GabapentinClass: Anticonvulsants, MiscellaneousVA Class: CN400Chemical Name: 1-(Aminomethyl)-cyclohexaneacetic acidMolecular Formula: C9H17NO2

CAS Number: 60142-96-3

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

≥60 900–3600300 –1200 mg 3 times daily

30–59 400–1400 200 –700 mg twice daily15–29 200–700 200 –700 mg once daily15a 100–300 100 –300 mg once dailyESRD 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

HydrocodonePossible 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

NaproxenIncreased 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

Routes Dosage Forms StrengthsOral Capsules 100 mg*

300 mg*400 mg*

Solution 250 mg/5 mLTablets 100 mg*

300 mg*400 mg*600 mg800 mg

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]

6. Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs. 1993; 46:409-27. [PubMed 7693432]

7. Graves NM, Leppik IE. Antiepileptic medications in development. DICP Ann Pharmacother. 1991; 25:978-86. [IDIS 285278] [PubMed 1949977]

8. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet. 1990; 335:1114-7. [IDIS 266256] [PubMed 1971862]

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.

11. Hill DR, Suman-Chauhan N, Woodruff GN. Localization of [3H] gabapentin to a novel site in rat brain: autoradiogaphic studies. Eur J Pharmacol. 1993; 244: 303-9. [PubMed 8384571]

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]

42. Pérez HE, Sánchez GF. Gabapentin therapy for diabetic neuropathic pain. Am J Med. 2000; 108; 689. (Letter)

43. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromusc Dis. 2001; 3:53-62.

44. Dallocchio C, Buffa C, Mazzarello P et al. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage. 2000; 20:280-5. [PubMed 11027910]

45. Morello CM, Leckband SG, Stoner CP et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999; 159:1931-7. [PubMed 10493324]

46. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology. 1998; 51:611-4. [PubMed 9710050]

47. Cheshire WP. Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain. 2002; 3:137-42. [PubMed 14622800]

48. Solaro C, Lunardi GL, Capello E et al. An open-label trial of gabapentin treatment of paroxysmal symptoms in multiple sclerosis patients. Neurology. 1998; 51:609-11. [PubMed 9710049]

49. Yetimalar Y, Gürgör N, Basoglu M. Clinical efficacy of gabapentin for paroxysmal symptoms in multiple sclerosis. Acta Neurol Scand. 2004; 109; 430-1. (Letter) [PubMed 15147470]

50. Hahn K, Arendt G, Braun JS et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004; 251:1260-6. [PubMed 15503108]

51. Caraceni A, Zecca E, Bonezzi C et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol. 2004; 22:2909-17. [PubMed 15254060]

52. Serpell MG, . Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002; 99:557-66. [PubMed 12406532]

53. van der Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in complex regional pain syndrome type 1. BMC Neurology. 2004. From Bio Med Central website (.)

54. Reddy SY, Warner H, Guttuso T et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol. 2006; 108:41-8. [PubMed 16816054]