Gabapentin

Pronunciation

(GA ba pen tin)

U.S. Brand Names

Neurontin®

Generic Available

Yes: Capsule, tablet

Canadian Brand Names

Apo-Gabapentin®; Neurontin®; Novo-Gabapentin; Nu-Gabapentin; PMS-Gabapentin

Use

Adjunct for treatment of partial seizures with and without secondary generalized seizures in patients >12 years of age with epilepsy; adjunct for treatment of partial seizures in pediatric patients 3-12 years of age; management of post-herpetic neuralgia (PHN) in adults

Use - Unlabeled/Investigational

Social phobia; chronic pain

Pregnancy Risk Factor

Pregnancy Implications

No data on crossing the placenta; there have been reports of normal pregnancy outcomes, as well as respiratory distress, pyloric stenosis, and inguinal hernia following 1st trimester exposure to gabapentin plus carbamazepine; epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Use during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to gabapentin or any component of the formulation

Warnings/Precautions

Avoid abrupt withdrawal, may precipitate seizures; may be associated with a slight incidence (0.6%) of status epilepticus and sudden deaths (0.0038 deaths/patient year); use cautiously in patients with severe renal dysfunction; rat studies demonstrated an association with pancreatic adenocarcinoma in male rats; clinical implication unknown. May cause CNS depression, which may impair physical or mental abilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. Pediatric patients (3-12 years of age) have shown increased incidence of CNS-related adverse effects, including emotional lability, hostility, thought disorder, and hyperkinesia. Safety and efficacy in children <3 years of age have not been established.

Adverse Reactions

As reported in patients >12 years of age, unless otherwise noted

>10%:

Central nervous system: Somnolence (20%), dizziness (17%), ataxia (12%), fatigue (11% in adults)

Miscellaneous: Viral infection (11% in children 3-12 years)

1% to 10%:

Cardiovascular: Peripheral edema (2%)

Central nervous system: Fever (10% in children 3-12 years), hostility (8% in children 3-12 years), somnolence (8% in children 3-12 years), emotional lability (4% to 6% in children 3-12 years), fatigue (3% in children 3-12 years), abnormal thinking (2% in children and adults), amnesia (2%), depression (2%), dizziness (2% in children 3-12 years), dysarthria (2%), nervousness (2%), abnormal coordination (1%), twitching (1%)

Dermatologic: Pruritus (1%)

Gastrointestinal: Nausea/vomiting (8% in children 3-12 years), weight gain (3% in adults and children), dyspepsia (2%), dry throat (2%), xerostomia (2%), appetite stimulation (1%), constipation (1%), dental abnormalities (1%)

Genitourinary: Impotence (1%)

Hematologic: Leukopenia (1%), decreased WBC (1%)

Neuromuscular & skeletal: Tremor (7%), hyperkinesia (3% to 5% in children 3-12 years), back pain (2%), myalgia (2%)

Ocular: Nystagmus (8%), diplopia (6%), blurred vision (4%)

Respiratory: Rhinitis (4%), bronchitis (3% in children 3-12 years), pharyngitis (3%), cough (2%), respiratory infection (2% in children 3-12 years)

Postmarketing and additional clinical reports (limited): Allergy, alopecia, angina pectoris, angioedema, anorexia, coagulation defect, erythema multiforme, ethanol intolerance, facial edema, flatulence, gingivitis, blood glucose fluctuation, subdural hematoma, hepatitis, hypercholesterolemia, hyperlipidemia, hypertension, hyponatremia, intracranial hemorrhage, jaundice, elevated liver function tests, malaise, palpitation, pancreatitis, peripheral vascular disorder, pneumonia, purpura, Stevens-Johnson syndrome, new tumor formation/worsening of existing tumors, vertigo, weakness

Overdosage/Toxicology

Acute oral overdoses of up to 49 g have been reported; double vision, slurred speech, drowsiness, lethargy, and diarrhea were observed. Patients recovered with supportive care. Decontaminate using lavage/activated charcoal with cathartic. Multiple dosing of activated charcoal may be useful; hemodialysis may be useful.

Drug Interactions

Antacids: Antacids may reduce the bioavailability of gabapentin by ~20%; gabapentin should be taken at least 2 hours following antacid administration

Cimetidine: Cimetidine may increase gabapentin serum concentrations; clearance of gabapentin is decreased by 14%

Felbamate: Serum concentrations may be increased by gabapentin; monitor for increased felbamate effect/toxicity

Morphine: Serum concentrations of gabapentin may be increased during concurrent use.

Norethindrone: Gabapentin may increase Cmax of norethindrone by 13%

Phenytoin: Phenytoin serum concentrations may be increased by gabapentin; limited documentation; monitor. Note: Valproic acid, carbamazepine, and phenobarbital do not seem to be affected by gabapentin.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Does not change rate or extent of absorption.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Mechanism of Action

Exact mechanism of action is not known, but does have properties in common with other anticonvulsants; although structurally related to GABA, it does not interact with GABA receptors

Pharmacodynamics/Kinetics

Absorption: 50% to 60%

Distribution: Vd: 0.6-0.8 L/kg

Protein binding: 0%

Bioavailability: As gabapentin dose increases, bioavailability decreases; it is absorbed from proximal small bowel into blood by L-amino transport system (which becomes saturated, therefore is a major contributor to lack of proportionality in plasma levels). Interpatient variability exists; standard gabapentin doses may result in different plasma concentrations in individual patients.

900 mg divided 3 times/day: 60%

1200 mg divided 3 times/day: 47%

2400 mg divided 3 times/day: 34%

3600 mg divided 3 times/day: 33%

4800 mg divided 3 times/day: 27%

Half-life elimination: 5-6 hours

Excretion: Urine (56% to 80%)

Dosage

Oral:

Children: Anticonvulsant:

3-12 years: Initial: 10-15 mg/kg/day in 3 divided doses; titrate to effective dose over ~3 days; dosages of up to 50 mg/kg/day have been tolerated in clinical studies

3-4 years: Effective dose: 40 mg/kg/day in 3 divided doses

5-12 years: Effective dose: 25-35 mg/kg/day in 3 divided doses

Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week

Children >12 years and Adults:

Anticonvulsant: Initial: 300 mg 3 times/day; if necessary the dose may be increased using 300 mg or 400 mg capsules 3 times/day up to 1800 mg/day

Dosage range: 900-1800 mg administered in 3 divided doses at 8-hour intervals

Pain (unlabeled use): 300-1800 mg/day given in 3 divided doses has been the most common dosage range

Adults: Post-herpetic neuralgia: Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times/day; dose may be titrated as needed for pain relief (range: 1800-3600 mg/day, daily doses >1800 mg do not generally show greater benefit)

Elderly: Studies in elderly patients have shown a decrease in clearance as age increases. This is most likely due to age-related decreases in renal function; dose reductions may be needed.

Dosing adjustment in renal impairment: Children 12 years and Adults: See table.

Hemodialysis

Neurontin Dosing Adjustments in Renal Impairment

Creatinine Clearance (mL/min)	Daily Dose Range
60	300-1200 mg tid
>30-59	200-700 mg bid
>15-29	200-700 mg daily
15¹	100-300 mg daily
Hemodialysis ²	125-350 mg
¹ Clcr<15 mL/minute: Reduce daily dose in proportion to creatinine clearance.
² Single supplemental dose administered after each 4 hours of hemodialysis

Administration

Maximum time interval between multiple daily doses should not exceed 12 hours; administer first dose on first day at bedtime to avoid somnolence and dizziness

Monitoring Parameters

Monitor serum levels of concomitant anticonvulsant therapy

Reference Range

Minimum effective serum concentration may be 2 mcg/mL

Test Interactions

False positives have been reported with the Ames N-Multistix SG® dipstick test for urine protein

Dietary Considerations

May be taken without regard to meals.

Patient Education

Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; may cause physical and/or psychological dependence. If prescribed once-a-day, take dose at bedtime. If taking antacids, take at least 2 hours after antacids. Do not stop medication abruptly, may lead to increased seizure activity. Avoid alcohol, caffeine, and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); diarrhea (buttermilk, yogurt, or boiled milk may help); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); or decreased sexual function or libido (reversible). Report persistent CNS effects (nervousness, restlessness, insomnia, anxiety, excitation, headache, sedation, seizures, mania, abnormal thinking); rash or skin irritation; muscle cramping, tremors, or change in gait; chest pain or palpitations; change in urinary pattern; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

CSF level is 20% of blood concentration. Gabapentin is not recommended for children <3 years of age.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), dry throat, and dental abnormalities.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Capsule (Neurontin®): 100 mg, 300 mg, 400 mg

Solution, oral (Neurontin®): 250 mg/5 mL (480 mL) [cool strawberry anise flavor]

Tablet: 100 mg, 300 mg, 400 mg

Neurontin®: 600 mg, 800 mg

Extemporaneously Prepared

A 100 mg/mL suspension was stable for 91 days when refrigerated or 56 days when kept at room temperature when compounded as follows:

Triturate sixty-seven 300 mg tablets in a mortar, reduce to a fine powder, then add a small amount of one of the following vehicles to make a paste; then add the remaining vehicle in small quantities while mixing:

Vehicle 1. Methylcellulose 1% (100 mL) and Simple Syrup N.F. (100 mL) mixed together in a graduate, or

Vehicle 2. Ora-Sweet® (100 mL) and Ora-Plus® (100 mL) mixed together in a graduate

Shake well before using and keep in refrigerator

Nahata MC, Morosco RS, and Hipple TF, Stability of Gabapentin in Extemporaneously Prepared Suspensions at Two Temperatures , American Society of Health System Pharmacists Midyear Meeting, December 7-11, 1997.

References

Adler CH, "Treatment of Restless Legs Syndrome With Gabapentin," Clin Neuropharmacol , 1997, 20(2):148-51.

Andrews CO and Fischer JH, "Gabapentin: A New Agent for the Management of Epilepsy," Ann Pharmacother , 1994, 28(10):1188-96.

Bourgeois BF, "Antiepileptic Drugs in Pediatric Practice," Epilepsia , 1995, 36(Suppl 2):34-45.

Fernandez M, Walter F, Petersen L, et al, "Gabapentin Overdose: Elevated Levels With Minimal Clinical Effects," Clin Toxicol , 1995, 33(5):521-2.

Fischer JH, Barr AN, Rogers SL, et al, "Lack of Serious Toxicity Following Gabapentin Overdose," Neurology , 1994, 44(5):982-3.

Goa KL and Sorkin EM, "Gabapentin: A Review of Its Pharmacological Properties and Clinical Potential in Epilepsy," Drugs , 1993, 46(3):409-27.

Khurana DS, Riviello J, Helmers S, et al, "Efficacy of Gabapentin Therapy in Children With Refractory Partial Seizures," J Pediatr , 1996, 128(6):829-33.

Lee DO, Steingard RJ, Cesena M, et al, "Behavioral Side Effects of Gabapentin in Children," Epilepsia , 1996, 37(1):87-90.

Leiderman D, Garofalo E, and LaMoreaux L, "Gabapentin Patients With Absence Seizures: Two Double-Blind, Placebo Controlled Studies," Epilepsia , 1993, 34(Suppl 6):45.

Mellick LB and Mellick GA, "Successful Treatment of Reflex Sympathetic Dystrophy With Gabapentin," Am J Emerg Med , 1995, 13(1):96.

Pande AC, Crockatt JG, Janney CA, et al, "Gabapentin in Bipolar Disorder: A Placebo-Controlled Trial of Adjunctive Therapy. Gabapentin Bipolar Disorder Study Group," Bipolar Disord , 2000, 2(3):249-55.

Short C and Cooke L, "Hypomania Induced by Gabapentin," Br J Psychiatry , 1995, 166(5):679-80.

International Brand Names

Apo-Gabapentin® (CA); Gabapentin 1A Farma® (DK); Gabapentina® (BR); Gabapentina Calier® (ES); Gabapentina Combino Pharm® (ES); Gabapentina Combuxium® (ES); Gabapentina Kern® (ES); Gabapentin AL® (DE); Gabapentina Vegal® (ES); Gabapentin beta® (DE); Gabapentin-biomo® (DE); Gabapentin DuraScan® (DK); Gabapentin Hexal® (DE); Gabapentin-neuraxpharm® (DE); Gabapentin Pfizer® (DK); Gabapentin Pliva® (DK); Gabapentin-ratiopharm® (DE); Gabapentin Stada® (DE); Gabapentin-Teva® (DE, IL); Gabapentin Torrex® (AT); Gabapentin UNP® (DK); Gabax® (DE, PL); Gagapentin dura® (DE); Kaptin® (CO); Neuril® (DK); Neurontin® (AR, AT, AU, BE, BR, CA, CH, CO, CY, CZ, DE, EG, ES, FI, FR, GB, HR, HU, ID, IE, IL, IN, IT, JO, KW, LB, MX, NL, NO, NZ, PL, PT, RO, SE, SG, SI, TH, TR, YU, ZA); Neurostil® (IE); Normatol® (CL); Novo-Gabapentin (CA); Nu-Gabapentin (CA); PMS-Gabapentin (CA); Progresse® (BR)

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