AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• Gabapentin

• Gabapentin Enacarbil

Gabapentin is an anticonvulsant structurally related to the inhibitory CNS neurotransmitter γ -aminobutyric acid (GABA); the drug also possesses analgesic activity.1,4,6,7,8,9,60,61 Gabapentin enacarbil is a prodrug of gabapentin.61,76,83

Conventional (immediate-release) preparations of gabapentin are used in the management of seizure disorders.1 Conventional preparations also may be used in the treatment of postherpetic neuralgia (PHN).1 Gabapentin also is commercially available as a gastroretentive tablet formulation (Gralise^®) for once-daily administration in the treatment of PHN.60,64 Because of differences in pharmacokinetic properties, gabapentin gastroretentive tablets are not interchangeable with other gabapentin preparations.60

Gabapentin enacarbil, a prodrug of gabapentin, is commercially available as an extended-release tablet formulation (Horizant^®) for once-daily administration in the treatment of PHN or primary restless legs syndrome.61 Because of differences in pharmacokinetic properties, gabapentin enacarbil extended-release tablets are not interchangeable with other gabapentin preparations.61

Seizure Disorders

Gabapentin (as conventional preparations) is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial seizures with or without secondary generalization.1,2,8,9 Clinical studies establishing efficacy of gabapentin for this indication were conducted with conventional (immediate-release) preparations of the drug; efficacy of gabapentin gastroretentive tablets (Gralise^®) and gabapentin enacarbil (Horizant^®) have not been established in patients with seizure disorders.60,61 The anticonvulsant potential of conventional gabapentin has been established in studies in which the drug was compared to placebo in adults and children 3 years of age or older with refractory partial seizures; comparative efficacy of therapeutically effective dosages of gabapentin versus other anticonvulsants remains to be established.1,8,9

In several placebo-controlled studies, gabapentin (administered as conventional preparations) was effective in reducing seizure frequency, including that of secondarily generalized tonic-clonic seizures, in 17-26% of patients with partial seizures refractory to therapy with other anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid).1,2,8,9 Patients in these studies had a history of at least 4 partial seizures (with or without secondary tonic-clonic generalization) per month despite optimum therapy with one or more anticonvulsants and were eligible for study entry if they continued to have at least 2-4 seizures per month during a 12-week baseline period while receiving their established anticonvulsant regimen.1,8,9,16 Efficacy of gabapentin in these studies was evaluated principally in terms of the percentage of patients with a reduction in seizure frequency of 50% or greater compared with baseline values (i.e., responder rate) and the change in seizure frequency associated with the addition of gabapentin or placebo to existing anticonvulsant treatment (i.e., response ratio, calculated as treatment seizure frequency minus baseline seizure frequency divided by the sum of the treatment and baseline seizure frequencies).1,8,9 Combined analysis of these response parameters in patients receiving various dosages of gabapentin (600, 900, 1200, or 1800 mg in 3 divided doses daily as conventional preparations) or placebo indicated a dose-related reduction in the frequency of partial seizures with gabapentin, although a dose-response relationship was not consistently found in the individual studies.1,8,9 The efficacy of adjunctive therapy with gabapentin for the management of partial seizures does not appear to be affected by patient gender or age, although the influence of these characteristics on efficacy has not been studied systematically.1,8,9

Efficacy of gabapentin (as conventional preparations) in children 3-12 years of age with partial seizures was established in a multicenter randomized controlled trial.1,18,19 Response ratios were substantially better in patients receiving gabapentin 25-35 mg/kg daily (as conventional preparations) compared with those receiving placebo; for the same population, the responder rate for the drug (21%) was not substantially different from placebo (18%).1,18,19 Another study in children 1 month to 3 years of age reported no substantial difference in either the response ratio or responder rate for those receiving gabapentin compared with those receiving placebo.1,19

Neuropathic Pain

Postherpetic Neuralgia

Gabapentin and gabapentin enacarbil are used in the management of postherpetic neuralgia (PHN) in adults.1,20,21,22,24,38,39,60,61,62,66,67,70,86

Efficacy of conventional (immediate-release) preparations of gabapentin for the management of PHN was established in 2 placebo-controlled studies of 7-8 weeks' duration in patients who were continuing to experience pain for longer than 3 months after healing of their herpes zoster rash.1,38,39 In these studies, gabapentin was titrated over several weeks up to a target dosage of 1.8, 2.4, or 3.6 g daily (administered in 3 divided doses as conventional preparations).1,38,39 Gabapentin substantially reduced weekly mean pain scores from baseline compared with placebo (assessed by an 11-point numeric rating scale); improvement was noted at 1 week and maintained throughout the duration of these studies.1,38,39 In addition, a greater proportion of patients receiving gabapentin compared with placebo achieved at least a 50% reduction in pain from baseline, and this was observed at all dosages evaluated.1

Efficacy of gabapentin gastroretentive tablets (Gralise^®) for the management of PHN was established in an 11-week double-blind, placebo-controlled study in patients who were experiencing persistent pain for at least 6 months after healing of their herpes zoster rash.60,62 Gabapentin (at a dosage of 1.8 g once daily as gastroretentive tablets) was substantially more effective than placebo in improving average pain scores from baseline; the extent of improvement was similar to that achieved with the conventional (immediate-release) formulation of the drug.60,62 In this study, the proportion of patients who experienced at least a 50% reduction in pain with gabapentin (29.5%) was not substantially different from placebo (22.6%).62

Efficacy of gabapentin enacarbil for the management of PHN was established in a 12-week randomized, double-blind, placebo-controlled multicenter study that evaluated 3 different dosages of the drug (600 mg, 1.2 g, or 1.8 g twice daily as extended-release tablets) in patients who were experiencing persistent pain for at least 3 months after healing of their herpes zoster rash.61,77 Compared with placebo, treatment with gabapentin enacarbil substantially reduced mean pain scores and increased the proportion of patients with at least a 50% reduction in pain intensity from baseline; improvements were noted as early as 1 week following initiation of therapy and were maintained throughout the duration of the study.61,77 Although benefits of gabapentin enacarbil were observed at all dosages evaluated, the 1.2-g daily dosage (administered as 600 mg twice daily) appeared to provide the greatest benefit-to-risk ratio.61,77

Results of a systematic review of 8 randomized controlled studies in patients with PHN indicated that treatment with gabapentin (administered orally as gabapentin or gabapentin enacarbil preparations at dosages of at least 1.2 g daily) provided substantial benefit (i.e., reduction in pain intensity by at least 50% or a score of “very much improved” on the Patient Global Impression of Change [PGIC] scale) in 32% of patients who received the drug compared with 17% of those who received placebo; a moderate benefit (i.e., reduction in pain intensity by at least 30% or a PGIC score of “much or very much improved”) was observed in 46% of patients who received the drug compared with 25% of those who received placebo.86 However, the strength of evidence was considered moderate because of uncertainties and differences between dosage regimens, formulations, and statistical methods used in the studies.86

Although gabapentin is considered by many experts to be one of several first-line therapies for PHN, the evidence suggests that only a small proportion of patients will derive a clinically meaningful benefit from the drug.67,86,88,89 Other drugs that have been recommended for the management of PHN include pregabalin, tricyclic antidepressants, and topical lidocaine.67,89 When selecting an appropriate regimen, clinicians should consider the relative efficacy and safety of the specific drugs as well as individual patient-related factors (e.g., age, preference, tolerability, contraindications, comorbid conditions, concomitant medications).67,68

Diabetic Peripheral Neuropathy

Gabapentin also has been used for the treatment of pain associated with diabetic peripheral neuropathy (DPN)†.20,21,22,24,25,41,42,43,44,45 70,86,91,94,95,96,102,103 The drug has been shown in a number of clinical studies to be more effective than placebo in relieving pain in patients with DPN; however, mixed results have been reported and when a benefit was observed, the effect size tended to be small.25,41,42,43,86,87,94,95 In a systematic review of 6-7 randomized controlled studies in patients with DPN, gabapentin (administered orally as gabapentin or gabapentin enacarbil formulations at dosages of at least 1.2 g daily) provided substantial benefit (i.e., reduction in pain intensity by at least 50% or a score of “very much improved” on the PGIC scale) in 38% of patients who received the drug compared with 23% of those who received placebo; a moderate benefit (i.e., reduction in pain intensity by at least 30% or a PGIC score of “much or very much improved”) was achieved in 52% of patients who received the drug compared with 37% of those who received placebo.86 However, the strength of evidence was considered moderate because of uncertainties and differences between dosage regimens, formulations, and statistical methods used in the studies.86

Although gabapentin is considered by many experts to be one of several first-line therapies for DPN, the evidence suggests that only a small proportion of patients will derive a clinically meaningful benefit from the drug.67,86,89,91,94,95,96 Other drugs that have been recommended for the management of DPN include pregabalin, tricyclic antidepressants, and serotonin- and norepinephrine-reuptake inhibitors (e.g., duloxetine, venlafaxine).67,86,91,94,95,96,105 Although comparative data are limited,86,91,105 studies generally have not found any substantial differences among the available treatments.20,21,24,44,45,104,105 When selecting an appropriate regimen, clinicians should consider the relative efficacy, safety, pharmacokinetics, drug interaction potential, and cost of the specific drugs in addition to individual patient-related factors (e.g., contraindications, comorbid conditions, concomitant medications).67,94,96

Other Types of Neuropathic Pain

Gabapentin also has been used for the management of other types of neuropathic pain†,67,88,89,90,92,100,101 including central neuropathic pain associated with spinal cord injury†,67,86,90,97,98,100 complex regional pain syndrome† (CRPS),20,52,53,86,90 cancer-related neuropathic pain†,20,21,51,67,85,86,92,99 pain associated with multiple sclerosis†,20,21,48,49,90,100 phantom limb pain†,86,90 radicular pain†,86,90,92 and HIV-related peripheral neuropathy†.20,21,50,86 Results of controlled studies have been negative or equivocal in many cases, and the evidence remains extremely limited for the use of gabapentin in neuropathic pain conditions other than PHN and DPN†.67,86,87,88,89,93 Although the majority of studies evaluating gabapentinoids (i.e., gabapentin and pregabalin) for chronic neuropathic pain were conducted in patients with PHN or DPN, the evidence is often extrapolated to other neuropathic pain conditions and many experts recommend these drugs as first-line agents for all types of neuropathic pain (except for trigeminal neuralgia).67,87,88,89,90,92,93,100,101 However, additional study and experience are needed to further elucidate the role of gabapentin in the management of these other neuropathic pain conditions.20,21,67,86,93

Restless Legs Syndrome

Gabapentin enacarbil is used for the symptomatic treatment of moderate-to-severe primary restless legs syndrome in adults.61,71,74,78,79,80,81,82 The drug is not recommended in patients who are required to sleep during the daytime and remain awake at night.61

Restless legs syndrome (also known as Ekbom syndrome) is a sensorimotor disorder characterized by a distressing urge to move the legs accompanied by sensations deep in the limbs that have been variously described as tingling, pulling, itching, aching, or jittering.61,71,73,74,78,82 These symptoms are present at rest, especially in the evening and at night, and are relieved by movement.61,71,73,74,78,82 Dopamine receptor agonists (e.g., pramipexole, ropinirole) traditionally have been considered the drugs of choice for patients with restless legs syndrome, particularly those with symptoms that occur nightly.71,73,74,81,82 Current evidence from randomized placebo-controlled studies also supports the use of gabapentin enacarbil for this condition.74,78,79,81 Although direct comparison studies have not been conducted to date, efficacy of gabapentin enacarbil appears to be comparable to that of the dopamine receptor agonists.74,80

Efficacy of gabapentin enacarbil for the management of restless legs syndrome was established in 2 randomized, placebo-controlled studies of 12 weeks' duration in adults with moderate-to-severe restless legs syndrome (defined as a score of at least 15 on the International Restless Legs Syndrome [IRLS] scale, and a history of symptoms for at least 15 days in the month prior to screening).61,78,79,80 The primary measure of efficacy in these studies was a composite of the change from baseline in IRLS total score and the proportion of patients considered to be responders (i.e., those with a “much improved” or “very much improved” rating on the Clinical Global Impression-Global Improvement [CGI-I] scale) at 12 weeks.61,79 Gabapentin enacarbil (600 mg or 1.2 g once daily as extended-release tablets) substantially improved both measures of efficacy compared with placebo; improvements were noted as early as 1 week and were maintained throughout the duration of the studies.61,72,78,79 At 12 weeks, the mean change in IRLS score was a reduction of 13-13.8 with gabapentin enacarbil (versus a reduction of 8.8-9.8 with placebo), and 73-77% of patients receiving gabapentin enacarbil compared with 39-45% of those receiving placebo were described as responders.61 The 1.2-g daily dosage of gabapentin enacarbil appeared to provide no additional benefit over the 600-mg daily dosage, and was associated with an increased incidence of adverse effects.61,72

Gabapentin also has been used in the treatment of restless legs syndrome†;26,27,28,71,73,74,78,81,82 however, the drug (unlike gabapentin enacarbil) currently is not labeled by the FDA for this use.72,78 Although evidence supporting the use of gabapentin for restless legs syndrome alone generally is insufficient, some experts state that the analgesic effects of the drug may provide some benefit in patients with both restless legs syndrome and pain.81

Vasomotor Symptoms

Gabapentin has been used for the management of vasomotor symptoms† in women with breast cancer30 and in postmenopausal women.31,34,54 Therapy with the drug has improved both the frequency and severity of vasomotor symptoms (e.g., hot flushes or flashes) in these women.30,31,34,37,54

Most women receiving systemic antineoplastic therapy for breast cancer experience vasomotor symptoms, particularly those receiving tamoxifen therapy.30 In a randomized, double-blind, placebo-controlled study in 420 women with breast cancer (68-75% were receiving tamoxifen) who were experiencing 2 or more episodes of hot flushes daily, the percentage reductions in hot flush severity score at 4 and 8 weeks of treatment were 21 and 15%, respectively, for placebo; 33 and 31%, respectively, for gabapentin 300 mg daily (100 mg 3 times daily); and 49 and 46%, respectively, for gabapentin 900 mg daily (300 mg 3 times daily).30 Comparisons among treatment groups showed that only the 900-mg daily dosage was associated with a statistically significant reduction in hot flush frequency and severity.30 Whether higher dosages will provide further reductions in vasomotor symptoms remains to be determined.30,31 The role of gabapentin in managing vasomotor symptoms in women with breast cancer relative to other nonhormonal therapies (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs]) remains to be determined.30,35,37 Well-designed, comparative studies are needed to establish optimum nonhormonal therapy, both in terms of efficacy and patient tolerance of adverse effects, in these women.30,36

Because of the risks associated with hormone replacement therapy (HRT) for vasomotor symptoms in perimenopausal and postmenopausal women, alternative nonhormonal therapies are being investigated.31,34,37 In a randomized, double-blind, placebo-controlled study in 59 postmenopausal women who were experiencing 7 or more hot flushes daily, intent-to-treat analysis revealed that 12 weeks of gabapentin 900 mg daily (300 mg 3 times daily) was associated with a 45% reduction in hot flush frequency and a 54% reduction in composite hot flush score (frequency and severity).31 In a continuation open-label phase in which patients were permitted upward titration of dosage as needed to a maximum of 2.7 g daily (25% received 900 mg or less daily, 61% received 900 mg-1.8 g daily, 14% received 1.8-2.7 g daily), the associated reductions in hot flush frequency and composite score were 54 and 67%, respectively.31 The role of gabapentin therapy relative to other nonhormonal therapies (e.g., SSRIs, SNRIs) for postmenopausal vasomotor symptoms, both in terms of efficacy and safety, as well as the optimum dosage remain to be established.31,34,35,36,37

Current evidence indicates that gabapentin is effective and well tolerated in the short-term treatment of vasomotor symptoms associated with breast cancer treatment and with menopause.30,31,34 The principal adverse effects associated with gabapentin therapy in women with vasomotor symptoms have been somnolence,30,31,34 fatigue,30 dizziness,31,34 and rash (with or without peripheral edema).31 Additional study and experience are needed to further elucidate the role of gabapentin relative to other nonhormonal therapies, and to establish longer-term (i.e., beyond 17 weeks) efficacy and safety.30,31 34

The possible role of gabapentin in the management of vasomotor symptoms† associated with antiandrogenic therapy in men with prostate cancer remains to be established.32,33 Current evidence of efficacy is limited; well-designed, controlled studies are under way in this population.19,36

Administration

Gabapentin and gabapentin enacarbil are administered orally.1,60,61

If discontinuance of gabapentin or gabapentin enacarbil therapy is required, gradual tapering of the dosage generally is recommended to avoid manifestations of abrupt withdrawal.1,60,61 (See Dosage and Administration: Dosage, and also see Cautions: Precautions and Contraindications.)

Patients who are currently receiving or beginning therapy with gabapentin, gabapentin enacarbil, and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,60,61 (See Suicidality under Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)

Gabapentin

Gabapentin is commercially available as conventional (immediate-release) capsules, tablets, or oral solution (e.g., Neurontin^®).1 The drug also is available as a gastroretentive tablet (Gralise^®) for once-daily administration in the treatment of postherpetic neuralgia (PHN).60 Although the gastroretentive tablet is not considered by FDA to be an extended-release formulation, it is sometimes referred to in this manner because of similar pharmacokinetic properties to an extended-release dosage form (see Description).60,62,63,64,65 Because of differences in pharmacokinetics that affect frequency of administration, gabapentin gastroretentive tablets are not interchangeable with other gabapentin preparations.60

Conventional (immediate-release) preparations of gabapentin should be administered orally in divided doses (3 times daily) without regard to meals; food does not substantially affect the bioavailability of gabapentin when administered as an immediate-release formulation.1 Gabapentin capsules should be swallowed whole with water.1 If film-coated scored tablets containing 600 or 800 mg of gabapentin are divided to allow administration of a 300- or 400-mg dose, the remaining half tablet should be used for the next dose; half tablets that are not used within 28 days should be discarded.1

Gabapentin gastroretentive tablets should be administered orally once daily with the evening meal; food increases the rate and extent of absorption of gabapentin when administered as the gastroretentive formulation.60,64 The gastroretentive tablets should be swallowed intact and not chewed, crushed, or split.60

If use of an antacid containing aluminum hydroxide and magnesium hydroxide is necessary in a patient receiving gabapentin, it is recommended that gabapentin be administered at least 2 hours after the antacid.1,60

Gabapentin Enacarbil

Gabapentin enacarbil is commercially available as extended-release tablets (Horizant^®) for administration once or twice daily depending on the indication.61 When used for the treatment of restless legs syndrome, the drug should be administered once daily at about 5 p.m.; if a dose is missed, the next dose should be taken the following day as scheduled.61 When used for the management of PHN, gabapentin enacarbil extended-release tablets should be administered twice daily; if a dose is missed, the dose should be skipped and the next dose taken at the regularly scheduled time.61 Gabapentin enacarbil extended-release tablets should be swallowed intact and not crushed, chewed, or cut.61

Because of differences in pharmacokinetics that affect frequency of administration, gabapentin enacarbil extended-release tablets are not interchangeable with other gabapentin preparations.61

Dosage

Seizure Disorders

For adjunctive therapy in the management of partial seizures with or without secondary generalization in adults and children 12 years of age or older, the manufacturer recommends an initial gabapentin dosage of 300 mg 3 times daily and a maintenance dosage of 300-600 mg 3 times daily (as conventional preparations).1 Dosages up to 2.4 g daily have been well tolerated in long-term clinical studies, and a small number of patients have tolerated dosages of 3.6 g daily for short periods.1 When administered 3 times daily, the interval between doses should not exceed 12 hours.1

In pediatric patients 3-11 years of age, the recommended initial dosage of gabapentin (as conventional preparations) for the management of partial seizures is 10-15 mg/kg daily in 3 divided doses.1 Dosage should be titrated upward over a period of approximately 3 days until an effective maintenance dosage is achieved.1 The recommended maintenance dosage of conventional gabapentin in pediatric patients 5-11 years of age is 25-35 mg/kg daily administered in 3 divided doses; for children 3-4 years of age, the recommended maintenance dosage is 40 mg/kg daily administered in 3 divided doses.1 Dosages up to 50 mg/kg daily have been well tolerated by pediatric patients 3-12 years of age in a long-term clinical study.1 When administered 3 times daily, the interval between doses should not exceed 12 hours.1

Gabapentin may be used concomitantly with other anticonvulsant agents without concern for alterations in plasma drug concentrations; therapeutic plasma concentration monitoring is not necessary during such concomitant therapy.1

If gabapentin dosage reduction or discontinuance or substitution of an alternative anticonvulsant is necessary, such changes in therapy should be made gradually over a period of at least 1 week.1

Postherpetic Neuralgia

For the management of PHN in adults, the initial dosage of gabapentin as conventional (immediate-release) preparations is 300 mg once daily on the first day, 300 mg twice daily on the second day, and 300 mg 3 times daily on the third day.1 Subsequently, the dosage may be increased as needed for pain relief up to a total dosage of 1.8 g daily administered in 3 divided doses.1 In clinical studies evaluating gabapentin for the treatment of PHN, dosages of the drug ranging from 1.8-3.6 g daily were effective, but there was no evidence that dosages exceeding 1.8 g daily provided any additional benefit.1 If gabapentin dosage reduction or discontinuance or substitution of an alternative drug is necessary, such changes in therapy should be made gradually over a period of at least 1 week.1,60

The recommended dosage of gabapentin as the gastroretentive preparation in adults with PHN is 1.8 g once daily; dosage should be titrated gradually over 2 weeks up to the recommended maintenance dosage as follows: 300 mg once daily on the first day, 600 mg once daily on the second day, 900 mg once daily on days 3-6, 1.2 g once daily on days 7-10, 1.5 g once daily on days 11-14, and 1.8 g once daily on day 15.60 If gabapentin dosage reduction or discontinuance or substitution of an alternative drug is necessary, such changes in therapy should be made gradually over a period of at least 1 week.60

If gabapentin enacarbil extended-release tablets are used for the management of PHN in adults, the recommended dosage is 600 mg twice daily; dosage should be initiated at 600 mg once daily in the morning for 3 days, then increased to 600 mg twice daily.61 In the principal efficacy study of gabapentin enacarbil in patients with PHN, dosages exceeding 1.2 g daily provided no additional benefit and were associated with an increased incidence of adverse effects.61 When discontinuing gabapentin enacarbil therapy, patients receiving a dosage of 600 mg twice daily should reduce their dosage to 600 mg once daily for 1 week prior to withdrawing therapy.61 (See Cautions: Precautions and Contraindications.)

Restless Legs Syndrome

For the treatment of restless legs syndrome, the recommended adult dosage of gabapentin enacarbil extended-release tablets is 600 mg once daily, administered at approximately 5 p.m.61 In clinical studies, a higher dosage of 1.2 g daily provided no additional benefit and was associated with an increased incidence of adverse effects.61

When discontinuing gabapentin enacarbil therapy in patients with restless legs syndrome, gradual tapering of the dosage is not necessary in patients receiving a daily dosage of 600 mg or less; however, in patients receiving higher than recommended dosages, dosage should be reduced to 600 mg once daily for 1 week prior to withdrawing therapy.61 (See Cautions: Precautions and Contraindications.)

Diabetic Neuropathy

For the symptomatic treatment of diabetic neuropathy† in adults, initial gabapentin dosages of 300 mg to 1.2 g daily (usually administered in divided doses; as conventional [immediate-release] preparations) have been used; gradual dosage titration is recommended based on patient response and tolerability. 25,91,94,95,96 Target daily dosages from 1.2 g up to a maximum of 3.6 g (administered in divided doses; given as conventional preparations) often are required for adequate pain relief in such patients.24,25,86,91,94,95,96

In a systematic review of gabapentin in chronic neuropathic pain, including diabetic neuropathy, in adults, some benefit was observed with gabapentin dosages of at least 1.2 g daily (administered orally as gabapentin or gabapentin enacarbil formulations).86

Vasomotor Symptoms

Although the optimum dosage remains to be established, a gabapentin dosage of 300 mg 3 times daily (as conventional [immediate-release] preparations) has been effective in reducing both the severity and frequency of vasomotor symptoms† in women with breast cancer30 and in postmenopausal women.31 Some clinicians recommend that therapy be initiated with a dosage of 300 mg once daily at bedtime.37 If needed, the dosage can be increased to 300 mg twice daily, and then to 300 mg 3 times daily, at 3- to 4-day intervals.37 A dosage of 100 mg 3 times daily appears to be no more effective than placebo, whereas dosages exceeding 900 mg daily (e.g., up to 2.7 g daily administered as 900 mg 3 times daily) may provide additional benefit in some women.30,31

Dosage in Renal Impairment

Gabapentin

In adults and children 12 years of age or older with impaired renal function or undergoing hemodialysis, dosage of gabapentin (as conventional preparations) should be reduced from the effective dosages for each indication based on the patient's creatinine clearance (see Table 1).1 In patients with a creatinine clearance of less than 15 mL/minute, dosage should be reduced in proportion to creatinine clearance (e.g., a patient with a creatinine clearance of 7.5 mL/minute should receive one-half the dosage that a patient with a creatinine clearance of 15 mL/minute should receive).1 Patients undergoing hemodialysis should receive a supplemental dose of gabapentin 125-350 mg immediately following each 4-hour hemodialysis session in addition to their renally adjusted daily dosage of the drug.1 The use of gabapentin conventional preparations in children younger than 12 years of age with impaired renal function has not been evaluated.1

If gabapentin gastroretentive tablets are used in adults with a creatinine clearance of 30-60 mL/minute, dosage of the drug should be reduced to a target daily dosage between 600 mg and 1.8 g once daily; dosage must be initiated at 300 mg once daily in these patients and may be titrated according to the same schedule recommended for those with normal renal function based on individual patient response and tolerability.60 Gabapentin gastroretentive tablets should not be used in patients with a creatinine clearance of less than 30 mL/minute or in those undergoing hemodialysis.60

Gabapentin Enacarbil

In patients with renal impairment, dosage of gabapentin enacarbil should be modified based on the degree of impairment as assessed by creatinine clearance (see Tables 2 or 3 depending on indication).61,84

Gabapentin generally is well tolerated,4 and adverse effects of the drug usually are mild to moderate in severity and may be self-limiting.1,4,6,8,9,16,60 CNS effects are the most frequently reported adverse affects of gabapentin and those most frequently requiring discontinuance of the drug.1,8,9,16

The most common adverse effects reported in clinical studies of conventional (immediate-release) gabapentin as adjunctive therapy for seizures in adults and children older than 12 years of age were somnolence, dizziness, ataxia, fatigue, and nystagmus.1 Discontinuance of gabapentin because of adverse effects was required in 7% of these patients, most frequently due to somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%).1 The most common adverse effects reported in clinical studies of conventional (immediate-release) gabapentin as adjunctive therapy of seizures in children 3-12 years of age were viral infection, fever, nausea and/or vomiting, somnolence, and hostility.1 Discontinuance of gabapentin because of adverse effects was required in approximately 7% of these patients, most frequently due to emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).1 Because clinical trials of gabapentin in the treatment of partial seizures involved specific patient populations and use of the drug as adjunctive therapy, it is difficult to determine whether a causal relationship exists for many reported adverse effects, to compare adverse effect frequencies with other clinical reports, and/or to extrapolate the adverse effect experience from controlled clinical trials to usual clinical practice.1,16

In placebo-controlled studies of gabapentin for the management of postherpetic neuralgia (PHN), adverse effects most frequently reported in adults receiving conventional (immediate-release) preparations of the drug were dizziness, somnolence, and peripheral edema.1 Discontinuance of gabapentin because of adverse effects was required in 16% of these patients, most frequently due to dizziness, somnolence, and nausea.1 In placebo-controlled studies using the gastroretentive formulation of gabapentin, dizziness was reported as the most frequent adverse effect (10.9%); in these trials, 9.7% of patients required premature discontinuance of therapy because of adverse effects, the most common of which was dizziness.60

Similar to gabapentin, the most frequently reported adverse effects of gabapentin enacarbil are CNS effects.61,79,80 In the principal efficacy study of gabapentin enacarbil for the management of PHN, the most common adverse effects were dizziness, somnolence, and headache.61 Adverse effects resulted in discontinuance of gabapentin enacarbil therapy in 6% of these patients.61 The most common adverse effects observed in patients receiving gabapentin enacarbil for the treatment of restless legs syndrome in placebo-controlled trials were somnolence/sedation, and dizziness; in these trials, 7% of patients required premature discontinuance of therapy because of adverse effects.61

Nervous System Effects

In controlled clinical trials of conventional (immediate-release) gabapentin as adjunctive therapy of seizures in adults and children older than 12 years of age, somnolence was the most frequent adverse CNS effect, occurring in about 19% of those receiving the drug;1 the incidence and severity of somnolence appear to be dose related.1 Dose-related dizziness or ataxia was reported in about 17 or 13%, respectively, of patients receiving gabapentin in these trials.1 Fatigue was reported in 11%, nystagmus in 8%, tremor in 7%, dysarthria in 2%, amnesia in 2%, depression in 2%, abnormal thinking in 2%, and abnormal coordination in 1% of patients receiving the drug.1

In controlled clinical trials of conventional gabapentin as adjunctive therapy of seizures in children 3-12 years of age, somnolence, hostility (including aggressive behavior), and emotional lability were reported in 8, 8, and 4%, respectively, of patients receiving the drug.1 Fatigue, hyperkinesia, and dizziness each were reported in 3% of these patients.1 Headache and convulsions were reported in more than 2%, and thought disorders (e.g., concentration difficulty, change in school performance) were reported in 1.7% of these children.1

In controlled clinical trials of conventional gabapentin for the management of PHN in adults, dizziness was reported in 28%, somnolence in 21%, asthenia in 6%, ataxia in 3%, and abnormal thinking in 3% of patients receiving the drug.1 Abnormal gait and incoordination occurred in 2% of these patients.1 Pain, tremor, and neuralgia were reported in greater than 1% of patients receiving gabapentin for PHN in clinical studies but occurred with equal or greater frequency in patients receiving placebo.1 Dizziness, somnolence, headache, and lethargy were reported in about 11, 5, 4, and 1%, respectively, of adults receiving gabapentin gastroretentive tablets for PHN in controlled clinical studies; vertigo occurred in about 1% of patients receiving the drug.60

In the placebo-controlled study of gabapentin enacarbil for the management of PHN, dizziness was reported in 17-30%, somnolence was reported in 10-14%, and headache was reported in 7-10% of patients receiving the drug.61 Fatigue or asthenia occurred in 4-10% and insomnia occurred in 3-7% of these patients.61 Somnolence/sedation (20-27%) and dizziness (13-22%) were the most common adverse effects reported in patients receiving gabapentin enacarbil for the treatment of restless legs syndrome in placebo-controlled studies.61,79,80 Headache occurred in 12-15%,61,79,80 fatigue61 in 6-7%, and irritability61 in 4% of patients receiving the drug;61 1-3% of these patients reported feeling intoxicated.61 Depression and decreased libido were reported in up to 3% and up to 2% of these patients, respectively.61

The effect of gabapentin enacarbil on driving performance was evaluated in several driving simulation studies.61,72 In one study in healthy individuals, gabapentin enacarbil (600 mg once daily for 5 days) did not appear to affect driving performance (as assessed by lane position variability) when tested at various time points after dosing.61 However, results of another driving simulation study in patients with moderate-to-severe primary restless legs syndrome showed evidence of substantial driving impairment with gabapentin enacarbil (1.2 or 1.8 g daily); patients receiving the drug had greater lane position variability and a higher incidence of simulated crashes compared with those receiving placebo or an active comparator (diphenhydramine).61 There is some evidence, however, that patients with restless legs syndrome may have impaired driving ability in the absence of medication.61

Suicidality

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants, including gabapentin, compared with placebo.1,60,61 The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,60,61 The increased suicidality risk was observed as early as 1 week after beginning therapy.1,60,61 Because most of these studies did not extend beyond 24 weeks, the suicidality risk beyond 24 weeks is not known.1 The results were generally consistent among the 11 drugs studied.1,60,61 Although patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo, the relative risk for suicidality was higher in patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,60,61 (See Cautions: Precautions and Contraindications.)

GI Effects

Dyspepsia, dry mouth or throat, constipation, and dental abnormalities each occurred in 2% of adults and children older than 12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Nausea and/or vomiting was reported in 8% of children 3-12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1 Diarrhea and anorexia were reported in more than 2% of children 3-12 years of age receiving the drug in these trials.1

Diarrhea was reported in 6%, dry mouth in 5%, constipation in 4%, nausea in 4%, and vomiting in 3% of adults receiving conventional (immediate-release) gabapentin for the management of PHN in controlled clinical trials.1 Dyspepsia was reported in greater than 1% of patients receiving conventional gabapentin for the management of PHN in clinical studies, but occurred with equal or greater frequency in patients receiving placebo.1 In controlled clinical trials evaluating gabapentin gastroretentive tablets for the management of PHN, diarrhea was reported in 3.3%, dry mouth in 2.8%, constipation in 1.4%, and dyspepsia in 1.4% of adults receiving the drug.60

In the principal efficacy study of gabapentin enacarbil in the management of PHN, nausea occurred in 4-9% of adults receiving the drug.61 Nausea, dry mouth, and flatulence were reported in 6-7%, 3-4%, and 2-3%, respectively, of patients receiving gabapentin enacarbil in placebo-controlled studies of the drug for restless legs syndrome.61

Cardiovascular Effects

Peripheral edema was reported in 2% and vasodilation in 1% of adults and children older than 12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Peripheral edema was reported in 8% of adults receiving conventional (immediate-release) gabapentin and in 3.9% of adults receiving gabapentin gastroretentive tablets for the management of PHN in controlled clinical trials.1,60

In controlled clinical studies, peripheral edema was reported in 6-7% of adults receiving gabapentin enacarbil for the management of PHN and in up to 3% of adults receiving the drug for restless legs syndrome.61

Respiratory Effects

Pharyngitis occurred in 3% and coughing in 2% of adults and children older than 12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Bronchitis and respiratory infection each were reported in 3% of children 3-12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1 Pharyngitis, upper respiratory infection, rhinitis, and coughing were reported in more than 2% of these children receiving the drug in these studies.1

Pharyngitis was reported in 1% of adults receiving conventional (immediate-release) gabapentin for the management of PHN in controlled clinical trials; dyspnea was reported in greater than 1% of patients receiving the drug, but occurred with equal or greater frequency in patients receiving placebo.1 Nasopharyngitis was reported in 2.5% of adults receiving gabapentin gastroretentive tablets for PHN in controlled clinical trials.60

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported in patients receiving gabapentinoids (i.e., gabapentin and pregabalin).1,60,61,106 In the majority of cases, the drugs were used in combination with an opiate analgesic (or other CNS depressant), in patients with preexisting respiratory risk factors (e.g., COPD), or in geriatric patients.1,106,107,108,109,110 During a 5-year period between 2012 and 2017, 49 cases of respiratory depression associated with gabapentinoid use (15 cases with gabapentin and 34 cases with pregabalin) were reported to the FDA, including 12 fatalities.106 Most of the cases (92%) reported either concomitant use of another CNS depressant or a respiratory risk factor, including age-related decreases in lung function.106 In all of the fatal cases, patients had at least one risk factor for developing respiratory depression or were receiving a CNS depressant concomitantly.106 In addition, there is evidence from small randomized studies in healthy individuals and observational studies in postoperative patients suggesting that use of gabapentinoids alone or in conjunction with opiate analgesics may increase the risk of respiratory depression.106,107,108,109,110 In one study, gabapentin increased the apnea-hypopnea index in men 60 years of age or older who did not have preexisting sleep apnea.108 Although findings from these studies as well as animal data suggest that gabapentinoids may have an independent respiratory depressant effect, there is less evidence supporting the risk of serious respiratory complications when these drugs are used alone in otherwise healthy individuals.106,107,108 (See Cautions: Precautions and Contraindications.)

Ocular and Otic Effects

Diplopia was reported in 6% and amblyopia in 4% of adults and children older than 12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Otitis media was reported in more than 2% of children 3-12 years of age receiving conventional gabapentin as adjunctive therapy for seizures in clinical studies.1

Amblyopia occurred in 3%, and conjunctivitis, diplopia, and otitis media each occurred in 1% of adults receiving conventional (immediate-release) gabapentin for the management of PHN in controlled clinical trials.1 In the placebo-controlled study of gabapentin enacarbil for the management of PHN, blurred vision occurred in 2-5% of adults receiving the drug.61

Musculoskeletal Effects

Back pain was reported in 2% of adults and children older than 12 years of age receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Elevated creatine kinase, rhabdomyolysis, and movement disorders have been reported during postmarketing experience with conventional gabapentin; however, the manufacturers state that data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to the drug.1

Back pain was reported in greater than 1% of adults receiving conventional (immediate-release) gabapentin in clinical studies for the management of PHN but occurred with equal or greater frequency in patients receiving placebo.1 Back pain and extremity pain were reported in 1.7 and 1.9%, respectively, of adults receiving gabapentin gastroretentive tablets for PHN in controlled clinical trials.60

Genitourinary Effects

Impotence was reported in 2% of patients receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Dermatologic and Sensitivity Reactions

Anaphylaxis and angioedema, sometimes requiring emergency treatment, have been reported in patients receiving conventional (immediate-release) gabapentin.1 Reported signs and symptoms include difficulty breathing; swelling of the lips, throat, and tongue; and hypotension.1

Abrasion occurred in 1% of adults and children older than 12 years of age receiving conventional gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Erythema multiforme and Stevens-Johnson syndrome have been reported during postmarketing experience with conventional gabapentin; however, the manufacturers state that data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to gabapentin.1

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients receiving anticonvulsants, including gabapentin.1,60,61 The clinical presentation is variable, but typically includes fever, rash, eosinophilia, and/or lymphadenopathy in association with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myositis, myocarditis).1,60,61 In some cases, these reactions have been life-threatening or fatal.1,60,61 Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even if a rash is not evident.1,60,61

Hepatic Effects

Elevated liver function test results and jaundice have been reported during postmarketing experience with conventional (immediate-release) gabapentin; however, the manufacturers state that data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to gabapentin.1

Electrolyte and Metabolic Effects

Weight gain has been reported in 3% of patients receiving conventional (immediate-release) gabapentin as adjunctive therapy for seizures in clinical trials.1

Weight gain and hyperglycemia were reported in 2 and 1%, respectively, of adults receiving conventional gabapentin for the management of PHN in controlled clinical trials.1 In studies evaluating gabapentin gastroretentive tablets for the management of PHN, weight gain was reported in about 2% of adults receiving the drug.60

Fluctuation in blood glucose concentrations and hyponatremia have been reported during postmarketing experience with conventional gabapentin; however, the manufacturers state that data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to the drug.1

Weight increase was reported in 3% of children 3-12 years of age receiving conventional gabapentin in controlled clinical trials.1

In placebo-controlled studies of gabapentin enacarbil for the treatment of restless legs syndrome, weight gain occurred in 2-3% and increased appetite occurred in 2% of patients receiving the drug; weight gain was reported in 3-5% of patients receiving gabapentin enacarbil for the management of PHN in the principal efficacy study.61

Other Adverse Effects

Breast enlargement has been reported during postmarketing experience with conventional (immediate-release) gabapentin; however, the manufacturers state that data are insufficient to provide an estimate of the incidence of such an effect or to establish a causal relationship to the drug.1

Viral infection and fever were reported in 11 and 10%, respectively, of children 3-12 years of age receiving conventional gabapentin as adjunctive therapy for seizures in controlled clinical trials.1

Infection and accidental injury were reported in 5 and 3%, respectively, of adults receiving conventional gabapentin for the management of PHN in controlled clinical trials.1 Flu syndrome was reported in greater than 1% of patients receiving conventional gabapentin for the management of PHN, but occurred with equal or greater frequency in patients receiving placebo.1 In controlled clinical trials evaluating gabapentin gastroretentive tablets for the management of PHN, urinary tract infection was reported in 1.7% of adults receiving the drug.60

In placebo-controlled studies of gabapentin enacarbil for the treatment of restless legs syndrome, up to 3% of patients reported feeling abnormal.61

Precautions and Contraindications

An increased risk of suicidality (suicidal behavior or ideation) has been observed with various anticonvulsants, including gabapentin.1,60,61 (See Suicidality under Cautions: Nervous System Effects.) Because gabapentin enacarbil is a prodrug of gabapentin, a similar risk with gabapentin enacarbil cannot be ruled out.61 Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and advise them to pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences.1 In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately.1,60,61 Clinicians who prescribe gabapentin or any other anticonvulsant should balance the risk for suicidality with the risk of untreated illness.1,60,61 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,60,61 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.1,60,61

Because serious and potentially fatal respiratory depression can occur when gabapentinoids (i.e., gabapentin and pregabalin) are used in combination with opiate analgesics or other CNS depressants (e.g., benzodiazepines), in the setting of underlying respiratory impairment, or in geriatric patients, patients should be monitored for respiratory depression and sedation in these situations.1,60,61,106 (See Cautions: Respiratory Effects.) Consideration should be given to initiating gabapentin therapy at the lowest dosage and titrating the dosage carefully; appropriate dosage adjustments should be made in patients with renal impairment and those undergoing hemodialysis.1,106 (See Dosage in Renal Impairment under Dosage and Administration: Dosage.) Patients and caregivers should be advised to seek immediate medical attention if signs or symptoms of respiratory depression occur (e.g., slow, shallow, or difficult breathing; confusion or disorientation; unusual dizziness or lightheadedness; extreme sleepiness or lethargy; bluish-colored or tinted skin, especially on the lips, fingers, and toes; unresponsiveness).1,106 Management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants, including gabapentin.1,106 If the decision is made to discontinue gabapentin, dosage should be reduced gradually.106

Because of the possibility of increased seizure frequency and other withdrawal symptoms (e.g., anxiety, insomnia, nausea), gabapentin and gabapentin enacarbil should not be discontinued suddenly; any changes in therapy (e.g., discontinuance, dosage reduction, substitution with an alternative drug) should be done gradually.1,60,61 (See Dosage and Administration: Dosage.) In controlled studies of gabapentin as conventional (immediate-release) formulations, the incidence of status epilepticus was 0.6% in adults and children older than 12 years of age receiving gabapentin and 0.5% in those receiving placebo.1 In all (uncontrolled and controlled) clinical studies of gabapentin as adjunctive therapy in adults and children older than 12 years of age, the incidence of status epilepticus was 1.5%.1 Because adequate historical data are unavailable for comparison, it has not been established whether the incidence of status epilepticus in patients with epilepsy treated with gabapentin is higher or lower than would be expected in a similar population of patients not treated with the drug.1

During the premarketing development of conventional (immediate-release) gabapentin, 8 sudden and unexplained deaths were reported among a cohort of 2203 patients with epilepsy (2103 patient-years of exposure).1 Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients not receiving gabapentin.1 This evidence suggests, but does not prove that the incidence of sudden, unexplained death observed with adjunctive gabapentin therapy may be reflective of the population itself rather than the effects of gabapentin.1

Gabapentin can produce drowsiness and dizziness, and patients should be cautioned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) or cause accidental injury (e.g., falls).1,61 Gabapentin enacarbil has been shown to cause substantial impairment in driving performance, which may be related to somnolence or other CNS effects of the drug; the duration of such impairment following administration of the drug is not known.61 Patients should not drive a car (or operate other complex machinery) until they have gained sufficient experience with these drugs; clinicians should consider that a patient's ability to assess their performance on these tasks or their degree of somnolence may not be reliable.1,61

Patients should be evaluated immediately if manifestations of multiorgan hypersensitivity (or DRESS) occur during gabapentin or gabapentin enacarbil therapy; the drug should be discontinued if an alternative etiology cannot be identified.1,60,61

Anaphylaxis and angioedema may occur after the first dose of gabapentin or at any time during therapy.1 Patients should be instructed to discontinue gabapentin and seek immediate medical attention if they develop any manifestations of anaphylaxis or angioedema.1

Concomitant use of alcohol or other drugs that can cause sedation or dizziness can potentiate the CNS effects of gabapentin and generally should be avoided.1,60,61 In addition, alcohol can increase the rate of drug release from gabapentin enacarbil extended-release tablets and should be avoided in patients receiving this formulation.61 Concomitant use of opiate analgesics in patients receiving gabapentin may result in increased plasma concentrations of gabapentin and increase the risk of adverse CNS effects and respiratory depression; dosage adjustments may be required with such concomitant use.1

Gabapentin is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,60 The manufacturer of gabapentin enacarbil states that there are no known contraindications to the use of this preparation.61

Pediatric Precautions

Safety and efficacy of conventional (immediate-release) gabapentin as adjunctive therapy in the management of partial seizures in children younger than 3 years of age have not been established.1 Safety and efficacy of conventional gabapentin in the management of PHN have not been established in pediatric patients.1 Safety and efficacy of gabapentin gastroretentive tablets and gabapentin enacarbil have not been established in pediatric patients.60,61

Geriatric Precautions

Safety and efficacy of conventional (immediate-release) gabapentin in the management of partial seizures in geriatric patients have not been evaluated systematically, and clinical trials did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than do younger patients.1 However, in clinical studies of the drug in patients ranging from 20-80 years of age, gabapentin plasma clearance, renal clearance, and renal clearance adjusted for body surface area declined with age.1 Although safety and efficacy of conventional gabapentin in geriatric patients with PHN have not been established specifically, 30% of the patients receiving the drug in clinical studies were 65-74 years of age and 50% were 75 years of age and older.1 In these studies, gabapentin appeared to be more effective for the management of PHN in patients older than 75 years of age than in younger patients.1 The manufacturers state that the apparent greater efficacy in geriatric patients may be related to decreased renal function in this age group.1 Although adverse effects reported in older patients receiving conventional gabapentin generally were similar to those reported in younger adults, the incidence of peripheral edema and ataxia appeared to increase with age.1 Among patients receiving the gastroretentive formulation of gabapentin in clinical studies, 63% were 65 years of age or older.60 Adverse effects reported in these studies generally were similar across all age groups except for the incidence of peripheral edema, which tended to increase with age.60

Clinical trials of gabapentin enacarbil for the treatment of restless legs syndrome did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.61 In the principal efficacy study of gabapentin enacarbil for the treatment of PHN, 37% of the patients were 65-74 years of age and 13% were 75 years of age and older.61 No overall differences in safety and efficacy were observed between these geriatric patients and younger patients.61

FDA warns that geriatric patients receiving gabapentinoids are at increased risk of potentially serious, life-threatening, or fatal respiratory depression; gabapentin therapy should be initiated at the lowest dosage and titrated carefully with close monitoring in such patients.106 The manufacturers state that if gabapentin or gabapentin enacarbil is used in geriatric patients, dosage reduction may be required because of age-related compromised renal function; caution should be exercised since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.1,16,60,61 (See Dosage and Administration: Dosage in Renal Impairment.)

Mutagenicity and Carcinogenicity

Gabapentin has not been shown to be mutagenic or genotoxic in various in vitro and in vivo tests.1

An increased incidence of pancreatic acinar cell tumors was observed with gabapentin and gabapentin enacarbil in rat carcinogenicity studies; the clinical importance of these findings to humans is not known.1,60,61,72 In clinical studies of gabapentin in patients older than 12 years of age with seizure disorders, new tumors or worsening of preexisting tumors was reported in 21 patients (based on 2085 patient-years of exposure); however, a causal relationship to the drug has not been established.60,61

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in pregnant women, gabapentin and gabapentin enacarbil have been shown to cause developmental toxicity when administered to pregnant animals during the period of organogenesis at doses similar to or lower than those used clinically.1,60 Such effects include skeletal abnormalities, hydroureter and hydronephrosis, and increased embryofetal mortality.1,16,60,61 In addition, abnormal or decreased synaptic formation was observed in neonatal mice exposed to intraperitoneal injections of gabapentin during the first postnatal week (corresponding to the last trimester of pregnancy in humans); the clinical importance of these findings is not known.61,69

Gabapentin and gabapentin enacarbil should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.60,61 Women who become pregnant while receiving gabapentin should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334; registry information also is available on the website at [Web].1

Fertility

Animal reproduction studies revealed no adverse effects on fertility or reproduction with gabapentin exposure levels 8 times those achieved in humans at the maximum recommended dosages.1

Lactation

Gabapentin is distributed into milk following oral administration.1,60,61 Because of the potential for serious adverse reactions to gabapentin in nursing infants, the drug should be administered to nursing women only if the potential benefits justify the risk to the infant.1,60 The manufacturer of gabapentin enacarbil states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.61

Description

Gabapentin is an anticonvulsant agent structurally related to the inhibitory CNS neurotransmitter γ-aminobutyric acid (GABA).1,4,6,7,8,9,60 Gabapentin enacarbil is a prodrug of gabapentin that is rapidly converted to gabapentin following oral administration; the therapeutic effects of gabapentin enacarbil are attributed to gabapentin.61,72,76,83 Although gabapentin was developed as a structural analog of GABA that would penetrate the blood-brain barrier (unlike GABA) and mimic the action of GABA at inhibitory neuronal synapses,1,4,6,7,9 the drug has no direct GABA-mimetic action and its precise mechanism of action has not been elucidated.1,4,5,7,8,9

Results of some studies in animals indicate that gabapentin protects against seizure and/or tonic extensions induced by the GABA antagonists picrotoxin and bicuculline or by GABA synthesis inhibitors (e.g., 3-mercaptopropionic acid, isonicotinic acid, semicarbazide).5,6,9 However, gabapentin does not appear to bind to GABA receptors1,4,5,6,7,17 nor affect GABA reuptake or metabolism1,6,7,17 and does not act as a precursor of GABA or of other substances active at GABA receptors.1,17 Gabapentin also has no affinity for binding sites on common neuroreceptors (e.g., benzodiazepine; glutamate; quisqualate; kainate; strychnine-insensitive or -sensitive glycine; α₁-, α₂-, or β-adrenergic; adenosine A₁ or A₂; cholinergic [muscarinic or nicotinic]; dopamine D₁ or D₂; histamine H₁; type 1 or 2 serotonergic [5-HT₁ or 5-HT₂]; opiate µ, δ, or κ) or ion channels (e.g., voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20α-benzoate).1,4,5,17 Conflicting results have been reported in studies of gabapentin affinity for and activity at N -methyl-d-aspartic acid (NMDA) receptors.4,5,6

In animal test systems, gabapentin exhibits anticonvulsant activity similar to that of other commonly used anticonvulsant drugs.1,17 The drug protects against seizures induced in animals by electrical stimulation or pentylenetetrazole, suggesting that it may be effective in the management of tonic-clonic (grand mal) and partial seizures1,5,6,7,9,17 or absence (petit mal) seizures, respectively.1,6,7,9 However, available data in animals and humans are conflicting regarding the effect of gabapentin on EEG spike and wave activity associated with absence (petit mal) seizures.5,6,17 Gabapentin also prevents seizures in some animals with congenital epilepsy1,4,6,7,9,17 and protects against audiogenic tonic extensions and clonic seizures in mice.6,7,17

Although the exact mechanism by which gabapentin exerts its analgesic effects is not known, the drug has been shown to prevent allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several models of neuropathic pain.1,20,60,61 Gabapentin also has been shown to decrease pain-related responses after peripheral inflammation in animals; however, the drug has not altered immediate pain-related behaviors.1 The clinical relevance of these findings is not known.1 In vitro studies demonstrate that gabapentin binds to the α₂δ subunit of voltage-activated calcium channels; however, the clinical importance of this effect is not known.1,66,69

The pharmacokinetic properties of gabapentin vary based on the specific formulation of the drug.60,61,63,64,65 (See Dosage and Administration: Administration.) Following oral administration, gabapentin is absorbed principally in the proximal small intestine via a saturable L-amino acid transport system; as a result, the bioavailability of the drug decreases with increasing doses.1,60,63,83,84 Gabapentin gastroretentive tablets are specifically formulated to swell upon contact with gastric fluid to a size that promotes gastric retention for approximately 8-10 hours when taken with a meal; this allows for gradual and slow release of the drug to the proximal small intestine, its principal site of absorption.60,63,64,65 Following administration of gabapentin gastroretentive tablets in healthy individuals, time to peak plasma concentrations of the drug was increased (about 4-6 hours longer), peak plasma concentrations were increased, and systemic exposure was decreased relative to conventional (immediate-release) gabapentin.60 Gabapentin enacarbil, a prodrug of gabapentin, is rapidly and efficiently converted to gabapentin by first-pass hydrolysis following oral administration.61,74 Unlike gabapentin, gabapentin enacarbil is absorbed via high-capacity transporters throughout the GI tract and is not affected by saturable absorption; this improves bioavailability of the drug and allows for dose-proportional exposure.61,72,74,78,80,83 Food has only a minimal effect on the pharmacokinetics of conventional (immediate-release) formulations of gabapentin, but increases the bioavailability of gabapentin gastroretentive tablets.1,60,63 Administration of gabapentin enacarbil extended-release tablets with food also increases systemic exposure of the drug compared with exposure under fasted conditions.61,76 Gabapentin does not bind to plasma proteins, is not appreciably metabolized, does not induce hepatic enzyme activity, and does not appear to alter the pharmacokinetics of commonly used anticonvulsant drugs (e.g., carbamazepine, phenytoin, valproate, phenobarbital, diazepam) or oral contraceptives.2,3,4,6,8,9,12,13,14 In addition, the pharmacokinetics of gabapentin are not altered substantially by concomitant administration of other anticonvulsant drugs.6,12,15

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Pfizer. Neurontin^® (gabapentin) capsules, tablets and oral solution prescribing information. New York, NY; 2020 Apr.

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