Gabapentin

Warnings and Precautions, Respiratory Depression ( 5.7 ) 04/2020

1 INDICATIONS AND USAGE Gabapentin is 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 is 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 • Postherpetic Neuralgia ( Error! Hyperlink reference not valid. ) o Dose can be titrated up as needed to a dose of 1,800 mg/day o Day 1: Single 300 mg dose o Day 2: 600 mg/day (i.e., 300 mg two times a day) o Day 3: 900 mg/day (i.e., 300 mg three times a day) • Epilepsy with Partial Onset Seizures ( Error! Hyperlink reference not valid. ) o 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 o Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; recommended dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the recommended dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses. The recommended dose is reached by upward titration over a period of approximately 3 days • Dose should be adjusted in patients with reduced renal function ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, gabapentin 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 1,800 mg/day (600 mg three times a day). In clinical studies, efficacy was demonstrated over a range of doses from 1,800 mg/day to 3,600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1,800 mg/day was not demonstrated. 2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 Years of Age and Above The starting dose is 300 mg three times a day. The recommended maintenance dose of gabapentin is 300 mg to 600 mg three times a day. Dosages up to 2,400 mg/day have been administered in long-term clinical studies. Doses of 3,600 mg/day have also been administered to a small number of patients for a relatively short duration. Administer gabapentin three times a day using 600 mg or 800 mg tablets. 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 recommended maintenance dose reached by upward titration over a period of approximately 3 days. The recommended maintenance dose of gabapentin in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses. The recommended maintenance 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. Gabapentin may be administered as the oral solution, capsule, or tablet, or using combinations of these formulations. Dosages up to 50 mg/kg/day have been administered in a long-term clinical study. The maximum time interval between doses should not exceed 12 hours. 2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment 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 Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dosage Regimen (mg) TID = Three times a day; BID = Two times a day; QD = Single daily dose ≥ 60 900 to 3,600 300 TID 400 TID 600 TID 800 TID 1,200 TID > 30 to 59 400 to 1,400 200 BID 300 BID 400 BID 500 BID 700 BID > 15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 For patients with creatinine clearance < 15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive). 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplement …

3 DOSAGE FORMS AND STRENGTHS • Gabapentin Tablets USP, 600 mg are white, elliptical, film-coated scored tablets debossed "O|E" on one side and "600" on the other side • Gabapentin Tablets USP, 800 mg are white, elliptical, film-coated scored tablets debossed "O|E" on one side and "800" on the other side • Tablets: 600 mg, and 800 mg ( Error! Hyperlink reference not valid. )

4 CONTRAINDICATIONS Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Known hypersensitivity to gabapentin or its ingredients ( Error! Hyperlink reference not valid. )

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 Error! Hyperlink reference not valid. ] • Anaphylaxis and Angioedema [see Error! Hyperlink reference not valid. ] • Somnolence/Sedation and Dizziness [see Error! Hyperlink reference not valid. ] • Withdrawal Precipitated Seizure, Status Epilepticus [see Error! Hyperlink reference not valid. ] • Suicidal Behavior and Ideation [see Error! Hyperlink reference not valid. ] • Respiratory Depression [see Error! Hyperlink reference not valid. ] • Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) [see Error! Hyperlink reference not valid. ] • Sudden and Unexplained Death in Patients with Epilepsy [see Error! Hyperlink reference not valid. ] Most common adverse reactions (incidence ≥ 8% and at least twice that for placebo) were: • Postherpetic neuralgia: Dizziness, somnolence, and peripheral edema ( Error! Hyperlink reference not valid. ) • Epilepsy in patients > 12 years of age: Somnolence, dizziness, ataxia, fatigue, and nystagmus ( Error! Hyperlink reference not valid. ) • Epilepsy in patients 3 to 12 years of age: Viral infection, fever, nausea and/or vomiting, somnolence, and hostility ( Error! Hyperlink reference not valid. ) To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-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 som …

7 DRUG INTERACTIONS • Concentrations increased by morphine; may need dose adjustment ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) 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 Error! Hyperlink reference not valid. ] . Hydrocodone Coadministration of gabapentin with hydrocodone decreases hydrocodone exposure [see Error! Hyperlink reference not valid. ] . 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 Error! Hyperlink reference not valid. ] . 7.2 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs [see Error! Hyperlink reference not valid. ] . 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 Error! Hyperlink reference not valid. ] . 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.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm ( Error! Hyperlink reference not valid. ) 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. 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 ] . 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. 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). The data from these observational studies should be interpreted with caution due to the potential for exposure misclassification, outcome misclassification, and residual confounding, including by underlying disease. Animal Data When pregnant mice received oral doses of gabapentin (500, 1,000, or 3,000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3,600 mg on a body surface area (mg/m 2 ) basis. In studies in which rats received oral doses of gabapentin (500 to 2,000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. The lowest dose tested is similar to the MRHD on a mg/m 2 basis. When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1,500 mg/kg). The lowest dose tested is less than the MRHD on a mg/m 2 basis. In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). …

12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. 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 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 is a white to off-white crystalline solid with a pK a1 of 3.7 and a pK a2 of 10.7. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is -1.25. Each gabapentin tablet, USP contains 600 mg or 800 mg of gabapentin and the following inactive ingredients: copovidone, corn starch, macrogol, magnesium stearate, polyvinyl alcohol, talc and titanium dioxide. Chemical Structure

10. Overdosage Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin have been reported. Symptoms have included double vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported with gabapentin overdose, alone and in combination with other CNS depressants. Gabapentin can be removed by hemodialysis. If overexposure occurs, call your poison control center at 1-800-222-1222.

16 HOW SUPPLIED/STORAGE AND HANDLING Gabapentin tablets, USP are supplied as follows: 600 mg tablets: White, elliptical, film-coated scored tablets debossed "O|E" on one side and "600" on the other side; available in: NDC 71335-1287-1: 30 Tablets in a BOTTLE NDC 71335-1287-2: 60 Tablets in a BOTTLE NDC 71335-1287-3: 180 Tablets in a BOTTLE NDC 71335-1287-4: 90 Tablets in a BOTTLE NDC 71335-1287-5: 100 Tablets in a BOTTLE NDC 71335-1287-6: 120 Tablets in a BOTTLE NDC 71335-1287-7: 500 Tablets in a BOTTLE NDC 71335-1287-8: 84 Tablets in a BOTTLE NDC 71335-1287-9: 112 Tablets in a BOTTLE NDC 71335-1287-0: 28 Tablets in a BOTTLE Store at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504