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Gabapentin

Gabapentin

Pronunciation Pronunciation: GAB-a-PEN-tin

Class: Anticonvulsant Gabapentin enacarbil

For ProfessionalsSide EffectsInteractionsMore…

Trade Names

Horizant

– Tablets, ER, oral 600 mg

Gabapentin (base)

Gralise

– Tablets, oral 300 mg

– Tablets, oral 600 mg

Neurontin

– Tablets, oral 600 mg

– Tablets, oral 800 mg

– Capsules, oral 100 mg

– Capsules, oral 300 mg

– Capsules, oral 400 mg

– Solution, oral 250 mg per 5 mL

Apo-Gabapentin (Canada)

CO Gabapentin (Canada)

Gen-Gabapentin (Canada)

Novo-Gabapentin (Canada)

PMS-Gabapentin (Canada)

ratio-Gabapentin (Canada)

Pharmacology

Mechanism unknown; gabapentin enacarbil is a prodrug of gabapentin.

Pharmacokinetics

Absorption

Bioavailability for the immediate-release tablets decreases as dose increases; bioavailability is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1,200, 2,400, 3,600, and 4,800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on rate and extent of absorption (14% increase in AUC and C max ). Bioavailability for the ER tablets is approximately 75% (with food) and 42% to 65% (fasting). T max was 7.3 h (with food) and 5 h (fasting).

Distribution

Less than 3% bound to plasma proteins. Vd is approximately 58 L (immediate release) and 76 L (ER).

Metabolism

Gabapentin enacarbil is hydrolyzed primarily in the intestines to the active metabolite gabapentin, which is not significantly metabolized in humans.

Elimination

Excreted as unchanged gabapentin in the urine. Half-life is 5 to 7 h. Renal Cl ranged from 5 to 7 L/h (ER).

Special Populations

Renal Function Impairment

In CrCl less than 30 mL/min, half-life is approximately 52 h (immediate release). In moderate and severe renal impairment, Cl was decreased to 3 and 1 L/h, respectively, compared with 5 to 7 L/h in nonrenal impairment patients (ER).

Hemodialysis The half-life is approximately 132 h on nondialysis days; during dialysis, half-life is reduced to 3.8 h (immediate release). Gabapentin is significantly removed by hemodialysis. Treatment with gabapentin enacarbil is not recommended for patients on hemodialysis (ER).

Hepatic Function Impairment

Studies have not been performed.

Elderly

Renal Cl decreases as a result of age-related decline in renal function.

Children

Immediate release Children between 1 mo and younger than 5 y achieved approximately 30% lower exposure (AUC) than that observed in those 5 y and older. Gabapentin elimination half-life averaged 4.7 h and was similar across the age groups studied. Higher oral Cl values were observed in children younger than 5 y compared with those observed in children 5 y and older, when normalized per body weight. The Cl was highly variable in infants younger than 1 y.

Gender

No clinical meaningful differences in pharmacokinetics were found between men and women.

Race

The effect of race was not studied.

Indications and Usage

Adjunctive therapy in treatment of partial seizures with or without secondary generalization in patients older than 12 y with epilepsy (immediate release); adjunctive therapy for partial seizures in children 3 to 12 y of age; management of postherpetic neuralgia in adults (immediate release); treatment of moderate to severe primary restless legs syndrome in adults (ER).

Unlabeled Uses

Agitation in dementia; alcohol withdrawal; bipolar disorder; cocaine withdrawal; diabetic neuropathy; fibromyalgia; headaches; hiccups (singultus); hot flashes (cancer- and/or postmenopausal-related); hyperhidrosis; nausea (cancer-related); neuralgia/neuropathy/chronic pain; prevention of migraine; pruritus (brachioradial/cholestatic/uremic); rectal administration; restless legs syndrome (immediate release); tremors in multiple sclerosis.

Contraindications

Hypersensitivity to the drug or its ingredients.

Dosage and Administration

Epilepsy (Immediate Release)

Adults and Children older than 12 y PO 300 mg 3 times daily initially. May increase as necessary to 900 to 1,800 mg/day (divided 3 times daily).

Children 5 to 12 y of age PO Initiate therapy at 10 to 15 mg/kg/day in 3 divided doses and titrate dose upward over a period of approximately 3 days to effective dose. Effective dosage is 25 to 35 mg/kg/day in 3 divided doses.

Children 3 to 4 y of age PO Initiate therapy at 10 to 15 mg/kg/day in 3 divided doses and titrate dose upward over a period of approximately 3 days to effective dose. Effective dosage is 40 mg/kg/day in 3 divided doses.

Postherpetic Neuralgia (Immediate Release)

Adults PO Start with a single 300 mg dose on day one, 600 mg on day two (divided twice daily), and 900 mg on day three (divided 3 times daily). Subsequently, titrate the dose upward as needed for pain relief to a daily dose of 1,800 mg (divided 3 times daily).

Restless Legs Syndrome (ER)

Adults PO 600 mg once daily taken at approximately 5 PM.

Renal Function Impairment

Adults and Children older than 12 y (immediate release) CrCl 60 mL/min or higher Total daily dose range, 900 to 3,600 mg/day.

CrCl 30 to 59 mL/min Total daily dose range, 400 to 1,400 mg/day.

CrCl 16 to 29 mL/min Total daily dose range, 200 to 700 mg/day.

CrCl 15 mL/min Total daily dose range, 100 to 300 mg/day.

CrCl less than 15 mL/min Reduce dose in proportion to CrCl (eg, patients with CrCl 7.5 mL/min should receive half the daily dose of patients with CrCl 15 mL/min).

Adults (ER) CrCl 30 to 59 mL/min 600 mg on days 1 and 3, and every day thereafter.

CrCl less than 30 mL/min Use is not recommended.

Patients on hemodialysis Immediate release Maintenance doses based on CrCl as recommended, plus a supplemental posthemodialysis dose administered after each 4 h of hemodialysis as follows: If maintenance dose is 100 mg daily, postdialysis dose is 125 mg; if maintenance dose is 125 mg daily, postdialysis dose is 150 mg; if maintenance dose is 150 mg daily, postdialysis dose is 200 mg; if maintenance dose is 200 mg daily, postdialysis dose is 250 mg; if maintenance dose is 300 mg daily, postdialysis dose is 350 mg.

Gabapentin available under the trade names Gralise (R) and Horizant (R) is contraindicated in patients receiving hemodialysis. ER Use is not recommended.

General Advice

  • ER
  • Administer with food. Tablets should be swallowed whole and should not be cut, crushed, or chewed.
  • May discontinue drug without tapering when receiving recommended dose. When recommended dose is exceeded, reduce dosage to 600 mg daily for 1 wk prior to discontinuation.
  • If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed.
  • Immediate release
  • Tablets, capsules, and oral solution are interchangeable on a mg-to-mg basis.
  • Max time between doses in 3-times-daily schedule should not exceed 12 h.
  • Administer without regard to meals. Administer with food if GI upset occurs.
  • If 600 or 800 mg scored tablet is split to administer a half-tablet, administer unused half-tablet at next dose. Discard any half-tablet not used within several days of splitting.
  • Measure and administer prescribed dose of oral solution using dosing syringe, dosing spoon, or dosing cup.
  • Reduce dose gradually over a minimum of 1 wk if gabapentin is discontinued.

Storage/Stability

Store tablets and capsules between 59° and 86°F. Store oral solution between 36° and 46°F.

Drug Interactions

Antacids May reduce bioavailability of gabapentin. Gabapentin should be taken 2 h after antacid.

Cimetidine Renal Cl of gabapentin may be reduced slightly. This interaction is not expected to be clinically important.

Hormonal contraceptives Norethindrone plasma levels may be increased by 13%, which is not expected to be clinically important.

Hydrocodone The AUC of gabapentin may be increased by 14% while the hydrocodone C max and AUC are decreased by gabapentin in a dose-dependent manner. Observe the clinical response of the patient when starting, stopping, or changing the gabapentin dose. If an interaction is suspected, adjust the hydrocodone dose as needed.

Morphine The AUC of gabapentin may be increased by morphine. The magnitude of this interaction at various gabapentin doses has not been evaluated. Observe the clinical response of the patient when starting, stopping, or changing the gabapentin dose. If an interaction is suspected, adjust the gabapentin dose as needed.

Naproxen In lower than therapeutic doses, gabapentin absorption was increased 12% to 15% by naproxen. The magnitude of this interaction within the recommended dose ranges of either drug is not known. Observe the clinical response of the patient when starting, stopping, or changing the dose of either drug. If an interaction is suspected, adjust the gabapentin dose as needed.

Laboratory Test Interactions

False-positive readings for Ames N-Multistix SG dipstick test when gabapentin is added to other antiepileptic drugs. Sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

Adverse Reactions

Cardiovascular

Hypertension (at least 1%); vasodilation (1%);

CNS

Dizziness (28%); sedation, somnolence (27%); headache (15%); ataxia (13%); fatigue (11%); hostility, nystagmus (8%); tremor (7%); asthenia (6%); emotional lability, irritability (4%); abnormal thinking, depression, feeling abnormal, feeling drunk, hyperkinesia, vertigo (3%); abnormal gait, amnesia, dysarthria, incoordination, libido decreased, nervousness (2%); balance disorder, lethargy (less than 2%); anxiety, confusion, malaise, paresthesia (at least 1%); abnormal coordination, hypesthesia, twitching (1%); aura disappeared, occipital neuralgia, sleepwalking; movement disorder (postmarketing).

Dermatologic

Abrasion, pruritus, rash (1%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).

EENT

Diplopia (6%); amblyopia, rhinitis (4%); pharyngitis (3%); abnormal vision (at least 1%); conjunctivitis, otitis media (1%).

GI

Nausea/vomiting (8%); diarrhea (6%); dry mouth (5%); constipation (4%); abdominal pain, flatulence (3%); dental abnormalities, dry mouth or throat, dyspepsia, increased appetite (2%); anorexia, gingivitis (at least 1%).

Genitourinary

Impotence (2%); breast hypertrophy (postmarketing).

Hematologic-Lymphatic

Purpura (at least 1%); decreased WBC, leukopenia (1%); coagulation defect.

Hepatic

Hepatitis; elevated LFTs, jaundice (postmarketing).

Metabolic-Nutritional

Peripheral edema (8%); weight gain (3%); hyperglycemia (1%); dehydration; blood glucose fluctuations, hyponatremia (postmarketing).

Musculoskeletal

Back pain, myalgia (2%); arthralgia, decreased or absent reflexes, increased reflexes (at least 1%); fracture (1%).

Respiratory

Bronchitis, respiratory tract infection (3%); coughing (2%); pneumonia (at least 1%); hoarseness, pseudocroup.

Miscellaneous

Viral infection (11%); fever (10%); infection (5%); accidental injury (3%); face edema (at least 1%); infectious mononucleosis; angioedema (postmarketing).

Precautions

Monitor

Monitor patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy or at times of dose changes (either increases or decreases), and during discontinuation of therapy.

Pregnancy

Category C .

Lactation

Excreted into breast milk.

Children

Effectiveness as adjunctive therapy in the treatment of partial seizures in children younger than 3 y not established; safety and efficacy in management of postherpetic neuralgia and restless legs syndrome in children not established.

Elderly

Because of age-related renal impairment, adjust dose based on CrCl.

Renal Function

Adjust dose based on CrCl.

Carcinogenesis

May have carcinogenic potential.

Hazardous Tasks

May cause significant driving impairment, dizziness, drowsiness, somnolence, sedation, and other symptoms of CNS depression.

Neuropsychiatric effects

Emotional lability, hostility, thought disorders, and hyperkinesia have been reported with increased frequency in patients 3 to 12 y of age with epilepsy.

Product interchangeability

Gabapentin enacarbil is not interchangeable with other gabapentin products.

Serious adverse reactions

During clinical trials, some patients experienced status epilepticus, and 8 sudden, unexplained deaths occurred. The association of these reactions with gabapentin use is unclear.

Suicidal ideation

Antiepileptic drugs increase the risk of suicidal thinking and behavior in patients taking these drugs for any indication.

Withdrawal

Do not discontinue antiepileptic drugs abruptly because of possible increased seizure frequency from drug withdrawal. ER tablets, if used at the recommended dose, may be discontinued without tapering.

Overdosage

Symptoms

Diarrhea, dizziness, double vision, drowsiness, lethargy, slurred speech, somnolence/sedation.

Patient Information

  • Advise patient or caregiver to read the Medication Guide before starting therapy and with each refill.
  • Counsel patients, families, or caregivers that antiepileptic drugs may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm, and to immediately report any of these symptoms to their health care provider.
  • Instruct patients with epilepsy to continue to take other medications for seizures unless advised otherwise by their health care provider.
  • Advise patients or caregivers that medication will be started at a low dose and then increased as tolerated until maximum benefit has been obtained.
  • Instruct patients or caregivers to take or administer gabapentin exactly as prescribed and not to change the dose or discontinue therapy unless advised by their health care provider.
  • Advise patients or caregivers to take the immediate-release tablets without regard to meals but to take with food if stomach upset occurs. Inform patients that the ER tablets should be taken with food at approximately 5 PM.
  • Advise patient or caregiver that maximum time between doses in the 3-times-daily schedule should not exceed 12 h.
  • Advise patient or caregiver that if they split the 600 or 800 mg scored immediate-release tablet to administer a half-tablet dose, they should take the unused half-tablet at the next dose. Half-tablets not used within several days of splitting should be discarded.
  • Inform patients that the ER tablet should be swallowed whole and not cut, crushed, or chewed.
  • Advise patients or caregivers using oral solution to measure and administer prescribed dose using dosing syringe, spoon, or cup.
  • Advise patients or caregivers that if the immediate-release tablet needs to be discontinued, it will be slowly withdrawn over a period of 1 wk or more unless safety concerns (eg, rash) require a more rapid withdrawal. The ER tablet, if used at the recommended dose, does not require tapering.
  • Caution patient that drug may cause dizziness, drowsiness, or incoordination, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Instruct patients or caregivers to contact their health care provider if seizures worsen or if new types of seizures occur.
  • Advise patients or caregivers to inform their health care provider if any of the following occur: emotional lability, hostility, thought disorders or abnormal thinking, restlessness or hyperactivity, excessive dizziness or drowsiness, swelling in the feet or ankles, any unexplained symptom or feeling.
  • Inform patients that doses of gabapentin enacarbil and other gabapentin products are not interchangeable.
  • Advise patient with epilepsy to carry medical identification (eg, card, bracelet) indicating medication usage and epilepsy.
  • Advise pregnant patients taking gabapentin to enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling 1-888-233-2334.

Copyright © 2009 Wolters Kluwer Health.

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Gabapentin

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Gabapentin

Pronunciation Pronunciation: GAB-a-PEN-tin

Class: Anticonvulsant Gabapentin enacarbil

For ProfessionalsSide EffectsInteractionsMore…

Trade Names

Horizant

– Tablets, ER, oral 600 mg

Gabapentin (base)

Gralise

– Tablets, oral 300 mg

– Tablets, oral 600 mg

Neurontin

– Tablets, oral 600 mg

– Tablets, oral 800 mg

– Capsules, oral 100 mg

– Capsules, oral 300 mg

– Capsules, oral 400 mg

– Solution, oral 250 mg per 5 mL

Apo-Gabapentin (Canada)

CO Gabapentin (Canada)

Gen-Gabapentin (Canada)

Novo-Gabapentin (Canada)

PMS-Gabapentin (Canada)

ratio-Gabapentin (Canada)

Pharmacology

Mechanism unknown; gabapentin enacarbil is a prodrug of gabapentin.

Pharmacokinetics

Absorption

Bioavailability for the immediate-release tablets decreases as dose increases; bioavailability is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1,200, 2,400, 3,600, and 4,800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on rate and extent of absorption (14% increase in AUC and C max ). Bioavailability for the ER tablets is approximately 75% (with food) and 42% to 65% (fasting). T max was 7.3 h (with food) and 5 h (fasting).

Distribution

Less than 3% bound to plasma proteins. Vd is approximately 58 L (immediate release) and 76 L (ER).

Metabolism

Gabapentin enacarbil is hydrolyzed primarily in the intestines to the active metabolite gabapentin, which is not significantly metabolized in humans.

Elimination

Excreted as unchanged gabapentin in the urine. Half-life is 5 to 7 h. Renal Cl ranged from 5 to 7 L/h (ER).

Special Populations

Renal Function Impairment

In CrCl less than 30 mL/min, half-life is approximately 52 h (immediate release). In moderate and severe renal impairment, Cl was decreased to 3 and 1 L/h, respectively, compared with 5 to 7 L/h in nonrenal impairment patients (ER).

Hemodialysis The half-life is approximately 132 h on nondialysis days; during dialysis, half-life is reduced to 3.8 h (immediate release). Gabapentin is significantly removed by hemodialysis. Treatment with gabapentin enacarbil is not recommended for patients on hemodialysis (ER).

Hepatic Function Impairment

Studies have not been performed.

Elderly

Renal Cl decreases as a result of age-related decline in renal function.

Children

Immediate release Children between 1 mo and younger than 5 y achieved approximately 30% lower exposure (AUC) than that observed in those 5 y and older. Gabapentin elimination half-life averaged 4.7 h and was similar across the age groups studied. Higher oral Cl values were observed in children younger than 5 y compared with those observed in children 5 y and older, when normalized per body weight. The Cl was highly variable in infants younger than 1 y.

Gender

No clinical meaningful differences in pharmacokinetics were found between men and women.

Race

The effect of race was not studied.

Indications and Usage

Adjunctive therapy in treatment of partial seizures with or without secondary generalization in patients older than 12 y with epilepsy (immediate release); adjunctive therapy for partial seizures in children 3 to 12 y of age; management of postherpetic neuralgia in adults (immediate release); treatment of moderate to severe primary restless legs syndrome in adults (ER).

Unlabeled Uses

Agitation in dementia; alcohol withdrawal; bipolar disorder; cocaine withdrawal; diabetic neuropathy; fibromyalgia; headaches; hiccups (singultus); hot flashes (cancer- and/or postmenopausal-related); hyperhidrosis; nausea (cancer-related); neuralgia/neuropathy/chronic pain; prevention of migraine; pruritus (brachioradial/cholestatic/uremic); rectal administration; restless legs syndrome (immediate release); tremors in multiple sclerosis.

Contraindications

Hypersensitivity to the drug or its ingredients.

Dosage and Administration

Epilepsy (Immediate Release)

Adults and Children older than 12 y PO 300 mg 3 times daily initially. May increase as necessary to 900 to 1,800 mg/day (divided 3 times daily).

Children 5 to 12 y of age PO Initiate therapy at 10 to 15 mg/kg/day in 3 divided doses and titrate dose upward over a period of approximately 3 days to effective dose. Effective dosage is 25 to 35 mg/kg/day in 3 divided doses.

Children 3 to 4 y of age PO Initiate therapy at 10 to 15 mg/kg/day in 3 divided doses and titrate dose upward over a period of approximately 3 days to effective dose. Effective dosage is 40 mg/kg/day in 3 divided doses.

Postherpetic Neuralgia (Immediate Release)

Adults PO Start with a single 300 mg dose on day one, 600 mg on day two (divided twice daily), and 900 mg on day three (divided 3 times daily). Subsequently, titrate the dose upward as needed for pain relief to a daily dose of 1,800 mg (divided 3 times daily).

Restless Legs Syndrome (ER)

Adults PO 600 mg once daily taken at approximately 5 PM.

Renal Function Impairment

Adults and Children older than 12 y (immediate release) CrCl 60 mL/min or higher Total daily dose range, 900 to 3,600 mg/day.

CrCl 30 to 59 mL/min Total daily dose range, 400 to 1,400 mg/day.

CrCl 16 to 29 mL/min Total daily dose range, 200 to 700 mg/day.

CrCl 15 mL/min Total daily dose range, 100 to 300 mg/day.

CrCl less than 15 mL/min Reduce dose in proportion to CrCl (eg, patients with CrCl 7.5 mL/min should receive half the daily dose of patients with CrCl 15 mL/min).

Adults (ER) CrCl 30 to 59 mL/min 600 mg on days 1 and 3, and every day thereafter.

CrCl less than 30 mL/min Use is not recommended.

Patients on hemodialysis Immediate release Maintenance doses based on CrCl as recommended, plus a supplemental posthemodialysis dose administered after each 4 h of hemodialysis as follows: If maintenance dose is 100 mg daily, postdialysis dose is 125 mg; if maintenance dose is 125 mg daily, postdialysis dose is 150 mg; if maintenance dose is 150 mg daily, postdialysis dose is 200 mg; if maintenance dose is 200 mg daily, postdialysis dose is 250 mg; if maintenance dose is 300 mg daily, postdialysis dose is 350 mg.

Gabapentin available under the trade names Gralise (R) and Horizant (R) is contraindicated in patients receiving hemodialysis. ER Use is not recommended.

General Advice

  • ER
  • Administer with food. Tablets should be swallowed whole and should not be cut, crushed, or chewed.
  • May discontinue drug without tapering when receiving recommended dose. When recommended dose is exceeded, reduce dosage to 600 mg daily for 1 wk prior to discontinuation.
  • If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed.
  • Immediate release
  • Tablets, capsules, and oral solution are interchangeable on a mg-to-mg basis.
  • Max time between doses in 3-times-daily schedule should not exceed 12 h.
  • Administer without regard to meals. Administer with food if GI upset occurs.
  • If 600 or 800 mg scored tablet is split to administer a half-tablet, administer unused half-tablet at next dose. Discard any half-tablet not used within several days of splitting.
  • Measure and administer prescribed dose of oral solution using dosing syringe, dosing spoon, or dosing cup.
  • Reduce dose gradually over a minimum of 1 wk if gabapentin is discontinued.

Storage/Stability

Store tablets and capsules between 59° and 86°F. Store oral solution between 36° and 46°F.

Drug Interactions

Antacids May reduce bioavailability of gabapentin. Gabapentin should be taken 2 h after antacid.

Cimetidine Renal Cl of gabapentin may be reduced slightly. This interaction is not expected to be clinically important.

Hormonal contraceptives Norethindrone plasma levels may be increased by 13%, which is not expected to be clinically important.

Hydrocodone The AUC of gabapentin may be increased by 14% while the hydrocodone C max and AUC are decreased by gabapentin in a dose-dependent manner. Observe the clinical response of the patient when starting, stopping, or changing the gabapentin dose. If an interaction is suspected, adjust the hydrocodone dose as needed.

Morphine The AUC of gabapentin may be increased by morphine. The magnitude of this interaction at various gabapentin doses has not been evaluated. Observe the clinical response of the patient when starting, stopping, or changing the gabapentin dose. If an interaction is suspected, adjust the gabapentin dose as needed.

Naproxen In lower than therapeutic doses, gabapentin absorption was increased 12% to 15% by naproxen. The magnitude of this interaction within the recommended dose ranges of either drug is not known. Observe the clinical response of the patient when starting, stopping, or changing the dose of either drug. If an interaction is suspected, adjust the gabapentin dose as needed.

Laboratory Test Interactions

False-positive readings for Ames N-Multistix SG dipstick test when gabapentin is added to other antiepileptic drugs. Sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

Adverse Reactions

Cardiovascular

Hypertension (at least 1%); vasodilation (1%);

CNS

Dizziness (28%); sedation, somnolence (27%); headache (15%); ataxia (13%); fatigue (11%); hostility, nystagmus (8%); tremor (7%); asthenia (6%); emotional lability, irritability (4%); abnormal thinking, depression, feeling abnormal, feeling drunk, hyperkinesia, vertigo (3%); abnormal gait, amnesia, dysarthria, incoordination, libido decreased, nervousness (2%); balance disorder, lethargy (less than 2%); anxiety, confusion, malaise, paresthesia (at least 1%); abnormal coordination, hypesthesia, twitching (1%); aura disappeared, occipital neuralgia, sleepwalking; movement disorder (postmarketing).

Dermatologic

Abrasion, pruritus, rash (1%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).

EENT

Diplopia (6%); amblyopia, rhinitis (4%); pharyngitis (3%); abnormal vision (at least 1%); conjunctivitis, otitis media (1%).

GI

Nausea/vomiting (8%); diarrhea (6%); dry mouth (5%); constipation (4%); abdominal pain, flatulence (3%); dental abnormalities, dry mouth or throat, dyspepsia, increased appetite (2%); anorexia, gingivitis (at least 1%).

Genitourinary

Impotence (2%); breast hypertrophy (postmarketing).

Hematologic-Lymphatic

Purpura (at least 1%); decreased WBC, leukopenia (1%); coagulation defect.

Hepatic

Hepatitis; elevated LFTs, jaundice (postmarketing).

Metabolic-Nutritional

Peripheral edema (8%); weight gain (3%); hyperglycemia (1%); dehydration; blood glucose fluctuations, hyponatremia (postmarketing).

Musculoskeletal

Back pain, myalgia (2%); arthralgia, decreased or absent reflexes, increased reflexes (at least 1%); fracture (1%).

Respiratory

Bronchitis, respiratory tract infection (3%); coughing (2%); pneumonia (at least 1%); hoarseness, pseudocroup.

Miscellaneous

Viral infection (11%); fever (10%); infection (5%); accidental injury (3%); face edema (at least 1%); infectious mononucleosis; angioedema (postmarketing).

Precautions

Monitor

Monitor patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy or at times of dose changes (either increases or decreases), and during discontinuation of therapy.

Pregnancy

Category C .

Lactation

Excreted into breast milk.

Children

Effectiveness as adjunctive therapy in the treatment of partial seizures in children younger than 3 y not established; safety and efficacy in management of postherpetic neuralgia and restless legs syndrome in children not established.

Elderly

Because of age-related renal impairment, adjust dose based on CrCl.

Renal Function

Adjust dose based on CrCl.

Carcinogenesis

May have carcinogenic potential.

Hazardous Tasks

May cause significant driving impairment, dizziness, drowsiness, somnolence, sedation, and other symptoms of CNS depression.

Neuropsychiatric effects

Emotional lability, hostility, thought disorders, and hyperkinesia have been reported with increased frequency in patients 3 to 12 y of age with epilepsy.

Product interchangeability

Gabapentin enacarbil is not interchangeable with other gabapentin products.

Serious adverse reactions

During clinical trials, some patients experienced status epilepticus, and 8 sudden, unexplained deaths occurred. The association of these reactions with gabapentin use is unclear.

Suicidal ideation

Antiepileptic drugs increase the risk of suicidal thinking and behavior in patients taking these drugs for any indication.

Withdrawal

Do not discontinue antiepileptic drugs abruptly because of possible increased seizure frequency from drug withdrawal. ER tablets, if used at the recommended dose, may be discontinued without tapering.

Overdosage

Symptoms

Diarrhea, dizziness, double vision, drowsiness, lethargy, slurred speech, somnolence/sedation.

Patient Information

  • Advise patient or caregiver to read the Medication Guide before starting therapy and with each refill.
  • Counsel patients, families, or caregivers that antiepileptic drugs may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm, and to immediately report any of these symptoms to their health care provider.
  • Instruct patients with epilepsy to continue to take other medications for seizures unless advised otherwise by their health care provider.
  • Advise patients or caregivers that medication will be started at a low dose and then increased as tolerated until maximum benefit has been obtained.
  • Instruct patients or caregivers to take or administer gabapentin exactly as prescribed and not to change the dose or discontinue therapy unless advised by their health care provider.
  • Advise patients or caregivers to take the immediate-release tablets without regard to meals but to take with food if stomach upset occurs. Inform patients that the ER tablets should be taken with food at approximately 5 PM.
  • Advise patient or caregiver that maximum time between doses in the 3-times-daily schedule should not exceed 12 h.
  • Advise patient or caregiver that if they split the 600 or 800 mg scored immediate-release tablet to administer a half-tablet dose, they should take the unused half-tablet at the next dose. Half-tablets not used within several days of splitting should be discarded.
  • Inform patients that the ER tablet should be swallowed whole and not cut, crushed, or chewed.
  • Advise patients or caregivers using oral solution to measure and administer prescribed dose using dosing syringe, spoon, or cup.
  • Advise patients or caregivers that if the immediate-release tablet needs to be discontinued, it will be slowly withdrawn over a period of 1 wk or more unless safety concerns (eg, rash) require a more rapid withdrawal. The ER tablet, if used at the recommended dose, does not require tapering.
  • Caution patient that drug may cause dizziness, drowsiness, or incoordination, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Instruct patients or caregivers to contact their health care provider if seizures worsen or if new types of seizures occur.
  • Advise patients or caregivers to inform their health care provider if any of the following occur: emotional lability, hostility, thought disorders or abnormal thinking, restlessness or hyperactivity, excessive dizziness or drowsiness, swelling in the feet or ankles, any unexplained symptom or feeling.
  • Inform patients that doses of gabapentin enacarbil and other gabapentin products are not interchangeable.
  • Advise patient with epilepsy to carry medical identification (eg, card, bracelet) indicating medication usage and epilepsy.
  • Advise pregnant patients taking gabapentin to enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling 1-888-233-2334.

Copyright © 2009 Wolters Kluwer Health.

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Gabapentin

Gabapentin

Dosage Form: capsule, tablet, oral suspension

Gabapentin Capsules

Gabapentin Tablets

Gabapentin Oral Solution

Gabapentin Description

Gabapentin Capsules, Gabapentin Tablets, and Gabapentin Oral Solution are supplied as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of Gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg of Gabapentin or an oral solution containing 250 mg/5 mL of Gabapentin.

The inactive ingredients for the capsules are lactose, cornstarch, and talc. The 100 mg capsule shell contains gelatin and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium dioxide, and yellow iron oxide. The 400 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.

The inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.

The inactive ingredients for the oral solution are glycerin, xylitol, purified water, and artificial cool strawberry anise flavor.

Gabapentin is described as 1-(aminomethyl)cyclohexaneacetic acid with a molecular formula of C9H17NO2 and a molecular weight of 171.24. The structural formula of Gabapentin is:

Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is −1.25.

Gabapentin – Clinical Pharmacology

Mechanism of Action

The mechanism by which Gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, Gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, Gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known.

The mechanism by which Gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, Gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100 µM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, Gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin.

In vitro studies with radiolabeled Gabapentin have revealed a Gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of Gabapentin binding, if any, remain to be elucidated.

Pharmacokinetics and Drug Metabolism

All pharmacological actions following Gabapentin administration are due to the activity of the parent compound; Gabapentin is not appreciably metabolized in humans.

Oral Bioavailability Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of Gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of Gabapentin (14% increase in AUC and Cmax).

Distribution Less than 3% of Gabapentin circulates bound to plasma protein. The apparent volume of distribution of Gabapentin after 150 mg intravenous administration is 58±6 L (mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of Gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.

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

Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance (see CLINICAL PHARMACOLOGY, Special Populations: Adult Patients With Renal Insufficiency, below). In elderly patients, and in patients with impaired renal function, Gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.

Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended (see DOSAGE AND ADMINISTRATION, Table 6).

Special Populations

Adult Patients With Renal Insufficiency

Subjects (N=60) with renal insufficiency (mean creatinine clearance ranging from 13–114 mL/min) were administered single 400 mg oral doses of Gabapentin. The mean Gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and Gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min.

Dosage adjustment in adult patients with compromised renal function is necessary (see DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been studied.

Hemodialysis

In a study in anuric adult subjects (N=11), the apparent elimination half-life of Gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of Gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on Gabapentin elimination in anuric subjects.

Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND ADMINISTRATION).

Hepatic Disease

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

Age

The effect of age was studied in subjects 20–80 years of age. Apparent oral clearance (CL/F) of Gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of Gabapentin with age can largely be explained by the decline in renal function. Reduction of Gabapentin dose may be required in patients who have age related compromised renal function. (See PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.)

Pediatric

Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of Gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied.

A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range.

These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving Gabapentin at 30 mg/kg/day (see DOSAGE AND ADMINISTRATION).

Gender

Although no formal study has been conducted to compare the pharmacokinetics of Gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.

Race

Pharmacokinetic differences due to race have not been studied. Because Gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

Clinical Studies

Postherpetic Neuralgia Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-blind, placebo-controlled, multicenter studies; N=563 patients in the intent-to-treat (ITT) population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of the herpes zoster skin rash.

TABLE 1. Controlled PHN Studies: Duration, Dosages, and Number of Patients
Study Study Duration Gabapentin (mg/day)*

Target Dose

Patients Receiving Gabapentin Patients Receiving Placebo
*
Given in 3 divided doses (TID)
1 8 weeks 3600 113 116
2 7 weeks 1800, 2400 223 111
Total 336 227

Each study included a 1 week baseline during which patients were screened for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day Gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication).

Both studies showed significant differences from placebo at all doses tested.

A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant differences were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1 and 2 show these changes for Studies 1 and 2.

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 with ≥50% reduction 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 (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T – B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated.

One study compared 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 (see Figure 4).

Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥12 Years of Age with Partial Seizures

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

Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to 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 25 – 35 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 and Usage for Gabapentin

Postherpetic Neuralgia

Gabapentin is indicated for the management of postherpetic neuralgia in adults.

Epilepsy

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy. Gabapentin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3–12 years.

Contraindications

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

Warnings

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

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 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Gabapentin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Neuropsychiatric Adverse Events-Pediatric Patients 3–12 years of age

Gabapentin use in pediatric patients with epilepsy 3–12 years of age is associated with the occurrence of central nervous system related adverse events. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the Gabapentin-treated patients, most of the events were mild to moderate in intensity.

In controlled trials in pediatric patients 3–12 years of age, the incidence of these adverse events was: emotional lability 6% (Gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these events, a report of hostility, was considered serious. Discontinuation of Gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of Gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability.

Withdrawal Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus in patients receiving Gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with Gabapentin across all studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with Gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with Gabapentin.

Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.) The clinical significance of this finding is unknown. Clinical experience during Gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of Gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with Gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

Sudden and Unexplained Death in Patients With Epilepsy

During the course of premarketing development of Gabapentin 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the Gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the Gabapentin cohort and the accuracy of the estimates provided.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Precautions

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Gabapentin. Instruct patients to take Gabapentin only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including Gabapentin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that Gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on Gabapentin to gauge whether or not it affects their mental and/or motor performance adversely.

Patients who require concomitant treatment with morphine may experience increases in Gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of Gabapentin or morphine should be reduced appropriately (see PRECAUTIONS, Drug Interactions).

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy).

Prior to initiation of treatment with Gabapentin, the patient should be instructed that a rash or other signs or symtoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Laboratory Tests

Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of Gabapentin. The value of monitoring Gabapentin blood concentrations has not been established. Gabapentin may be used in combination with other antiepileptic drugs without concern for alteration of the blood concentrations of Gabapentin or of other antiepileptic drugs.

Drug Interactions

In vitro studies were conducted to investigate the potential of Gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 µg/mL; 1 mM) was a slight degree of inhibition (14%–30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at Gabapentin concentrations up to 171 µg/mL (approximately 15 times the Cmax at 3600 mg/day).

Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs.

The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.

Phenytoin In a single (400 mg) and multiple dose (400 mg TID) study of Gabapentin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, Gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on Gabapentin pharmacokinetics.

Carbamazepine Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant Gabapentin (400 mg TID; N=12) administration. Likewise, Gabapentin pharmacokinetics were unaltered by carbamazepine administration.

Valproic Acid The mean steady-state trough serum valproic acid concentrations prior to and during concomitant Gabapentin administration (400 mg TID; N=17) were not different and neither were Gabapentin pharmacokinetic parameters affected by valproic acid.

Phenobarbital Estimates of steady-state pharmacokinetic parameters for phenobarbital or Gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or together.

Naproxen Coadministration (N=18) of naproxen sodium capsules (250 mg) with Gabapentin (125 mg) appears to increase the amount of Gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known.

Hydrocodone Coadministration of Gabapentin (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cmax and AUC values are 3% to 4% lower, respectively, after administration of 125 mg Gabapentin and 21% to 22% lower, respectively, after administration of 500 mg Gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases Gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known.

Morphine A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg Gabapentin capsule (N=12), mean Gabapentin AUC increased by 44% compared to Gabapentin administered without morphine (see PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by administration of Gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known.

Cimetidine In the presence of cimetidine at 300 mg QID (N=12), the mean apparent oral clearance of Gabapentin fell by 14% and creatinine clearance fell by 10%. Thus, cimetidine appeared to alter the renal excretion of both Gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of Gabapentin by cimetidine is not expected to be of clinical importance. The effect of Gabapentin on cimetidine was not evaluated.

Oral Contraceptive Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of Gabapentin (400 mg TID; N=13). The Cmax of norethindrone was 13% higher when it was coadministered with Gabapentin; this interaction is not expected to be of clinical importance.

Antacid (Maalox®) Maalox reduced the bioavailability of Gabapentin (N=16) by about 20%. This decrease in bioavailability was about 5% when Gabapentin was administered 2 hours after Maalox. It is recommended that Gabapentin be taken at least 2 hours following Maalox administration.

Effect of Probenecid Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that Gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.

Drug/Laboratory Test Interactions

Because false positive readings were reported with the Ames N-Multistix SG® dipstick test for urinary protein when Gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of Gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize, and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear.

Studies designed to investigate the mechanism of Gabapentin-induced pancreatic carcinogenesis in rats indicate that Gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether Gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

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

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m2 basis).

Pregnancy

Pregnancy Category C Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/m2 basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m2 basis.

When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/m2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m2 basis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m2 basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/m2 basis.

In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

To provide information regarding the effects of in utero exposure to Gabapentin, physicians are advised to recommend that pregnant patients taking Gabapentin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Use in Nursing Mothers

Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of Gabapentin. Because the effect on the nursing infant is unknown, Gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks.

Pediatric Use

Safety and effectiveness of Gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established.

Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical Studies).

Geriatric Use

The total number of patients treated with Gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since Gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥75 years may be a consequence of increased Gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.

Clinical studies of Gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

Adverse Reactions

Postherpetic Neuralgia

The most commonly observed adverse events associated with the use of Gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema.

In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received Gabapentin and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event. The adverse events that most frequently led to withdrawal in Gabapentin-treated patients were dizziness, somnolence, and nausea.

Incidence in Controlled Clinical Trials Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of Gabapentin-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the Gabapentin group than in the placebo group. Adverse events were usually mild to moderate in intensity.

Table 3. Treatment-Emergent Adverse Event Incidence in Controlled Trials in Postherpetic Neuralgia (Events in at least 1% of Gabapentin-Treated Patients and Numerically More Frequent Than in the Placebo Group)
Body System/

Preferred Term

Gabapentin N=336

%

Placebo N=227

%

*
Reported as blurred vision
Body as a Whole
  Asthenia 5.7 4.8
  Infection 5.1 3.5
  Headache 3.3 3.1
  Accidental injury 3.3 1.3
  Abdominal pain 2.7 2.6
Digestive System
  Diarrhea 5.7 3.1
  Dry mouth 4.8 1.3
  Constipation 3.9 1.8
  Nausea 3.9 3.1
  Vomiting 3.3 1.8
  Flatulence 2.1 1.8
Metabolic and Nutritional Disorders
  Peripheral edema 8.3 2.2
  Weight gain 1.8 0.0
  Hyperglycemia 1.2 0.4
Nervous System
  Dizziness 28.0    7.5
  Somnolence 21.4    5.3
  Ataxia 3.3 0.0
  Thinking abnormal 2.7 0.0
  Abnormal gait 1.5 0.0
  Incoordination 1.5 0.0
  Amnesia 1.2 0.9
  Hypesthesia 1.2 0.9
Respiratory System
  Pharyngitis 1.2 0.4
Skin and Appendages
  Rash 1.2 0.9
Special Senses
  Amblyopia* 2.7 0.9
  Conjunctivitis 1.2 0.0
  Diplopia 1.2 0.0
  Otitis media 1.2 0.0

Other events in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome.

There were no clinically important differences between men and women in the types and incidence of adverse events. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse events by race.

Epilepsy

The most commonly observed adverse events associated with the use of Gabapentin in combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most commonly observed adverse events reported with the use of Gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility (see WARNINGS, Neuropsychiatric Adverse Events-Pediatric Patients 3–12 years of age).

Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449 pediatric patients 3 to 12 years of age who received Gabapentin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).

Incidence in Controlled Clinical Trials Table 4 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 were numerically more common in the Gabapentin group. In these studies, either Gabapentin or placebo was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity.

The prescriber should be aware that these figures, obtained when Gabapentin was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

TABLE 4. Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials In Patients >12 years of age (Events in at least 1% of Gabapentin patients and numerically more frequent than in the placebo group)
Body System/Adverse Event Gabapentin* N=543

%

Placebo* N=378

%

*
Plus background antiepileptic drug therapy
Amblyopia was often described as blurred vision.
Body As A Whole
  Fatigue 11.0   5.0
  Weight Increase 2.9 1.6
  Back Pain 1.8 0.5
  Peripheral Edema 1.7 0.5
Cardiovascular
  Vasodilatation 1.1 0.3
Digestive System
  Dyspepsia 2.2 0.5
  Mouth or Throat Dry 1.7 0.5
  Constipation 1.5 0.8
  Dental Abnormalities 1.5 0.3
  Increased Appetite 1.1 0.8
Hematologic and Lymphatic Systems
  Leukopenia 1.1 0.5
Musculoskeletal System
  Myalgia 2.0 1.9
  Fracture 1.1 0.8
Nervous System
  Somnolence 19.3   8.7
  Dizziness 17.1   6.9
  Ataxia 12.5   5.6
  Nystagmus 8.3 4.0
  Tremor 6.8 3.2
  Nervousness 2.4 1.9
  Dysarthria 2.4 0.5
  Amnesia 2.2 0.0
  Depression 1.8 1.1
  Thinking Abnormal 1.7 1.3
  Twitching 1.3 0.5
  Coordination Abnormal 1.1 0.3
Respiratory System
  Rhinitis 4.1 3.7
  Pharyngitis 2.8 1.6
  Coughing 1.8 1.3
Skin and Appendages
  Abrasion 1.3 0.0
  Pruritus 1.3 0.5
Urogenital System
  Impotence 1.5 1.1
Special Senses
  Diplopia 5.9 1.9
  Amblyopia† 4.2 1.1
Laboratory Deviations
  WBC Decreased 1.1 0.5

Other events in more than 1% of patients >12 years of age but equally or more frequent in the placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne.

Among the treatment-emergent adverse events occurring at an incidence of at least 10% in Gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship.

The overall incidence of adverse events and the types of adverse events seen were similar among men and women treated with Gabapentin. The incidence of adverse events increased slightly with increasing age in patients treated with either Gabapentin or placebo. Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to support a statement regarding the distribution of adverse events by race.

Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of Gabapentin-treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the Gabapentin group. Adverse events were usually mild to moderate in intensity.

TABLE 5. Treatment-Emergent Adverse Event Incidence in Pediatric Patients Age 3 to 12 Years in a Controlled Add-On Trial (Events in at least 2% of Gabapentin patients and numerically more frequent than in the placebo group)
Body System/Adverse Event Gabapentin* N=119

%

Placebo* N=128

%

*
Plus background antiepileptic drug therapy
Body As A Whole
  Viral Infection 10.9   3.1
  Fever 10.1   3.1
  Weight Increase 3.4 0.8
  Fatigue 3.4 1.6
Digestive System
  Nausea and/or Vomiting 8.4 7.0
Nervous System
  Somnolence 8.4 4.7
  Hostility 7.6 2.3
  Emotional Lability 4.2 1.6
  Dizziness 2.5 1.6
  Hyperkinesia 2.5 0.8
Respiratory System
  Bronchitis 3.4 0.8
  Respiratory Infection 2.5 0.8

Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.

Other Adverse Events Observed During All Clinical Trials

Clinical Trials in Adults and Adolescents (Except Clinical Trials in Neuropathic Pain)

Gabapentin has been administered to 4717 patients >12 years of age during all adjunctive therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 4717 patients >12 years of age exposed to Gabapentin who experienced an event of the type cited on at least one occasion while receiving Gabapentin. All reported events are included except those already listed in Table 4, those too general to be informative, 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: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect.

Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis.

Digestive System: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, 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 Systems: Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased.

Musculoskeletal System: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.

Nervous System: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction.

Respiratory System: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema.

Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.

Urogenital System: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain.

Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.

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

Hematologic and Lymphatic Systems: 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: Infrequent: chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare: body odor, cyst, fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection.

Cardiovascular System: Infrequent: hypertension, syncope, palpitation, migraine, hypotension, peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure, myocardial infarction, vasodilatation; Rare: angina pectoris, heart failure, increased capillary fragility, phlebitis, thrombophlebitis, varicose vein.

Digestive System: Infrequent: gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal, periodontal abscess; Rare: cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis.

Endocrine System: Infrequent: diabetes mellitus.

Hematologic and Lymphatic System: Infrequent: ecchymosis, anemia; Rare: lymphadenopathy, lymphoma-like reaction, prothrombin decreased.

Metabolic and Nutritional: Infrequent: edema, gout, hypoglycemia, weight loss; Rare: alkaline phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased.

Musculoskeletal: Infrequent: arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare: shin bone pain, joint disorder, tendon disorder.

Nervous System: Frequent: confusion, depression; Infrequent: vertigo, nervousness, paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare: agitation, hypertonia, libido increased, movement disorder, myoclonus, vestibular disorder.

Respiratory System: Infrequent: cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung disorder, epistaxis; Rare: hemoptysis, voice alteration.

Skin and Appendages: Infrequent: pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare: acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin hypertrophy.

Special Senses: Infrequent: abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare: conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein thrombosis, taste loss.

Urogenital System: Infrequent: urinary tract infection, dysuria, impotence, urinary incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention; Rare: cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency, urinary urgency, urine abnormality.

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, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, rhabdomyolysis, 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.

CONTROLLED SUBSTANCE

Gabapentin is not a scheduled drug.

ABUSE

Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta or kappa), or cannabinoid 1 receptor sites. A small number of postmarketing cases report Gabapentin misuse and abuse. These individuals were taking higher than recommended doses of Gabapentin for unapproved uses. Most of the individuals described in these reports had a history of poly-substance abuse or used Gabapentin to relieve symptoms of withdrawal from other substances. When prescribing Gabapentin carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of Gabapentin misuse or abuse (e.g. development of tolerance, self-dose escalation, and drug-seeking behavior).

DEPENDENCE

There are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of Gabapentin used to treat illnesses for which the drug is not approved. Such symptoms included agitation, disorientation and confusion after suddenly discontinuing Gabapentin that resolved after restarting Gabapentin. Most of these individuals had a history of poly-substance abuse or used Gabapentin to relieve symptoms of withdrawal from other substances. The dependence and abuse potential of Gabapentin has not been evaluated in human studies.

Overdosage

A lethal dose of Gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.

Acute oral overdoses of Gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy, and diarrhea, were observed. All patients recovered with supportive care.

Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Gabapentin Dosage and Administration

Gabapentin is given orally with or without food. Patients should be informed that, should they break the scored 600 or 800 mg tablet in order to administer a half-tablet, they should take the unused half-tablet as the next dose. Half-tablets not used within several days of breaking the scored tablet should be discarded.

If Gabapentin dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber).

Postherpetic Neuralgia

In adults with postherpetic neuralgia, Gabapentin therapy may be initiated as a single 300-mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range. Additional benefit of using doses greater than 1800 mg/day was not demonstrated.

Epilepsy

Gabapentin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness in pediatric patients below the age of 3 years has not been established.

Patients >12 years of age: The effective dose of Gabapentin is 900 to 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg tablets. The starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300 or 400 mg capsules, or 600 or 800 mg tablets three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the TID schedule should not exceed 12 hours.

Pediatric Patients Age 3–12 years: The starting dose should range from 10–15 mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of Gabapentin in patients 5 years of age and older is 25–35 mg/kg/day and given in divided doses (three times a day). The effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see CLINICAL PHARMACOLOGY, Pediatric). Gabapentin may be administered as the oral solution, capsule, or tablet, or using combinations of these formulations. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours.

It is not necessary to monitor Gabapentin plasma concentrations to optimize Gabapentin therapy. Further, because there are no significant pharmacokinetic interactions among Gabapentin and other commonly used antiepileptic drugs, the addition of Gabapentin does not alter the plasma levels of these drugs appreciably.

If Gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week.

Dosage in Renal Impairment Creatinine clearance is difficult to measure in outpatients. In patients with stable renal function, creatinine clearance (CCr) can be reasonably well estimated using the equation of Cockcroft and Gault:

for females CCr=(0.85)(140-age)(weight)/[(72)(SCr)]

for males CCr=(140-age)(weight)/[(72)(SCr)]

in which age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL.

Dosage adjustment in patients ≥12 years of age with compromised renal function or undergoing hemodialysis is recommended as follows (see dosing recommendations above for effective doses in each indication).

TABLE 6. Gabapentin Dosage Based on Renal Function
Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg)
*
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table.
≥60 900–3600 300 TID 400 TID 600 TID 800 TID 1200 TID
>30–59 400–1400 200 BID 300 BID 400 BID 500 BID 700 BID
>15–29 200–700 200 QD 300 QD 400 QD 500 QD 700 QD
15* 100–300 100 QD 125 QD 150 QD 200 QD 300 QD
Post-Hemodialysis Supplemental Dose (mg)†
Hemodialysis 125† 150† 200† 250† 350†

The use of Gabapentin in patients <12 years of age with compromised renal function has not been studied.

Dosage in Elderly Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients.

How is Gabapentin Supplied

Gabapentin capsules, tablets and oral solution are supplied as follows:

100 mg capsules;

    White hard gelatin capsules printed with “G” on one side and “5026″ on the other; available in:

    Bottles of 100: NDC 59762-5026-1

300 mg capsules;

    Yellow hard gelatin capsules printed with “G” on one side and “5027″ on the other; available in:

    Bottles of 100: NDC 59762-5027-1

    Bottles of 500: NDC 59762-5027-2

400 mg capsules;

    Orange hard gelatin capsules printed with “G” on one side and “5028″ on the other; available in:

    Bottles of 100: NDC 59762-5028-1

600 mg tablets;

    White elliptical film-coated scored tablets debossed with “G” and “21″ on one side; available in:

    Bottles of 100: NDC 59762-5023-1

800 mg tablets;

    White elliptical film-coated scored tablets debossed with “G” and “22″ on one side; available in:

    Bottles of 100: NDC 59762-5024-1

250 mg/5 mL oral solution;

    Clear colorless to slightly yellow solution; each 5 mL of oral solution contains 250 mg of Gabapentin; available in:

    Bottles containing 470 mL: NDC 59762-5025-1

Storage (Capsules)

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

Storage (Tablets)

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

Storage (Oral Solution)

Store refrigerated, 2° – 8°C (36° – 46°F)

Rx only

LAB-0290-14.0

December 2012

MEDICATION GUIDE

Gabapentin

Capsules, Tablets, and Oral Solution

Read the Medication Guide before you start taking Gabapentin and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Gabapentin?

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

Stopping Gabapentin suddenly can cause serious problems.

Gabapentin can cause serious side effects including:

1.
Like other antiepileptic drugs, Gabapentin may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

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

  • Stopping Gabapentin suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

2.
Changes in behavior and thinking - Using Gabapentin in children 3 to 12 years of age can cause emotional changes, aggressive behavior, problems with concentration, restlessness, changes in school performance, and hyperactivity.
3.
Gabapentin may cause a serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash when you get this type of reaction. It may cause you to be hospitalized or to stop Gabapentin. Call a healthcare provider right away if you have any of the following symptoms:
  • skin rash
  • hives
  • fever
  • swollen glands that do not go away
  • swelling of your lip and tongue
  • yellowing of your skin or of the whites of the eyes
  • unusual bruising or bleeding
  • severe fatigue or weakness
  • unexpected muscle pain
  • frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking Gabapentin.

What is Gabapentin?

Gabapentin is a prescription medicine used to treat:

  • Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes after a herpes zoster infection) in adults.
  • Partial seizures when taken together with other medicines in adults and children 3 years of age and older.

Who should not take Gabapentin?

Do not take Gabapentin if you are allergic to Gabapentin or any of the other ingredients in Gabapentin. See the end of this Medication Guide for a complete list of ingredients in Gabapentin.

What should I tell my healthcare provider before taking Gabapentin?

Before taking Gabapentin, tell your healthcare provider if you:

  • have or have had kidney problems or are on hemodialysis
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • 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.
    • 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.
  • 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.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking Gabapentin with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Gabapentin?

  • Take Gabapentin exactly as prescribed. Your healthcare provider will tell you how much Gabapentin to take.
    • 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. If taking capsules, always swallow them whole with plenty of water.
  • Gabapentin can be taken 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 before taking your next dose of Gabapentin.
  • 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?

  • 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.
  • 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?

  • See “What is the most important information I should know about Gabapentin?”
  • The most common side effects of Gabapentin include:
     
    • dizziness
    • lack of coordination
    • viral infection
    • feeling drowsy
    • feeling tired
    • fever
    • jerky movements
    • difficulty with speaking
    • temporary loss of memory

      (amnesia)

    • tremor
    • difficulty with coordination
    • double vision
    • unusual eye movement

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Gabapentin. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Gabapentin?

  • Store Gabapentin Capsules between 59°F to 86°F (15°C to 30°C).
  • Store Gabapentin Tablets between 59°F to 86°F (15°C to 30°C).
  • Store Gabapentin Oral Solution in the refrigerator between 36°F to 46°F (2°C to 8°C).

Keep Gabapentin and all medicines out of the reach of children.

General information about the safe and effective use of Gabapentin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Gabapentin for a condition for which it was not prescribed. Do not give Gabapentin to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Gabapentin. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Gabapentin that was written for healthcare professionals.

For medical inquiries or to report side effects regarding Gabapentin, please call 1-800-438-1985.

What are the ingredients in Gabapentin?

Active ingredient: Gabapentin

Inactive ingredients in the capsules: lactose, cornstarch, and talc.

The 100-mg capsule shell also contains: gelatin and titanium dioxide.

The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.

The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.

Inactive ingredients in the tablets: poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.

Inactive ingredients in the oral solution: glycerin, xylitol, purified water, and artificial flavor.

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

This product’s label may have been updated. For current full prescribing information, please visit www.greenstonellc.com

.

LAB-0437-5.0

July 2012

PRINCIPAL DISPLAY PANEL – 100 mg capsule bottle label

NDC 59762-5026-1

100 Capsules

GREENSTONE® BRAND

Gabapentin

capsules

100 mg

Rx only

PRINCIPAL DISPLAY PANEL – 300 mg capsule bottle label

NDC 59762-5027-1

100 Capsules

GREENSTONE® BRAND

Gabapentin

capsules

300 mg

Rx only

PRINCIPAL DISPLAY PANEL – 400 mg capsule bottle label

NDC 59762-5028-1

100 Capsules

GREENSTONE® BRAND

Gabapentin

capsules

400 mg

Rx only

PRINCIPAL DISPLAY PANEL – 600 mg tablet bottle label

NDC 59762-5023-1

100 Tablets

GREENSTONE® BRAND

Gabapentin

tablets

600 mg

Rx only

PRINCIPAL DISPLAY PANEL – 800 mg tablet bottle label

NDC 59762-5024-1

100 Tablets

GREENSTONE® BRAND

Gabapentin

tablets

800 mg

Rx only

PRINCIPAL DISPLAY PANEL – 470 mL Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 59762-5025-1

470 mL

GREENSTONE® BRAND

Gabapentin

oral solution

250 mg / 5 mL

Rx only

Gabapentin 

Gabapentin capsule

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5026
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Gabapentin (Gabapentin) Gabapentin 100 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
STARCH, CORN  
TALC  
GELATIN  
TITANIUM DIOXIDE  
FD&C BLUE NO. 2  
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 16mm
Flavor Imprint Code G;5026
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5026-1 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA020235 12/30/1993
Gabapentin 

Gabapentin capsule

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5027
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Gabapentin (Gabapentin) Gabapentin 300 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
STARCH, CORN  
TALC  
GELATIN  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
FD&C BLUE NO. 2  
Product Characteristics
Color YELLOW Score no score
Shape CAPSULE Size 19mm
Flavor Imprint Code G;5027
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5027-1 100 CAPSULE in 1 BOTTLE
2 NDC:59762-5027-2 500 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA020235 12/30/1993
Gabapentin 

Gabapentin capsule

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5028
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Gabapentin (Gabapentin) Gabapentin 400 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE  
STARCH, CORN  
TALC  
GELATIN  
FERRIC OXIDE RED  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
FD&C BLUE NO. 2  
Product Characteristics
Color ORANGE Score no score
Shape CAPSULE Size 22mm
Flavor Imprint Code G;5028
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5028-1 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA020235 12/30/1993
Gabapentin 

Gabapentin tablet, film coated

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5023
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
POLOXAMER 407  
STARCH, CORN  
MAGNESIUM STEARATE  
HYDROXYPROPYL CELLULOSE (TYPE H)  
TALC  
CANDELILLA WAX  
WATER  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL Size 18mm
Flavor Imprint Code G;21
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5023-1 100 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA020882 10/09/1998
Gabapentin 

Gabapentin tablet, film coated

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5024
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
POLOXAMER 407  
STARCH, CORN  
MAGNESIUM STEARATE  
HYDROXYPROPYL CELLULOSE (TYPE H)  
TALC  
CANDELILLA WAX  
WATER  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL Size 19mm
Flavor Imprint Code G;22
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5024-1 100 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA020882 10/09/1998
Gabapentin 

Gabapentin suspension

Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59762-5025
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Gabapentin (Gabapentin) Gabapentin 250 mg  in 5 mL
Inactive Ingredients
Ingredient Name Strength
GLYCERIN  
XYLITOL  
WATER  
Product Characteristics
Color      Score     
Shape Size
Flavor STRAWBERRY (cool strawberry anise) Imprint Code
Contains         
Packaging
# Item Code Package Description
1 NDC:59762-5025-1 470 mL in 1 BOTTLE, GLASS
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA AUTHORIZED GENERIC NDA021129 03/29/2011
Labeler - Greenstone LLC (825560733)
Registrant - Pfizer Inc (113480771)
Establishment
Name Address ID/FEI Operations
Pfizer Ireland Pharmaceuticals 989811526 API MANUFACTURE(59762-5023, 59762-5024, 59762-5025, 59762-5026, 59762-5027, 59762-5028)
Establishment
Name Address ID/FEI Operations
Pfizer Asia Pacific PTE LTD 894677996 API MANUFACTURE(59762-5023, 59762-5024, 59762-5025, 59762-5026, 59762-5027, 59762-5028)
Establishment
Name Address ID/FEI Operations
Pfizer Pharmaceuticals LLC 829084552 MANUFACTURE(59762-5023, 59762-5024, 59762-5025, 59762-5026, 59762-5027, 59762-5028)
Establishment
Name Address ID/FEI Operations
Hikal Ltd. 918602129 API MANUFACTURE(59762-5023, 59762-5024, 59762-5025, 59762-5026, 59762-5027, 59762-5028)
Establishment
Name Address ID/FEI Operations
DPT Laboratories, Ltd. 832224526 MANUFACTURE(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026), PACK(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026)
Establishment
Name Address ID/FEI Operations
Johnson & Johnson Healthcare Products Division of McNEIL-PPC, Inc. 801375143 MANUFACTURE(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026), PACK(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026)
Establishment
Name Address ID/FEI Operations
Orchid Chemicals & Pharmaceuticals Limited 650288850 MANUFACTURE(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026)
Establishment
Name Address ID/FEI Operations
ZACH SYSTEM SPA 517259979 API MANUFACTURE(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026)
Establishment
Name Address ID/FEI Operations
Pharmacia and Upjohn Company 829076566 MANUFACTURE(59762-5025, 59762-5024, 59762-5023, 59762-5028, 59762-5027, 59762-5026)

Revised: 12/2012   Greenstone LLC

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Gabapentin

Gabapentin

Pronunciation Generic Name: gabapentin (GAB-a-PEN-tin)

Brand Name: Gralise

OverviewSide EffectsInteractionsFor ProfessionalsMore…

Gabapentin is used for:

Treating nerve pain caused by shingles. It may also be used for other conditions as determined by your doctor.

Gabapentin is an analgesic for neuropathic (nerve) pain. Exactly how it works to treat nerve pain is not known.

Do NOT use gabapentin if:

  • you are allergic to any ingredient in gabapentin
  • you have severe kidney problems or are on dialysis

Contact your doctor or health care provider right away if any of these apply to you.

Video: Treatment for Depression Treatments for depression are getting better everyday and there are things you can start doing right away.

Before using gabapentin:

Some medical conditions may interact with gabapentin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

  • if you are pregnant, planning to become pregnant, or are breast-feeding
  • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
  • if you have allergies to medicines, foods, or other substances
  • if you have kidney problems
  • if you have a history of seizures, mental or mood problems (eg, depression), or suicidal thoughts or actions

Some MEDICINES MAY INTERACT with gabapentin. Tell your health care provider if you are taking any other medicines, especially any of the following:

  • Morphine or naproxen because they may increase the risk of gabapentin’s side effects, including drowsiness
  • Hydrocodone because its effectiveness may be decreased by gabapentin

This may not be a complete list of all interactions that may occur. Ask your health care provider if gabapentin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use gabapentin:

Use gabapentin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

  • Gabapentin comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get gabapentin refilled.
  • Take gabapentin by mouth with the evening meal, unless directed otherwise by your doctor.
  • Swallow gabapentin whole. Do not break, crush, or chew before swallowing.
  • Do not take an antacid that has aluminum or magnesium in it within 2 hours before you take gabapentin.
  • Gabapentin works best if it is taken at the same time each day.
  • Do not suddenly stop taking gabapentin. You may experience side effects such as anxiety, insomnia, nausea, pain, and sweating. Patients with seizure disorder may also experience increased seizures. If you need to stop gabapentin or add a new medicine, your doctor will gradually lower your dose.
  • If you miss a dose of gabapentin, take it with food as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use gabapentin.

Important safety information:

  • Gabapentin may cause drowsiness or dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use gabapentin with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
  • Check with your doctor before you drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are taking gabapentin; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.
  • Do not change your dose of gabapentin without checking with your doctor.
  • Do not switch between gabapentin and other gabapentin products without first checking with your doctor.
  • Patients who take gabapentin may be at increased risk of suicidal thoughts or actions. The risk may be greater in patients who have had suicidal thoughts or actions in the past. Watch patients who take gabapentin closely. Contact the doctor at once if new, worsened, or sudden symptoms, such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur.
  • A serious and sometimes life-threatening or fatal reaction that may affect your skin or other parts of your body (eg, liver, blood cells) has been reported in patients taking medicines for seizures, including gabapentin. A rash may or may not occur along with this reaction. Contact your doctor right away if you develop decreased urination; rash; red, swollen, blistered, or peeling skin; swollen glands or lymph nodes; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, stomach pain, yellowing of the skin or eyes); unusual bruising or bleeding; severe tiredness or weakness; unusual muscle pain; or symptoms of infection (eg, fever, chills, sore throat).
  • Diabetes patients – Gabapentin may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.
  • Gabapentin may interfere with certain lab tests. Be sure your doctor and lab personnel know you are taking gabapentin.
  • Use gabapentin with caution in the ELDERLY; they may be more sensitive to its effects, especially swelling of the hands, legs, or feet.
  • Gabapentin should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.
  • PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of taking gabapentin while you are pregnant. Gabapentin is found in breast milk. If you are or will be breast-feeding while you take gabapentin, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of gabapentin:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness; drowsiness; dry mouth; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); behavior changes; confusion; difficult or painful urination; fever; memory problems; new or worsening mental or mood changes (eg, depression, agitation, anxiety, panic attacks, aggressiveness, impulsiveness, irritability, hostility, exaggerated feeling of well-being, restlessness, inability to sit still); new or worsening trouble sleeping; red, swollen, blistered, or peeling skin; severe headache or dizziness; suicidal thoughts or actions; swelling of the hands, legs, or feet.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include diarrhea; double vision; drowsiness; sluggishness; slurred speech.

Proper storage of gabapentin: Store gabapentin at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep gabapentin out of the reach of children and away from pets.

General information:

  • If you have any questions about gabapentin, please talk with your doctor, pharmacist, or other health care provider.
  • Gabapentin is to be used only by the patient for whom it is prescribed. Do not share it with other people.
  • If your symptoms do not improve or if they become worse, check with your doctor.
  • Check with your pharmacist about how to dispose of unused medicine.

This information should not be used to decide whether or not to take gabapentin or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about gabapentin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to gabapentin. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using gabapentin.

Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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Gabapentin

Gabapentin

Pronunciation Class: Anticonvulsants, Miscellaneous

VA Class: CN400

Chemical Name: 1-(Aminomethyl)-cyclohexaneacetic acid

Molecular Formula: C9H17NO2

CAS Number: 60142-96-3

Brands: Neurontin

For ProfessionalsSide EffectsInteractionsMore…

Warning(s)

Special Alerts:

[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)
  • Gabapentin (marketed as Neurontin)
  • Lamotrigine (marketed as Lamictal)
  • Levetiracetam (marketed as Keppra)
  • Oxcarbazepine (marketed as Trileptal)
  • Pregabalin (marketed as Lyrica)
  • Tiagabine (marketed as Gabitril)
  • Topiramate (marketed as Topamax)
  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
  • Zonisamide (marketed as Zonegran)

For more information visit the FDA website at: and .

[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.

For more information visit the FDA website at: and .

[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)
  • Gabapentin (marketed as Neurontin)
  • Lamotrigine (marketed as Lamictal)
  • Levetiracetam (marketed as Keppra)
  • Oxcarbazepine (marketed as Trileptal)
  • Pregabalin (marketed as Lyrica)
  • Tiagabine (marketed as Gabitril)
  • Topiramate (marketed as Topamax)
  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
  • Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for gabapentin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; structurally related to the inhibitory CNS neurotransmitter GABA.1 4 6 7 8 9

Uses for Gabapentin

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures with or without secondary generalization in adults and children >12 years of age.1 2 8 9

Management (in combination with other anticonvulsants) of partial seizures in children 3–12 years of age.1

Neuropathic Pain

Management of postherpetic neuralgia in adults.1 20 21 22 23 24 38 39 40

Treatment of pain associated with diabetic neuropathy†.20 21 22 23 24 25 40 41 42 43 44 45 40% of patients who receive gabapentin for pain associated with diabetic neuropathy obtain good pain relief.40

Some evidence of benefit for the relief of chronic neurogenic pain† in a variety of conditions including trigeminal neuralgia†,20 21 46 47 pain and control of paroxysmal symptoms of multiple sclerosis†,20 21 48 49 complex regional pain syndromes†,20 52 53 HIV-related peripheral neuropathy†,20 21 50 and neuropathic pain associated with cancer†.20 21 51 Also has been used in the treatment of restless legs syndrome†.26 27 28 Additional study needed to further elucidate precise role in the management of these conditions.

Vasomotor Symptoms

Has been used for the management of vasomotor symptoms (e.g., hot flashes) in women with breast cancer†.30

Has been used for the management of vasomotor symptoms (e.g., hot flashes) associated with menopause†.31 34 54

Gabapentin Dosage and Administration

General

Seizure Disorders

  • Monitoring of plasma gabapentin concentrations is not necessary to optimize therapy.1 Because addition of gabapentin to existing anticonvulsant therapy does not appreciably alter steady-state plasma concentrations of concomitantly administered anticonvulsants, additional monitoring of plasma concentrations of anticonvulsants generally is not necessary.1 (See Specific Drugs under Interactions.)

  • Discontinuance of gabapentin and/or addition of an alternative anticonvulsant drug to therapy should be done gradually over ≥1 week.1

Administration

Oral Administration

Administer orally without regard to meals.1

If Neurontin film-coated scored tablets containing 600 or 800 mg of gabapentin are to be used in patients requiring a 300- or 400-mg dose, divide the tablet in half to allow administration of the appropriate dose.1 Instruct patients to take one-half tablet and to use the remaining half-tablet for the next dose.1 Half-tablets that are not used within several days should be discarded.1

Seizure Disorders

Administer orally 3 times daily.1 The interval between doses in this schedule should not exceed 12 hours.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

Seizure Disorders
Partial Seizures

Oral Children 3–12 years of age: Initially, 10–15 mg/kg daily in 3 divided doses.1 Maintenance dosage of 40 mg/kg daily in 3 divided doses for children 3 or 4 years of age and 25–35 mg/kg daily in 3 divided doses for children 5–12 years of age.1

Children >12 years of age: Initially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.1

Adults

Seizure Disorders
Partial Seizures

Oral Initially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.1

Neuropathic Pain
Postherpetic Neuralgia

Oral 300 mg on the first day, 300 mg twice daily on the second day, and 300 mg 3 times daily on the third day.1 Increase dosage as needed for relief of pain up to a total daily dosage of 1.8 g in 3 divided doses.1 No evidence of additional benefit with dosages >1.8 g daily.1

Diabetic Neuropathy

Oral Dosages of 900 mg to 3.6 g daily have been used; however, pain relief generally observed in patients receiving dosages >1.8 g daily.24 25

Vasomotor Symptoms†
Oral

300 mg 3 times daily has been effective; higher dosages may provide additional benefit.30 31 37

Prescribing Limits

Pediatric Patients

Children 3–12 years of age: Dosages up to 50 mg/kg daily in divided doses have been tolerated as adjunctive therapy in the management of partial seizures.1

Children >12 years of age: Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.1

Adults

Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.1

Special Populations

Renal Impairment

Not studied in children <12 years of age with renal impairment.1

In adults and children ≥12 years of age, base dosage on measured or estimated Clcr:1 16

aIn patients with Clcr <15 mL/min, reduce dosage proportionally (e.g., a patient with a Clcr of 7.5 mL/min should receive one-half the dosage that a patient with a Clcr of 15 mL/min should receive).

bGive maintenance doses based on Clcr, with supplemental doses (125–350 mg) given after each 4-hour hemodialysis session.1

Dosage for Adults and Children ≤12 Years of Age with Renal Impairment
Clcr (mL/min)

Total Daily Dosage (mg/day)

Dosage Regimen

≥60

900–3600

300 –1200 mg 3 times daily

30–59

400–1400

200 –700 mg twice daily

15–29

200–700

200 –700 mg once daily

15a

100–300

100 –300 mg once daily

ESRD patients undergoing hemodialysis

125–350 mgb

Geriatric Patients

Select dosage carefully, usually initiating therapy at the low end of the dosage range.1 Adjust dosage based on Clcr.1

Cautions for Gabapentin

Contraindications

  • Known hypersensitivity to gabapentin or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cognitive/Neuropsychiatric Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Emotional lability (primarily behavioral problems), hostility (including aggressive behaviors), thought disorders (including concentration and school performance changes), and hyperkinesia (primarily restlessness and hyperactivity) associated with use in children 3–12 years of age with epilepsy.1

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency; withdraw gabapentin gradually and reduce dosage slowly over ≥1 week.1

Status Epilepticus

Not established whether incidence of status epilepticus (1.5% in controlled and uncontrolled trials of gabapentin) is higher or lower than would be expected in patients with epilepsy not treated with the drug.1

Tumorigenic Potential

Unexpectedly high incidence of pancreatic acinar adenocarcinomas in male but not female rats.1 Clinical relevance unknown.1

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk; use only if potential benefits outweigh the risks.1

Pediatric Use

Safety and efficacy as adjunctive therapy in the management of partial seizures not established in children <3 years of age.1

Safety and efficacy for the management of postherpetic neuralgia not established in children.1

Geriatric Use

Insufficient experience with gabapentin for the management of partial seizures in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Select dosage carefully.1 (See Geriatric Patients under Dosage and Administration.)

Appeared to be more effective for the management of postherpetic neuralgia in patients >75 years of age than in younger patients; apparent difference in efficacy may be related to decreased renal function in older patients.1

Adverse effects in older patients with postherpetic neuralgia generally similar to those in younger adults; however, the incidence of peripheral edema and ataxia appears to increase with age.1

Geriatric patients may have decreased hepatic, renal, or cardiac function, with increased risk of adverse effects.1 16 Use with caution; renal function monitoring may be useful.1

Renal Impairment

Clearance decreased; adjust dosage in adults and children ≥12 years of age with renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Use in children <12 years of age with renal impairment has not been studied.1

Common Adverse Effects

Children 3–12 years of age receiving gabapentin as adjunctive therapy for partial seizures: viral infection, fever, nausea and/or vomiting, somnolence, hostility.1

Adults and children >12 years of age receiving gabapentin as adjunctive therapy for partial seizures with or without secondary generalization: somnolence, dizziness, ataxia, fatigue, nystagmus.1

Adults receiving gabapentin for management of postherpetic neuralgia: dizziness, somnolence, peripheral edema.1

Interactions for Gabapentin

Not metabolized by CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; causes slight inhibition of CYP2A6 at high concentrations.1

Specific Drugs

Drug

Interaction

Comments

Antacids

Reduced bioavailability of gabapentin1

Administer gabapentin at least 2 hours after antacid1

Anticonvulsants

Plasma concentrations of carbamazepine, phenytoin, valproic acid, phenobarbital, and diazepam in existing treatment regimens not affected by gabapentin;1 3 12 13 14 pharmacokinetics of gabapentin not affected by these drugs1 6 12 15

Cimetidine

Possible decrease in gabapentin clearance 1

Not likely to be clinically important1

Hydrocodone

Possible dose-dependent decrease in plasma concentrations of hydrocodone; possible increase in plasma concentrations of gabapentin1

Morphine

Increase in plasma concentrations of gabapentin1

Decrease in dosage of morphine or gabapentin may be required in patients with symptoms of CNS depression (e.g., somnolence)1

Naproxen

Increased bioavailability of gabapentin at subtherapeutic dosages of both drugs1

Extent of interaction at usual therapeutic dosages is unknown1

Oral Contraceptives

Possible increase in peak plasma concentrations of norethindrone1

Not likely to be clinically important1

Probenecid

No pharmacokinetic interaction observed1

Gabapentin Pharmacokinetics

Absorption

Bioavailability

Bioavailability of 60–27% for doses ranging from 900 mg to 4.8 g daily.1 Bioavailability is not dose proportional.1

Food

Food increases extent of absorption and peak plasma concentration by 14%.1

Distribution

Extent

Readily crosses the blood-brain barrier and concentrates in brain tissue.29 Distributed into breast milk.1 Not known whether gabapentin crosses the placenta.1

Plasma Protein Binding

<3%.1

Elimination

Metabolism

Not appreciably metabolized.1

Elimination Route

Excreted renally as unchanged drug.1

Half-life

5–7 hours.1

Special Populations

In children <5 years of age, clearance normalized for weight is higher than in adults and children ≥5 years of age.1

In patients with renal impairment, plasma clearance is decreased and half-life is prolonged.1 In patients with Clcr <30 mL/minute, half-life of 52 hours reported.1 In anuric patients, half-life reported to be 132 hours on nondialysis days and 3.8 hours during hemodialysis.1

Stability

Storage

Oral

Capsules and Tablets

25°C (may be exposed to 15–30°C).1

Oral Solution

2–8°C.1

Actions

  • Mechanism of anticonvulsant action is unknown.1 4 5 7 8 9 Does not bind to GABA receptors,1 4 5 6 7 17 affect GABA reuptake or metabolism, 1 6 7 17 or act as a precursor of GABA or other substances active at GABA receptors.1 17

  • Mechanism of analgesic action is unknown.1 20 21 22 23 Prevents allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several animal models of neuropathic pain.1 20 Decreases pain-related responses after peripheral inflammation in animals; however, has not altered immediate pain-related behaviors.1 Clinical relevance of these findings is not known.1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of taking gabapentin exactly as prescribed.1 Importance of not abruptly discontinuing therapy.1

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1
  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
  • Importance of informing patients of other important precautionary information. (See Cautions.)1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Gabapentin
Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg*

Gabapentin Capsules

Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva

Neurontin

Pfizer

300 mg*

Gabapentin Capsules

Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva

Neurontin

Pfizer

400 mg*

Gabapentin Capsules

Actavis, Apotex, Mutual, Ranbaxy, Sandoz, Teva

Neurontin

Pfizer

Solution

250 mg/5 mL

Neurontin

Pfizer

Tablets

100 mg*

Gabapentin Tablets

Greenstone, Ranbaxy, Teva

300 mg*

Gabapentin Tablets

Greenstone, Ranbaxy, Teva

400 mg*

Gabapentin Tablets

Greenstone, Ranbaxy, Teva

600 mg

Gabapentin Tablets

Teva

800 mg

Gabapentin Tablets

Teva

Tablets, film-coated

600 mg

Gabapentin Tablets

Actavis

Neurontin

Pfizer

800 mg

Gabapentin Tablets

Actavis

Neurontin

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gabapentin 100MG Capsules (AMNEAL PHARMACEUTICALS): 90/$43.99 or 270/$115.97

Gabapentin 250MG/5ML Solution (HI-TECH): 470/$139.99 or 1410/$399.96

Gabapentin 300MG Capsules (AMNEAL PHARMACEUTICALS): 90/$18.99 or 270/$39.96

Gabapentin 400MG Capsules (AMNEAL PHARMACEUTICALS): 90/$74.99 or 270/$209.98

Gabapentin 600MG Tablets (GLENMARK PHARMACEUTICALS): 90/$98.99 or 270/$251.96

Gabapentin 800MG Tablets (GLENMARK PHARMACEUTICALS): 90/$99.99 or 100/$107.97

Neurontin 100MG Capsules (PFIZER U.S.): 100/$93.99 or 300/$269.97

Neurontin 250MG/5ML Solution (PFIZER U.S.): 470/$172.99 or 1410/$475.97

Neurontin 300MG Capsules (PFIZER U.S.): 30/$72.99 or 90/$199.96

Neurontin 400MG Capsules (PFIZER U.S.): 30/$83.99 or 90/$245.97

Neurontin 600MG Tablets (PFIZER U.S.): 90/$396.98 or 100/$435.99

Neurontin 800MG Tablets (PFIZER U.S.): 90/$481.00 or 270/$1,399.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug’s actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Parke-Davis. Neurontin (gabapentin) capsules prescribing information. New York, NY; 2005 Dec.

2. Anon. Parke-Davis’ Neurontin recommended for approval as “add on” therapy for refractory seizures in epilepsy; gabapentin monotherapy trials under way. F-D-C Rep. 1992 Dec:7-8.

3. Anon. Warner Lambert’s Neurontin approved for adjunctive therapy in epilepsy patients Dec 30; “1P” drug does not interact with other anticonvulsants. F-D-C Rep. 1994 Jan:11.

4. Ramsay ER. Advances in the pharmacotherapy of epilepsy. Epilepsia. 1993; 34(Suppl 5):S9-16. [PubMed 8339715]

5. MacDonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1993; 34(Suppl 5):S1-8. [IDIS 319353] [PubMed 7687957]

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9. US Gabapentin Study Group. Gabapentin as add-on therapy in refractory partial epilepsy: a double blind, placebo-controlled, parallel-group study. Neurology. 1993; 43:2292-8. (IDIS 321974) [IDIS 321974] [PubMed 8232945]

10. Suman-Chauhan N, Webdale L, Hill DR et al. Characterisation of [3H] gabapentin binding to a novel site in rat brain: homogenate binding studies. Eur J Pharmacol. 1993; 244:293-301.

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12. Anhut H, Leppik I, Schmidt B et al. Drug interaction study of the new anticonvulsant gabapentin with phenytoin in epileptic patients. Naunyn- Schmiedeberg Arch Pharmacol. 1988; 337(Suppl):R127. Abstract No. 507.

13. Graves NM, Leppik IE, Wagner ML et al. Effect of gabapentin on carbamazepine levels. Epilepsia. 1990; 31:644. Abstract.

14. Uthman BM, Hammond EJ, Wilder BJ. Absence of gabapentin and valproate interaction: an evoked potential and pharmacokinetic study. Epilepsia. 1990; 31:645. Abstract.

15. Hooper WD, Kavanagh MC, Herkes GK et al. Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin. Br J Clin Pharmacol. 1991; 31:171-4. [IDIS 277831] [PubMed 2049232]

16. Parke-Davis, Morris Plains, NJ: Personal communication.

17. Taylor CP. Mechanism of action of new anti-epileptic drugs. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine Services Ltd; 1993:13-40.

18. Appleton R, Fichtner K, LaMoreaux L et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Epilepsia. 1999; 40:1147-54. [IDIS 432135] [PubMed 10448830]

19. Pfizer, Morris Plains, NJ: Personal communication.

20. Rose MA, Kam PCA. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002; 57:451-62. [IDIS 483415] [PubMed 11966555]

21. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes. Drugs. 2000; 60:1029-1052. [PubMed 11129121]

22. Ross EL. The evolving role of antiepileptic drugs in treating neuropathic pain. Neurology. 2000; 55(supp 1):S41-S46. [IDIS 453200] [PubMed 11001361]

23. Wiffen P, Collins S, McQuay H et al. Anticonvulsant drugs for acute and chronic pain (Cochrane Review). In: The Cochrane Library, Issue 3. Oxford, United Kingdom: update software 2002.

24. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology. 2002; 59(suppl 2):S14-S17.

25. Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA. 1998; 280:1831-6. [IDIS 418038] [PubMed 9846777]

26. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin. Neurology. 2002;59:1573-79.

27. Happe S, Klosch G, Saletu, et al. Treatment of restless legs syndrome (RLS) with gabapentin. Neurology. 2001;57:1717-19.

28. Thorp MK, Morris DC, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J of Kidney Diseases. 2001;38:104-8.

29. Luer MS, Hamani C, Dujovny M et al. Saturable transport of gabapentin at the blood-brain barrier. Neurol Res. 1999; 21:559-62. [PubMed 10491815]

30. Pandya KJ, Morrow GR, Roscoe JA et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet. 2005;366:818-24.

31. Guttuso T, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337-45.

32. Jeffery SM, Pepe JJ, Popovich LM et al. Gabapentin for hot flashes in prostate cancer. Ann Pharmacother. 2002; 36:433-6. [IDIS 477342] [PubMed 11895055]

33. Stearns V. Management of hot flashes in breast cancer survivors and men with prostate cancer. Curr Oncol Rep. 2004; 6:285-90. [PubMed 15161582]

34. Fugate SE, Church CO. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. Ann Pharmacother. 2004; 38:1482-99. [IDIS 528920] [PubMed 15292498]

35. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet. 2000; 356:2059-63. [IDIS 459837] [PubMed 11145492]

36. Reviewers’ comments (personal observations).

37. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society. Menopause. 2004; 11:11-33. [PubMed 14716179]

38. Rice AS, Maton S, . Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001; 94:215-24. [PubMed 11690735]

39. Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998; 280:1837-42. [PubMed 9846778]

40. Wiffen PJ, McQuay HJ, Edwards JE et al. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005; 3:CD005452. [PubMed 16034978]

41. Gorson KC, Schott C, Herman R, Ropper AH. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999; 66 :251-2. (Letter) [PubMed 10071116]

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