg packaged in bottles of 100 tablets

NDC 0093-4444-05 800 mg packaged in bottles of 500 tablets

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Medication Guide

Inform patients ofthe availabilityofa Medication Guide, and instruct themto read the Medication Guideprior to taking gabapentin. Instruct patients to take gabapentin only as prescribed.

Drug Reaction with Eosinophilia and SystemicSymptoms (DRESS)/Multiorgan Hypersensitivity

Priorto initiation oftreatment with gabapentin, instruct patients that a rash orothersigns or symptoms of hypersensitivity (such as feveror lymphadenopathy)may herald aserious medical event and that the patient should report anysuch occurrenceto aphysician immediately[see Warnings and Precautions (5.1)].

Effects on Driving andOperating Heavy Machinery

Inform patients that gabapentin may causeasignificant drivingimpairment. Accordingly, advisethem not to drivea caruntil theyhave gained sufficient experienceon gabapentin to assess whether gabapentin impairs their abilityto drive, although patients’ abilityto determinetheirlevel of impairment can beunreliable. Inform patients that it is not known how longthis effect lasts. Theyshould betold thesamething regardingtheoperation ofheavy machinery.

Dizziness and Somnolence

Advisepatients that gabapentin may causedizziness, somnolence, andother symptoms and signs ofCNS depression. Accordingly, advisethem neitherto drivea car norto operateother complexmachineryuntilthey have gained sufficient experienceon gabapentin to gauge whetherornot it affects theirmental and/ormotorperformance adversely.

SuicidalThinking andBehavior

Patients, their caregivers, and families should be counseled that AEDs, including gabapentin, mayincreasethe risk of suicidal thoughts and behavior and should be advised oftheneed to be alert forthe emergence or worseningof symptoms ofdepression, anyunusual changes in mood orbehavior, orthe emergenceofsuicidal thoughts,behavior, orthoughts about self-harm. Report behaviors of concern immediatelyto healthcare providers [see Warnings and Precautions (5.3)].

Usein Pregnancy

Instruct patients to notifytheirphysician iftheybecomepregnant orintendto becomepregnant duringtherapy, and to notifytheirphysician ifthey arebreast feedingorintend to breast feed duringtherapy[see Use in Specific Populations (8.1)and (8.3)].

Encouragepatients to enroll in the NAAEDPregnancyRegistryiftheybecomepregnant. This registryis collectinginformation about thesafetyof antiepilepticdrugs duringpregnancy. To enroll, patients can call thetoll freenumber1-888-233-2334 [see Usein Specific Populations (8.1)].

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. L 10/2014

MEDICATION GUIDE

GABAPENTIN (GA-ba-PEN'-tin) TABLETS USP

 
Read theMedication Guidebefore you start taking Gabapentin Tablets and eachtime you get a refill. Theremay benewinformation. This information does not taketheplace oftalkingto your healthcareprovider about yourmedical conditionortreatment.

Whatis the most importantinformation I should know about Gabapentin Tablets?

Do notstop taking Gabapentin Tablets without first talking to yourhealthcareprovider.

Stopping Gabapentin Tablets suddenly can causeserious problems.

Gabapentin Tablets can cause serious side effects including:

1.
SuicidalThoughts. Likeotherantiepilepticdrugs, Gabapentin Tablets may causesuicidal thoughts oractions in avery small numberof people, about1 in 500.

Call a healthcareprovider rightaway ifyou haveany of thesesymptoms, especially if they arenew, worse, or

worry you:

 
thoughts about suicideor dying
attempts to commit suicide
newor worsedepression
newor worse anxiety
feeling agitated or restless
panic attacks
troublesleeping (insomnia)
newor worseirritability
acting aggressive, being angry, orviolent
actingon dangerous impulses
an extremeincreasein activity and talking (mania)
otherunusual changes in behaviorormood

How can I watch for early symptoms ofsuicidal thoughts and actions?

Pay attention to any changes, especiallysudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcareprovider as scheduled.
 
Call yourhealthcareproviderbetween visits as needed, especiallyif you are worried about symptoms.

Do not stop taking Gabapentin Tablets without first talking to a healthcare provider.

Stopping Gabapentin Tablets suddenly can causeserious problems. Stoppingaseizure medicinesuddenlyin a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
Suicidal thoughts or actions can be caused bythings otherthan medicines. If you havesuicidal thoughts or actions, yourhealthcareprovidermay check for other causes.
2.
Changes in behaviorand thinking -Using Gabapentin Tablets in children 3 to12 years of age can cause emotional changes, aggressive behavior, problems with concentration, restlessness, changes in school performance, and hyperactivity.
3.
Gabapentintablets may causea serious orlife-threatening allergic reaction that may affect yourskin orotherparts of yourbodysuch as yourliverorblood cells. You may or maynot have rash when you get this typeof reaction. It may cause you to behospitalized or to stop Gabapentin Tablets. Call ahealthcareprovider right awayif you have anyofthe following symptoms:
skin rash
hives
fever
swollen glands that do not go away
swellingof yourlip and tongue
yellowingof yourskin orofthe whites ofthe eyes
unusual bruisingorbleeding
severe fatigueor weakness
unexpected musclepain
frequent infections
 
These symptoms may bethe first signs ofaserious reaction. A healthcare provider should examine you to decideif you should continuetaking Gabapentin Tablets.

What are Gabapentin Tablets?

 
Gabapentin Tablets are a prescription medicineused to treat:
Pain from damaged nerves (postherpetic pain)that follows healingofshingles (apainful rash that comes afteraherpes zosterinfection)in adults.
Partial seizures when taken together with other medicines in adults and children 3 years of age andolder with seizures.

Who should not take Gabapentin Tablets?

Do not take Gabapentin Tablets if you are allergictogabapentin or any ofthe otheringredients in Gabapentin Tablets. Seetheend ofthis Medication Guide fora completelist ofingredients in Gabapentin Tablets.

WhatshouldI tell my healthcareproviderbefore taking Gabapentin Tablets?

Before taking Gabapentin Tablets, tell yourhealthcareproviderifyou:

haveorhavehad kidneyproblems or areon hemodialysis
haveorhavehad depression, mood problems, orsuicidal thoughts orbehavior
arepregnant orplan to becomepregnant. It is not known ifGabapentin Tablets can harm your unborn baby. Tell your healthcareprovider right awayif you becomepregnant while takingGabapentin Tablets. You and yourhealthcareprovider will decideif youshould take Gabapentin Tablets while you arepregnant.
 
oIf you becomepregnant whiletakingGabapentin Tablets, talk to yourhealthcare provider about registering with the North American Antiepileptic Drug (NAAED)PregnancyRegistry. Thepurposeofthis registryis to collect information about thesafetyof antiepilepticdrugsduringpregnancy. You can enroll in this registry by calling1-888-233-2334.
arebreast-feedingorplan to breast-feed. Gabapentin can pass into breast milk. You and yourhealthcareprovidershould decidehow you will feed yourbaby while you take Gabapentin Tablets.

Tell yourhealthcareprovideraboutall the medicines you take, includingprescription and over-the-counter medicines, vitamins, and herbal supplements.

TakingGabapentin Tablets with certain other medicines can causeside effects or affect how well they work. Do not start orstop othermedicines without talkingto yourhealthcareprovider.

Knowthemedicines youtake. Keep alist ofthem and showit to your healthcare provider and pharmacist when yougetanewmedicine.

Howshould I takeGabapentin Tablets?

TakeGabapentin Tablets exactly as prescribed. Your healthcareprovider will tell you how much gabapentinto take.
o
Do not change yourdoseofGabapentin Tablets without talkingto yourhealthcare provider.
o
If you takegabapentintablets and break atablet in half, theunused halfof thetablet should betaken at your next scheduled dose. Halftablets not used within 28 days of breakingshould bethrown away
Gabapentintablets can betaken with or without food. If you take an antacid containing aluminum and magnesium, such as Maalox®, Mylanta®, Gelusil®, Gaviscon®, or Di-Gel®, you should wait at least 2 hours beforetaking yournext doseof gabapentin.
 
If you taketoo much gabapentin, call yourhealthcareprovideror your local Poison Control Center right away at 1-800-222-1222.

WhatshouldI avoid while taking Gabapentin Tablets?

Do not drink alcohol or takeothermedicines thatmake you sleepyordizzy whiletaking Gabapentin Tablets without first talking with yourhealthcare provider. Taking Gabapentin Tablets with alcohol ordrugs that causesleepiness ordizziness maymake yoursleepiness or dizziness worse.
Do not drive, operateheavymachinery, ordo otherdangerous activities until you know howGabapentin Tablets affect you. Gabapentin Tablets can slow yourthinking andmotorskills.

Whatare thepossibleside effects ofGabapentin Tablets?

Gabapentin Tablets may causeserious side effects including:

 
See “What is themost important informationIshould know about Gabapentin Tablets?”
problems driving while usinggabapentin. See “Whatshould I avoid whiletaking Gabapentin Tablets?”
sleepiness and dizziness
The most common side effects ofGabapentin Tablets include:
lackof coordination•fee lin g tire d
viralinfection•fe ver
feelingdrowsy• jerk y move me nts
nausea andvomiting• diff ic ult y w ith c oor dina tion
difficulty withspeaking• double vision
tremor• unusua l ey e move me nt
swelling, usuallyoflegs and feet

Tell your healthcareproviderif you have anyside effect that bothers you orthat does not go away.

These arenot all thepossibleside effects ofGabapentin Tablets. Formoreinformation, ask your healthcareproviderorpharmacist.

Call yourdoctor for medical adviceaboutside effects. You may reportside effects to FDA at1-800-FDA-1088.

Howshould IstoreGabapentin Tablets?

StoreGabapentin Tablets between 68°Fto 77°F (20°C to25°C).

Keep Gabapentin Tablets and all medicines outof the reach of children.

General information about the safe and effective use ofGabapentin Tablets

Medicines aresometimes prescribed forpurposesotherthan thoselisted in aMedication Guide. Do not useGabapentin Tablets fora condition for which they were not prescribed. Do not give Gabapentin Tablets to other people, even iftheyhave thesame symptoms that you have. They mayharm them.

This Medication Guide summarizes themost important information aboutGabapentin Tablets. If you would likemoreinformation, talk with yourhealthcare provider. You can ask yourhealthcare providerorpharmacist forinformation about Gabapentin Tablets that was written forhealthcare professionals.

Formoreinformationabout Gabapentin Tablets, please call 1-888-838-2872.

Whatare theingredients in Gabapentin Tablets?

Activeingredient:gabapentin

Inactiveingredients:lactose monohydrate, microcrystalline cellulose and polyethylene glycol.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

This Medication Guide has been approved bythe U.S. Food and Drug Administration.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. C 10/2014

Package/Label Display Panel

Gabapentin Tablets USP 600mg 100s Label Text

NDC 0093-4443-01

GABAPENTIN
Tablets USP
600 mg

PHARMACIST: Dispense the accompanying
Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

Package/Label Display Panel

Gabapentin Tablets USP 800mg 100s Label Text

NDC 0093-4444-01

GABAPENTIN
Tablets USP
800 mg

PHARMACIST: Dispense the accompanying
Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

GABAPENTIN 
gabapentin tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0093-4443
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GABAPENTIN (GABAPENTIN) GABAPENTIN 600 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 8000  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL Size 18mm
Flavor Imprint Code 4443;600
Contains         
Packaging
# Item Code Package Description
1 NDC:0093-4443-01 100 TABLET in 1 BOTTLE
2 NDC:0093-4443-05 500 TABLET in 1 BOTTLE
3 NDC:0093-4443-10 1000 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076017 07/11/2008
GABAPENTIN 
gabapentin tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0093-4444
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GABAPENTIN (GABAPENTIN) GABAPENTIN 800 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL 8000  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL Size 19mm
Flavor Imprint Code 4444;800
Contains         
Packaging
# Item Code Package Description
1 NDC:0093-4444-01 100 TABLET in 1 BOTTLE
2 NDC:0093-4444-05 500 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076017 08/01/2008
Labeler - Teva Pharmaceuticals USA Inc (001627975)
Revised: 11/2014
 
Teva Pharmaceuticals USA Inc
Hide
(web3)