Neurontin

Gabapentin.

Gabapentin is supplied as capsules containing 100 mg, 300 mg, and 400 mg of active drug substance for oral administration.
Gabapentin is also supplied as 600 mg tablets.
Gabapentin is a white to off-white crystalline solid. It is freely soluble in water and both basic and acidic aqueous solutions.
Excipients/Inactive Ingredients: Each capsule also contains lactose, cornstarch, and talc.
Each tablet also contains poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, talc, hydroxypropyl cellulose, and candelilla wax.

Pharmacology: Pharmacodynamics: Gabapentin readily enters the brain and prevents seizures in a number of animal models of epilepsy. Gabapentin does not possess affinity for either GABAA or GABAB receptor nor does it alter the metabolism of GABA. It does not bind to other neurotransmitter receptors of the brain and does not interact with sodium channels. Gabapentin binds with high affinity to the α2δ (alpha-2-delta) subunit of voltage-gated calcium channels and it is proposed that binding to the α2δ subunit may be involved in gabapentin's anti-seizure effects in animals. Broad panel screening does not suggest any other drug target other than α2δ.
Evidence from several pre-clinical models inform that the pharmacological activity of gabapentin may be mediated via binding to α2δ through a reduction in release of excitatory neurotransmitters in regions of the central nervous system. Such activity may underlie gabapentin's anti-seizure activity. The relevance of these actions of gabapentin to the anticonvulsant effects in humans remains to be established.
Gabapentin also displays efficacy in several pre-clinical animal pain models. Specific binding of gabapentin to the α2δ subunit is proposed to result in several different actions that may be responsible for analgesic activity in animal models. The analgesic activities of gabapentin may occur in the spinal cord as well as at higher brain centers through interactions with descending pain inhibitory pathways. The relevance of these pre-clinical properties to clinical action in humans is unknown.
Pharmacokinetics: Gabapentin bioavailability is not dose-proportional. That is, as the dose is increased, bioavailability decreases. Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Absolute bioavailability of gabapentin capsules is approximately 60%. Food, including a high-fat diet, has no effect on gabapentin pharmacokinetics.
Gabapentin elimination from plasma is best described by linear pharmacokinetics.
The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.
Gabapentin pharmacokinetics are not affected by repeated administration, and steady-state plasma concentrations are predictable from single-dose data. Although plasma gabapentin concentrations were generally between 2 μg/mL and 20 μg/mL in clinical studies, such concentrations were not predictive of safety or efficacy. Plasma gabapentin concentrations are dose proportional at doses of 300 mg or 400 mg given every 8 hours. Pharmacokinetic parameters are given in Table 1. (See Table 1.)

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Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 L. In patients with epilepsy, gabapentin concentrations in the Cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Gabapentin is eliminated solely by renal excretion. There is no evidence of metabolism in man. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
Gabapentin is removed from plasma by hemodialysis. Dose adjustment in patients with compromised renal function or in those undergoing hemodialysis is recommended (see Dose adjustment in impaired renal function in patients with neuropathic pain or epilepsy and Dose adjustment in patients undergoing hemodialysis under Dosage & Administration).
Gabapentin pharmacokinetics in children were determined in 24 healthy subjects between the ages of 4 and 12 years. In general, gabapentin plasma concentrations in children are similar to those in adults.
In a pharmacokinetic study in 24 healthy infants and children, pediatric subjects between 1 and 48 months of age achieved approximately 30% lower exposure (AUC) than that observed in pediatric subjects older than 5 years of age; C_max was lower and the clearance per body weight was higher in infants and younger children.
Toxicology: Preclinical Safety Data: Carcinogenesis: Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell tumors was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000 mg/kg/day were 10 times higher than plasma concentrations in humans given at 3600 mg/day. The pancreatic acinar cell tumors in male rats were low-grade malignancies, which did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumors in male rats to carcinogenic risk in humans is unclear.
Mutagenesis: Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
Impairment of fertility: No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum daily human dose, on a mg/m² basis).
Teratogenesis: Gabapentin did not increase the incidence of malformations, compared to controls, in the offsprings of mice, rats, or rabbits at doses up to 50, 30, and 25 times, respectively, the daily human dose of 3600 mg (4, 5 or 8 times, respectively, the human daily dose, on a mg/m² basis).
Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during organogenesis and in rats given 2000 mg/kg/day prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600 mg, on a mg/m² basis.
No effects were observed in pregnant mice given 500 mg/kg/day (approximately half of the daily human dose, on a mg/m² basis).
An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000 mg/kg/day in a fertility and general reproduction study; 1500 mg/kg/day in a teratology study; and 500, 1000, and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m² basis.
In a teratology study in rabbits, an increased incidence of post-implantation fetal loss occurred in female rabbits given 60, 300, and 1500 mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600 mg, on a mg/m² basis.

Epilepsy: Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and children aged 3 years and older. Safety and effectiveness for adjunctive therapy in pediatric patients younger than 3 years have not been established (see Epilepsy: Pediatric patients aged 3 to 12 years under Dosage & Administration).
Neuropathic pain: Gabapentin is indicated for the treatment of neuropathic pain which includes diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia in adults aged 18 years and older. Safety and effectiveness in patients younger than 18 years have not been established.

General: Gabapentin is given orally with or without food.
When in the judgment of the clinician there is a need for dose reduction, discontinuation, or substitution with an alternative medication, this should be done gradually over a minimum of 1 week.
Epilepsy: Adults and pediatric patients older than 12 years of age: In clinical trials, the effective dosing range was 900 mg/day to 3600 mg/day. Therapy may be initiated by administering 300 mg three times a day on Day 1 or by titrating the dose (Table 2). Thereafter, the dose can be increased in three equally divided doses up to a maximum dose of 3600 mg/day. Doses up to 4800 mg/day have been well tolerated in long-term open-label clinical studies. The maximum time between doses in the three times a day schedule should not exceed 12 hours to prevent breakthrough convulsions. (See Table 2.)

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Pediatric patients aged 3 to 12 years: The starting dose should range from 10 to 15 mg/kg/day given in equally divided doses (three times a day), and the effective dose reached by upward titration over a period of approximately 3 days. The effective dose of gabapentin in pediatric patients aged 5 years and older is 25 to 35 mg/kg/day given in equally divided doses (three times a day). The effective dose in pediatric patients aged 3 to less than 5 years is 40 mg/kg/day given in equally divided doses (three times a day). Doses 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, gabapentin may be used in combination with other antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic drugs.
Neuropathic pain in adults: The starting dose is 900 mg/day given in three equally divided doses, and increased if necessary, based on response, up to a maximum dose of 3600 mg/day. Therapy should be initiated by titrating the dose (Table 2).
Dose adjustment in impaired renal function in patients with neuropathic pain or epilepsy: Dose adjustment is recommended in patients with compromised renal function (Table 3) and/or in those undergoing hemodialysis. (See Table 3.)

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Dose adjustment in patients undergoing hemodialysis: For patients undergoing hemodialysis who have never received gabapentin, a loading dose of 300 mg to 400 mg is recommended, and then 200 mg to 300 mg of gabapentin following each 4 hours of hemodialysis.

Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 g. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy, and mild diarrhea. All patients recovered fully with supportive care. Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, minimize toxicity from overdoses.
Although gabapentin can be removed by hemodialysis, based on prior experience, it is usually not required. However, in patients with severe renal impairment, hemodialysis may be indicated.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, hypoactivity, or excitation.

Gabapentin is contraindicated in patients who are hypersensitive to gabapentin or the product's components.

General: Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus (see General under Dosage & Administration).
Gabapentin is generally not considered effective in the treatment of absence seizures.
Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been postmarketing reports of confusion, loss of consciousness and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Patients who require concomitant treatment with opioids may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression and the dose of gabapentin or opioid should be reduced appropriately (see Interactions).
Respiratory depression: Gabapentin has been associated with severe respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly might be at higher risk of experiencing this severe adverse reaction. Dose adjustments might be necessary in these patients.
Potential for an increase in risk of suicidal thoughts or behaviors.
Drug rash with eosinophilia and systemic symptoms: Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs, including gabapentin.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Anaphylaxis: Gabapentin can cause anaphylaxis. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis.
Abuse and dependence: Cases of abuse and dependence have been reported in the post-marketing database. As with any CNS active drug, carefully evaluate patients for a history of drug abuse and observe them for possible signs of gabapentin abuse.
Information for patients: To assure safe and effective use of gabapentin, the following information and instructions should be given to patients: The patient should inform the physician about any prescription or nonprescription medications, alcohol, or drugs the patient is now taking or is planning to take during the treatment with gabapentin.
The patient should inform the physician if the patient is pregnant, or if the patient is planning to become pregnant, or if the patient become pregnant while the patient is taking gabapentin.
Gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. The patient should inform the physician if the patient is breast-feeding an infant (see Lactation under Use in Pregnancy & Lactation).
Gabapentin may impair the ability to drive a car or operate potentially dangerous machinery. Until it is known that this medication does not affect the ability to engage in these activities, do not drive a car or operate potentially dangerous machinery.
The patient should not allow more than 12 hours between gabapentin doses to prevent breakthrough convulsions.
Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity, such as fever or lymphadenopathy may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
Effects on Ability to Drive and Use Machines: Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.

Fertility: There is no effect on fertility in animal studies (see Pharmacology: Toxicology: Preclinical safety data: Impairment of fertility under Actions).
Pregnancy: Gabapentin crosses the human placenta.
Congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use, however, there are no adequate and well-controlled studies in pregnant women and no definite conclusions can be made as to whether gabapentin is causally associated with an increased risk of congenital malformations or other adverse developmental outcomes when taken during pregnancy. The risk of birth defects is increased by a factor of 2 - 3 in the offspring of mothers treated with an antiepileptic medicinal product.
Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data: Teratogenesis under Actions). The potential risk for humans is unknown. Gabapentin should be used during pregnancy only if the potential benefit to the mother clearly outweighs the potential risk to the fetus.
Lactation: Gabapentin is excreted in human milk. Because the effect on the nursing infant is unknown, caution should be exercised when gabapentin is administered to a nursing mother. Gabapentin should be used in nursing mothers only if the benefits clearly outweigh the risks.

Epilepsy: Gabapentin has been evaluated for safety in more than 2000 subjects and patients in adjunctive therapy studies and was well tolerated. Of these, 543 patients participated in controlled clinical trials. Since gabapentin was most often administered in combination with other antiepileptic agents, it was not possible to determine which agent(s), if any, was associated with adverse events.
Incidence in controlled adjunctive therapy clinical trials: Table 4 lists the treatment-emergent signs and symptoms that occurred in at least 1% of patients with partial seizures participating in placebo-controlled adjunctive therapy studies. In these studies, either gabapentin or placebo was added to the patient's current antiepileptic drug therapy. Adverse events were usually reported as mild to moderate. (See Table 4.)

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Other adverse events observed during all clinical trials: Adjunctive therapy: Those events that occurred in at least 1% of the study participants with epilepsy who received gabapentin as adjunctive therapy in any clinical study and that are not described in the previous section as frequently occurring treatment-emergent signs and symptoms during placebo-controlled studies are summarized as follows.
Body as a Whole: Asthenia, malaise, facial edema.
Cardiovascular System: Hypertension.
Digestive System: Flatulence, anorexia, gingivitis.
Hematologic and Lymphatic Systems: Purpura, most often described as bruises resulting from physical trauma.
Musculoskeletal System: Arthralgia.
Nervous System: Vertigo; hyperkinesia; increased, decreased or absent reflexes; paresthesia; anxiety; hostility.
Respiratory System: Pneumonia.
Urogenital System: Urinary tract infection.
Special Senses: Abnormal vision, most often described as a visual disturbance.
Geriatric use: Fifty-nine individuals aged 65 years or older received gabapentin in pre-marketing clinical trials. Side effects reported among these patients did not differ in kind from those reported in younger individuals. For patients with compromised renal function, the dose should be adjusted (see Dose adjustment in impaired renal function for patients with neuropathic pain or epilepsy and Dose adjustment in patients undergoing hemodialysis under Dosage & Administration).
Pediatric use: The most commonly observed adverse events reported with the use of gabapentin in combination with other antiepileptic drugs in children aged 3 to 12 years, not seen in equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, and somnolence. (See Table 5.)

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Other events in more than 2% of children that occurred equally or more frequent in the placebo group included pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Withdrawal from treatment due to adverse events: Adjunctive therapy: Approximately 7% of the more than 2000 healthy volunteers and patients with epilepsy, spasticity, or migraine who received gabapentin in clinical studies withdrew due to adverse events.
In all clinical studies, the most frequently occurring events that contributed to discontinuation of gabapentin included somnolence, ataxia, dizziness, fatigue, and nausea and/or vomiting. Almost all participants had multiple complaints, none of which could be characterized as primary.
Pediatric: Approximately 8% of the 292 children aged 3 to 12 years who received gabapentin in clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in children were somnolence, hyperkinesia, and hostility.
Neuropathic pain: (See Table 6.)

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Post-marketing experience: Sudden, unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established.
Additional post-marketing adverse events reported include blood creatine phosphokinase increased, rhabdomyolysis, acute kidney failure, agitation, allergic reaction including urticaria, alopecia, anaphylaxis, angioedema, hyperglycemia and hypoglycemia (most often observed in patients with diabetes), breast hypertrophy, chest pain, drug rash with eosinophilia and systemic symptoms, elevated liver function tests (LFTs), erythema multiforme, fall, generalized edema, gynecomastia, hallucinations, hepatitis, hypersensitivity including systemic reactions, hyponatremia, jaundice, loss of consciousness, movement disorders, such as choreoathetosis, dyskinesia, and dystonia, myoclonus, palpitation, pancreatitis, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia), Stevens-Johnson syndrome, thrombocytopenia, tinnitus and urinary incontinence.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating.
Rare cases of gabapentin with respiratory depression have been reported (see Precautions).

There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin and opioid use. In some of these reports, the authors considered this a particular concern with the combination of gabapentin and opioids, especially in elderly patients.
Morphine: In a study involving healthy volunteers (N = 12), when a 60-mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. This was associated with an increased pain threshold (cold pressor test). The clinical significance of such changes has not been defined. Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The observed opioid-mediated side effects associated with morphine plus gabapentin did not differ significantly from morphine plus placebo. The magnitude of interaction at other doses is not known (see General under Precautions).
No interaction between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine has been observed. Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving these antiepileptic agents.
Coadministration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol does not influence the steady-state pharmacokinetics of either component.
Coadministration of gabapentin with antacids containing aluminum and magnesium reduces gabapentin bioavailability by about 20%. It is recommended that gabapentin be taken about 2 hours following antacid administration.
Renal excretion of gabapentin is unaltered by probenecid.
A slight decrease in renal excretion of gabapentin that is observed when it is coadministered with cimetidine is not expected to be of clinical importance.
Laboratory Tests: False-positive readings were reported with the Ames N-Multistix SG dipstick test when gabapentin was added to other anticonvulsant drugs. To determine urinary protein, the more specific sulfosalicylic acid precipitation procedure is recommended.

Special Precautions for Disposal and Other Handling: Not applicable.
Incompatibilities: None known.

Capsule: Store below 30°C.
Tablet: Store below 25°C.

Anticonvulsants / Drugs for Neuropathic Pain

N02BF01 - gabapentin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

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