Gabapentin

RECENT MAJOR CHANGES Warnings and Precautions ( 5.5 , 5.6 ) 4/2025 Warnings and Precautions, removal- Sudden and Unexplained Death in Patients with Epilepsy ( 5.10 ) 4/2025 Warnings and Precautions ( 5.5 , 5.6 ) 4/2025 Warnings and Precautions, removal- Sudden and Unexplained Death in Patients with Epilepsy ( 5.10 ) 4/2025

1 INDICATIONS AND USAGE Gabapentin capsules are indicated for: • Management of postherpetic neuralgia in adults • Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy Gabapentin capsules are indicated for: • Postherpetic neuralgia in adults ( 1 ) • Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy ( 1 )

2 DOSAGE AND ADMINISTRATION Gabapentin capsules are given orally with or without food. Gabapentin capsules should be swallowed whole with plenty of water. If gabapentin dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber). Postherpetic Neuralgia ( 2.1 ) Dose can be titrated up as needed to a dose of 1800 mg/day Day 1: Single 300 mg dose Day 2: 600 mg/day (i.e., 300 mg two times a day) Day 3: 900 mg/day (i.e., 300 mg three times a day) Epilepsy with Partial Onset Seizures ( 2.2 ) Patients 12 years of age and older: starting dose is 300 mg three times daily; may be titrated up to 600 mg three times daily Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; the effective dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the effective dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses. The effective dose is reached by upward titration over a period of approximately 3 days Dose should be adjusted in patients with reduced renal function ( 2.3 ) 2.1 Postherpetic Neuralgia In adults with postherpetic neuralgia, gabapentin therapy may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day). The dose can subsequently be titrated up as needed for pain relief to a dose of 1800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1800 mg/day was not demonstrated. 2.2 Epilepsy with Partial Onset Seizures Gabapentin is recommended for add-on therapy in patients 3 years of age and older. Effectiveness in pediatric patients below the age of 3 years has not been established. Patients 12 years of age and above: The starting dose is 300 mg three times a day. The effective dose of gabapentin is 300 mg to 600 mg three times a day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. Gabapentin should be administered three times a day using 300 mg or 400 mg capsules. The maximum time between doses should not exceed 12 hours. Pediatric Patients Age 3 to 11 years: The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of gabapentin in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The effective dose of gabapentin in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, because there are no significant pharmacokinetic interactions among gabapentin and other commonly used antiepileptic drugs, the addition of gabapentin does not alter the plasma levels of these drugs appreciably. If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week. 2.3 Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with compromised renal function or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1. Gabapentin Dosage Based on Renal Function Renal Function Total Daily D …

3 DOSAGE FORMS AND STRENGTHS Capsules: • 100 mg: White to off-white powder filled in size “3” hard gelatin capsules with opaque white colored cap and opaque white colored body imprinted SG on cap and 179 on body with black ink. • 300 mg: White to off-white powder filled in size “1” hard gelatin capsules with opaque yellow colored cap and opaque yellow colored body imprinted SG on cap and 180 on body with black ink. • 400 mg: White to off-white powder filled in size “0” hard gelatin capsules with opaque orange colored cap and opaque orange colored body imprinted SG on cap and 181 on body with black ink. Tablets: • 600 mg: White to off white, modified capsule shape, biconvex, film-coated functional scored tablets debossed with “SG” on one side and “177” on other side with bisect line on both sides. • 800 mg: White to off white, modified capsule shape, biconvex, film-coated functional scored tablets debossed with “SG” on one side and “178” on other side with bisect line on both sides. • Capsules : 100 mg, 300 mg, and 400 mg ( 3 ) • Tablets (functional scored): 600 mg, and 800 mg ( 3 )

4 CONTRAINDICATIONS Gabapentin capsules are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Gabapentin capsules are contraindicated in patietns who have demonstrated hypersensitivity to the drug or its ingredients

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.1) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.2) ] Somnolence/Sedation and Dizziness [see see Warnings and Precautions (5.4) ] Withdrawal Precipitated Seizure, Status Epilepticus [see see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see see Warnings and Precautions (5.6) ] Neuropsychiatric Adverse Reactions (Pediatric Patients 3-12 Years of Age) [see see Warnings and Precautions (5.7) ] Sudden and Unexplained Death in Patients with Epilepsy [see see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence ≥8% and at least twice that for placebo) were: Postherpetic neuralgia: Dizziness, somnolence, and peripheral edema (6.1) Epilepsy in patients >12 years of age: Somnolence, dizziness, ataxia, fatigue, and nystagmus (6.1) Epilepsy in patients 3 to 12 years of age: Viral infection, fever, nausea and/or vomiting, somnolence, and hostility (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ACI HealthcareUSA, Inc. at 1-888-802-1213 or www.acihealthcareusa.com or FDA at1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Postherpetic Neuralgia The most common adverse reactions associated with the use of Gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema. In the 2 controlled trials in postherpetic neuralgia, 16% of the 336 patients who received Gabapentin and 9% of the 227 patients who received placebo discontinued treatment because of an adverse reaction. The adverse reactions that most frequently led to withdrawal in Gabapentin-treated patients were dizziness, somnolence, and nausea. Table 3 lists adverse reactions that occurred in at least 1% of Gabapentin-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the Gabapentin group than in the placebo group. TABLE 3. Adverse Reactions in Pooled Placebo-Controlled Trials in Postherpetic Neuralgia Gabapentin N=336 % Placebo N=227 % Body as a Whole Asthenia 6 5 Infection 5 4 Accidental injury 3 1 Digestive System Diarrhea 6 3 Dry mouth 5 1 Constipation 4 2 Nausea 4 3 Vomiting 3 2 Metabolic and Nutritional Disorders Peripheral edema 8 2 Weight gain 2 0 Hyperglycemia 1 0 Nervous System Dizziness 28 8 Somnolence 21 5 Ataxia 3 0 Abnormal thinking 3 0 Abnormal gait 2 0 Incoordination 2 0 Respiratory System Pharyngitis 1 0 Special Senses Amblyopia Reported as blurred vision 3 1 Conjunctivitis 1 0 Diplopia 1 0 Otitis media 1 0 Other reactions in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome. There were no clinically important differences between men and women in the types and incidence of adverse reactions. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse reactions by race. Epilepsy with Partial Onset Seizures (Adjunctive Therapy) The most common adverse reactions with Gabapentin in combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most common adverse reactions with Gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal freque …

7 DRUG INTERACTIONS Concentrations increased by morphine; may need dose adjustment (5.4, 7.1 ) 7.1 Opioids Respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone, buprenorphine) [ see Warnings and Precautions (5.7) ]. Hydrocodone Coadministration of gabapentin with hydrocodone decreases hydrocodone exposure [ see Clinical Pharmacology (12.3) ]. The potential for alteration in hydrocodone exposure and effect should be considered when gabapentin is started or discontinued in a patient taking hydrocodone. Morphine When gabapentin is administered with morphine, patients should be observed for signs of CNS depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3) ]. 7.2 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs [ see Clinical Pharmacology (12.3) ] . 7.3 Maalox ® (aluminum hydroxide, magnesium hydroxide) The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox ® ) containing magnesium and aluminum hydroxides. It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3)] . 7.4 Drug/Laboratory Test Interactions Because false positive readings were reported with the Ames N-Multistix SG ® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

7.1 Opioids Respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone, buprenorphine) [ see Warnings and Precautions (5.7) ]. Hydrocodone Coadministration of gabapentin with hydrocodone decreases hydrocodone exposure [ see Clinical Pharmacology (12.3) ]. The potential for alteration in hydrocodone exposure and effect should be considered when gabapentin is started or discontinued in a patient taking hydrocodone. Morphine When gabapentin is administered with morphine, patients should be observed for signs of CNS depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3) ].

7.2 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs [ see Clinical Pharmacology (12.3) ] .

7.3 Maalox ® (aluminum hydroxide, magnesium hydroxide) The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox ® ) containing magnesium and aluminum hydroxides. It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3)] .

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

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

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as gabapentin, during pregnancy. Encourage women who are taking gabapentin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll - free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary The totality of available data from published prospective and retrospective cohort studies pertaining to gabapentin use during pregnancy has not indicated an increased risk of major birth defects or miscarriage. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. There are important methodological limitations hindering interpretation of these studies [see Data] . In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see Data] . Postmarketing data suggest that extended gabapentin use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone [see Clinical Considerations] . Although there is at least one report of neonatal withdrawal syndrome in an infant exposed to gabapentin alone during pregnancy, there are no comparative epidemiologic studies evaluating this association. Therefore, whether exposure to gabapentin alone late in pregnancy may cause withdrawal signs and symptoms is not known. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to gabapentin and opioids for signs and symptoms of neonatal withdrawal and manage accordingly. Data Human Data An observational study based on routinely collected data from administrative and medical registers in Denmark, Finland, Norway, and Sweden, compared the prevalence of major congenital malformations in approximately 1,500 pregnancies exposed to gabapentin monotherapy in the first trimester to pregnancies unexposed to antiepileptics (n=2,995,816) and pregnancies exposed to lamotrigine monotherapy in the first trimester (n=7,582). The adjusted prevalence ratios in a pooled analysis were 1.00 (95% CI: 0.80-1.24) compared to pregnancies unexposed to antiepileptics and 1.29 (95% CI: 1.00-1.67) compared to pregnancies exposed to lamotrigine monotherapy in the first trimester. Data from another observational study in the US based on Medicaid data, which compared the risk for major congenital malformations in more than 4,600 pregnancies exposed to gabapentin during the first trimester to unexposed pregnancies (n=1,753,865), estimated an adjusted relative risk of 1.07 (95% CI: 0.94-1.21). Data from a cohort study of over 200,000 Medicaid-eligible pregnancies with prescription opioid exposure in the last 45 days of pregnancy found that the risk of …

12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. In animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and mice (e.g., spinal nerve ligation models, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test), but does not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to human pain is not known. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake or degradation. Gabapentin did not exhibit affinity for a number of other common receptor ion channel, or transporter proteins. In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.

11 DESCRIPTION The active ingredient in gabapentin capsules and tablets, USP is gabapentin, which has the chemical name 1-(aminomethyl)cyclohexaneacetic acid. The molecular formula of gabapentin is C 9 H 17 NO 2 and the molecular weight is 171.24. The structural formula of gabapentin is: Gabapentin, USP is a white to off-white crystalline solid with a pK a1 of 4.72±0.10 and a pK a2 of 10.27±0.29. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient is -1.083±0.235 at 25°C temperature. Each gabapentin capsule contains 100 mg, 300 mg or 400 mg of gabapentin, USP and the following inactive ingredients: pregelatinized starch (maize), and talc. The 100 mg capsule shell contains gelatin, sodium lauryl sulfate (SLS) and titanium dioxide. The 300 mg capsule shell contains gelatin, titanium dioxide, FD&C Red 40, D&C Yellow 10, and sodium lauryl sulfate (SLS). The 400 mg capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate (SLS), D&C Yellow 10, and FD&C Red 40. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide. Each gabapentin tablet contains 600 mg or 800 mg of gabapentin, USP and the following inactive ingredients: poloxamer 407, mannitol, magnesium stearate, hydroxypropyl cellulose, talc, copovidone, crospovidone, colloidal silicon dioxide and coating agent contains hypromellose, titanium dioxide, polyethylene glycol and talc. Gabapentin Structural Formula

10 OVERDOSAGE A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8,000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy, and diarrhea, were observed. All patients recovered with supportive care. Coma, resolving with dialysis, has been reported in patients with chronic renal failure who were treated with gabapentin. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. If overexposure occurs, call your poison control center at 1-800-222-1222.

16 HOW SUPPLIED/STORAGE AND HANDLING Gabapentin capsules and tablets, USP are supplied as follows: 100 mg capsules: White to off-white powder filled in size "3" hard gelatin capsules with opaque white colored cap and opaque white colored body imprinted SG on cap and 179 on body with black ink, available in: Bottles of 30: NDC 71205-928-30 Bottles of 60: NDC 71205-928-60 Bottles of 90: NDC 71205-928-90 Bottles of 100: NDC 71205-928-00 Bottles of 120: NDC 71205-928-72 Bottles of 180: NDC 71205-928-78 Bottles of 240: NDC 71205-928-64 Bottles of 270: NDC 71205-928-67 Bottles of 360: NDC 71205-928-76 Bottles of 500: NDC 71205-928-55 300 mg capsules: White to off-white powder filled in size "1" hard gelatin capsules with opaque yellow colored cap and opaque yellow colored body imprinted SG on cap and 180 on body with black ink, available in: Bottles of 30: NDC 71205-929-30 Bottles of 60: NDC 71205-929-60 Bottles of 90: NDC 71205-929-90 Bottles of 100: NDC 71205-929-00 Bottles of 120: NDC 71205-929-72 Bottles of 180: NDC 71205-929-78 Bottles of 240: NDC 71205-929-64 Bottles of 270: NDC 71205-929-67 Bottles of 360: NDC 71205-929-76 Bottles of 500: NDC 71205-929-55 400 mg capsules: White to off-white powder filled in size "0" hard gelatin capsules with opaque orange colored cap and opaque orange colored body imprinted SG on cap and 181 on body with black ink, available in: Bottles of 30: NDC 71205-930-30 Bottles of 60: NDC 71205-930-60 Bottles of 90: NDC 71205-930-90 Bottles of 100: NDC 71205-930-00 Bottles of 120: NDC 71205-930-72 Bottles of 180: NDC 71205-930-78 Bottles of 240: NDC 71205-930-64 Bottles of 270: NDC 71205-930-67 Bottles of 360: NDC 71205-930-76 Bottles of 500: NDC 71205-930-55 600 mg tablets: White to off white, modified capsule shape, biconvex, film-coated functional scored tablets debossed with "SG" on one side and "177" on other side with bisect line on both sides, available in: Bottles of 30: NDC 71205-931-30 Bottles of 60: NDC 71205-931-60 Bottles of 90: NDC 71205-931-90 Bottles of 100: NDC 71205-931-00 Bottles of 120: NDC 71205-931-72 Bottles of 180: NDC 71205-931-78 Bottles of 240: NDC 71205-931-64 Bottles of 270: NDC 71205-931-67 Bottles of 360: NDC 71205-931-76 Bottles of 500: NDC 71205-931-55 800 mg tablets: White to off white, modified capsule shape, biconvex, film-coated functional scored tablets debossed with "SG" on one side and "178" on other side with bisect line on both sides, available in: Bottles of 30: NDC 71205-932-30 Bottles of 60: NDC 71205-932-60 Bottles of 90: NDC 71205-932-90 Bottles of 100: NDC 71205-932-00 Bottles of 120: NDC 71205-932-72 Bottles of 180: NDC 71205-932-78 Bottles of 240: NDC 71205-932-64 Bottles of 270: NDC 71205-932-67 Bottles of 360: NDC 71205-932-76 Bottles of 500: NDC 71205-932-55 Store gabapentin capsules and tablets at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].