PMS-Gabapentin

Gabapentin.

Drug Substance: Proper Name: Gabapentin.
Chemical Name: 1-(aminomethyl)cyclohexaneacetic acid.
Molecular Formula: C₉H₁₇NO₂.
Molecular Mass: 171.24 g/mol.
Physicochemical Properties: Description: A white to off-white crystalline solid.
Solubility: Freely-soluble in water and both basic and acidic aqueous solutions.
pH and pK values: pK_a1 = 3.68; pK_a2 = 10.70; partition coefficient at pH 7.4 = 1.25 (Log P).
Excipients/Inactive Ingredients: Corn Starch, Lactose Anhydrous, and Talc. Capsule shells contain Gelatin and Titanium Dioxide.

Pharmacology: Pharmacodynamics: Mechanism of Action: Gabapentin readily enters the brain and prevents seizures in a number of animal models of epilepsy. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid), but does not possess affinity for either GABA_A or GABA_B receptor.
Gabapentin binds with high affinity to the α2-δ (alpha-2-delta) subunit of voltage-gated calcium channels. Broad panel screening suggests it does not bind to other neurotransmitter receptors of the brain and does not interact with sodium channels.
The relevance of the binding activity of gabapentin to the anticonvulsant effects in animal models and in humans remains to be established (see DETAILED PHARMACOLOGY as follows).
CLINICAL TRIALS: Comparative Bioavailability Studies: A comparative bioavailability study of pms-GABAPENTIN 400 mg capsules was performed. Pharmacokinetic and bioavailability data were measured in 30 volunteers in the fasting state. The results are summarized as follows in Table 1. (See Table 1.)

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A single center, randomized, single-dose, double-blinded, 2-period, 2-sequence, crossover, comparative oral bioavailability study was conducted to compare pms-GABAPENTIN (gabapentin) 600 mg tablets of Pharmascience Inc. Canada and NEURONTIN (gabapentin) 600 mg tablets of Warner-Lambert Company LLC Canada Inc. (currently manufactured by Pfizer Canada Inc.) both administered as a 1 x 600 mg dose to 23 healthy male volunteers under fasting conditions. Bioavailability data were measured and the results are summarized in Table 2. (See Table 2.)

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DETAILED PHARMACOLOGY: Animal Pharmacology: In Vitro Studies: The mechanism of the anticonvulsant action of gabapentin appears to be distinctly different from that of other antiepileptic drugs. Although structurally similar to GABA, gabapentin at concentrations up to 1,000 mcM, did not bind to GABA receptors, it was not metabolized to GABA or a GABA agonist, and it did not inhibit the uptake of GABA or its degradation by GABA-transaminase. Therefore, it does not appear to act through any known GABA mechanism, in contrast to the benzodiazepines, barbiturates, sodium valproate and other similar agents. Gabapentin (0.01-100 mcM) did not interact with neuronal sodium channels or L-type calcium channels, in contrast to phenytoin, carbamazepine and sodium valproate which interact with these to promote the stability of excitable membranes. Finally, gabapentin (0.01-100 mcM) did not interact with glutamate, glycine or N-methyl-D-aspartate (NMDA) receptors, in contrast to other drugs that have demonstrated anticonvulsant activity in animal models following interaction with these receptors. These neurophysiological findings indicate that gabapentin has a mechanism of action different from that of commonly used antiepileptic drugs.
Gabapentin binds with high affinity to the α2-δ (alpha-2-delta) subunit of voltage-gated calcium channels. Auto-radiographic studies have confirmed that there are high levels of gabapentin binding in the outer layers of the cerebral cortex and other regions of the brain with major excitatory input, such as the hippocampus and cerebellum, that are known to be associated with seizure activity.
In Vivo Studies: Gabapentin has been shown to have anticonvulsant activity in animal models typically used to characterize anticonvulsant activity. Gabapentin prevented seizures induced by maximal electroshock in mice and rats in a dose-dependent manner (ED₅₀, 200 mg/kg and 9 mg/kg in mice and rats, respectively). Peak anticonvulsant effects were seen approximately 120-240 minutes post-dose.
Gabapentin prevented threshold clonic convulsions induced by the convulsant pentylenetetrazol in mice (ED₅₀ 450 mg/kg); the threshold dose of pentylenetetrazol needed to produce clonic seizures was significantly elevated by gabapentin.
Gabapentin treatment prevented tonic extensor seizures in mice from a variety of convulsant agents, including bicuculline, picrotoxin, strychnine and thiosemicarbazide.
Administration of gabapentin to kindled rats significantly reduced motor seizures from electrical stimulation of the brain, but had relatively little effect on the threshold for electrical after discharges at the site of stimulation.
Experiments with genetically-susceptible animals showed that gabapentin prevented generalized convulsive seizures. However, results with other genetic models indicated that gabapentin would be ineffective against photosensitive myoclonic seizures and absence seizures.
The anticonvulsant effects of gabapentin add to those of several other anticonvulsants against maximal electroshock in mice, thus suggesting that gabapentin would be useful as add-on therapy.
Pharmacokinetics: All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not metabolized to a significant extent in humans.
Plasma gabapentin concentrations are dose-proportional at doses of 300 to 400 mg q8h, ranging between 1 mcg/mL and 10 mcg/mL, but are less than dose-proportional above the clinical range (>600 mg q8h). There is no correlation between plasma levels and efficacy.
Gabapentin pharmacokinetics are not affected by repeated administration, and steady-state plasma concentrations are predictable from single dose data. Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving antiepileptic agents.
Absorption: Following oral administration of gabapentin, peak plasma concentrations are observed within 2 to 3 hours. Absolute bioavailability of a 300 mg dose of gabapentin capsules is approximately 59%. At doses of 300 and 400 mg, gabapentin bioavailability is unchanged following multiple dose administration.
Food has no effect on the rate or extent of absorption of gabapentin.
Distribution: Less than 3% of gabapentin is bound to plasma proteins. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58+6 L (Mean ± SD). In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid are approximately 20% of corresponding steady-state trough plasma concentrations.
Metabolism: Gabapentin is not metabolized to a significant extent in humans. Gabapentin does not induce or inhibit hepatic mixed function oxidase enzymes responsible for drug metabolism and does not interfere with the metabolism of commonly co-administered antiepileptic drugs.
Excretion: Gabapentin is eliminated solely by renal excretion as unchanged drug, and can be removed from plasma by hemodialysis. Gabapentin elimination rate constant, plasma clearance and renal clearance are directly proportional to creatinine clearance. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours in subjects with normal renal function.
Table 3 summarizes the mean steady-state pharmacokinetic parameters of gabapentin capsules. (See Table 3.)

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Bioequivalence of Dosage Forms: Gabapentin 600 mg and 800 mg tablets are bioequivalent to two 300 mg capsules and two 400 mg capsules, respectively. The results of a single-dose, two-way crossover, comparative bioavailability study in the fasted state comparing gabapentin 600 mg tablets and 2 x 300 mg gabapentin capsules are summarized as follows (Table 4). (See Table 4.)

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Special Populations and Conditions: Pediatrics: There are no pharmacokinetic data available in children under 18 years of age.
Geriatrics: Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in subjects under 30 years of age to about 125 mL/min in subjects over 70 years of age. Renal clearance (CLr) of gabapentin also declined with age; however, this decrease can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age-related compromised renal function (see Dosing Considerations under DOSAGE & ADMINISTRATION).
Hepatic Insufficiency: Because gabapentin is not metabolized to a significant extent in humans, no study was performed in patients with hepatic impairment.
Renal Insufficiency: In patients with impaired renal function, gabapentin clearance is markedly reduced and dosage adjustment is necessary (see Dosing Considerations and Special Patient Populations: Geriatrics and Renal Impairment (Table 5) under DOSAGE AND ADMINISTRATION).
Hemodialysis: In a study in anuric subjects (N = 11), the apparent elimination half-life of gabapentin on non-dialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects.
Dosage adjustment in patients undergoing hemodialysis is necessary (see Dosing Considerations and Special Patient Populations: Geriatrics and Renal Impairment (Table 5) under DOSAGE AND ADMINISTRATION).
Toxicology: Acute Toxicity: Gabapentin exhibited a very low order of acute toxicity in rodents and monkeys. In adult and 3-week-old mice, no deaths occurred and median lethal doses (MLD's) were not identified, being greater than 8,000, 2,000, and 4,000 mg/kg by the oral, intravenous, and subcutaneous routes, respectively. In adult and 3-week-old rats, MLD's after single oral and intravenous doses were greater than 8,000 and 2,000 mg/kg, respectively. No signs of toxicity were noted in monkeys given single oral doses of gabapentin up to 1,250 mg/kg.
Chronic Toxicity: Multi-dose oral administration of gabapentin was well tolerated in all species tested (mice, rats, dogs, monkeys). Decreased body weight gain was observed in rats; hypoactivity, emesis, and salivation were observed in dogs; and changes in fecal consistency were noted in all species except mice. Increased kidney weights in male rats correlated with the accumulation of hyaline droplets in renal proximal tubular epithelium. No changes were found in the kidneys of female rats. Reversible increases in liver weight were observed in rats administered gabapentin at 3,000 mg/kg for 13 weeks or 1,500 mg/kg for 26 weeks; and in dogs at 2,000 mg/kg for 6 months. No pathologic findings were noted in mice given up to 2,000 mg/kg gabapentin for 13 weeks or in monkeys given up to 500 mg/kg for 52 weeks.
In rats, plasma gabapentin concentrations increased with increasing dose. The increases were not dose proportional between 2,000 and 3,000 mg/kg, suggesting saturation of absorption at high doses.
Carcinogenesis and Mutagenesis: Gabapentin was given in the diet to mice at 200, 600, and 2,000 mg/kg/day and to rats at 250, 1,000, and 2,000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose, but not in female rats or in mice of either sex. Peak plasma drug concentrations and areas under the concentration time curve in rats at 2,000 mg/kg are 20 times higher than the therapeutic concentrations in humans given 1,200 mg/day and are 14 times higher than the therapeutic concentrations in humans given 2,400 mg/day.
The pancreatic acinar cell tumours in male rats are low grade malignancies, did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. Furthermore, higher concentrations of gabapentin in pancreas relative to plasma have been observed in rats but not monkeys, which may account for the species-specific effects.
The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is unclear, as the biologic characteristics of the tumours in rats are unlike those observed in humans. Ductal carcinoma comprises over 90% of all primary cancers of human exocrine pancreas, whereas acinar cell adenomas represent the primary pancreatic exocrine tumours in rats. In humans, pancreatic neoplasia exhibits local and distant tumour spread at the time of diagnosis. Metastasis occurs in 67% of cases, and survival is between 2 and 6 months after diagnosis. In contrast, pancreatic acinar cell tumours in male rats given gabapentin did not metastasize, exhibit aggressive behaviour or affect survival.
Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay or at the HGPRT locus in mammalian cells in the presence or absence of metabolic activation. 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.
Reproduction Studies: In a fertility and general reproduction study in rats with dietary doses of gabapentin up to 2,000 mg/kg, (approximately 5 times the maximum daily human dose, on a mg/m² basis), no adverse effects were noted on fertility, precoital interval, pregnancy rate, gestation length, parturition, nesting/nursing behaviour, or lactation.
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 3,600 mg, (4, 5 or 8 times, respectively, the human daily dose, on a mg/m² basis).
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 incidence of skeletal variations) was observed at 1,000 and 3,000 mg/kg/day (17 and 50 times, respectively the human daily dose of 3,600 mg; 1.3 and 4 times, respectively, the human daily dose on a mg/m² basis). The no-effect dose for embryofetal developmental toxicity in mice was observed at 500 mg/kg/day (8 times the human daily dose of 3,600 mg; 0.7 times the human daily dose, on a mg/m²) 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 incidence of hydroureter and/or hydronephrosis) were observed at all doses. The lowest dose tested is similar to the MRHD on a mg/m² 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/m² 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). Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels; a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown.

Adults: pms-GABAPENTIN (gabapentin) is indicated as adjunctive therapy for the management of patients with epilepsy who are not satisfactorily controlled by conventional therapy.
Geriatrics (> 65 years of age): Systematic studies in geriatric patients have not been conducted (see Use in the Elderly (>65 years of age) under PRECAUTIONS).
Pediatrics (< 18 years of age): The safety and efficacy in patients under the age of 18 have not been established (see Use in Children (<18 years of age) under PRECAUTIONS).

Dosing Considerations: Because pms-GABAPENTIN is eliminated solely by renal excretion, dosage adjustments are recommended for patients with renal impairment (including elderly patients with declining renal function) and patients undergoing hemodialysis (see Special Patient Populations: Geriatrics and Renal Impairment (Table 5) as follows; and Neurologic under PRECAUTIONS).
Adults: pms-GABAPENTIN (gabapentin) is given orally with or without food.
Initial Dose: The starting dose is 300 mg three times a day.
Dose Range: The dose may be increased, depending on the response and tolerance of the patient, using 300 or 400 mg capsules, or 600 or 800 mg tablets 3 times a day up to 1,800 mg/ day. In clinical trials, the effective dosage range was 900 to 1,800 mg/day, given 3 times a day using 300 mg or 400 mg capsules, or 600 mg or 800 mg tablets. Dosages up to 2,400 mg/day have been well tolerated in long-term open-label clinical studies. Doses of 3,600 mg/day have also been administered to a small number of patients for a relatively short duration and have been well tolerated.
Although data from clinical trials suggest that doses higher than 1,200 mg/day may have increased efficacy in some patients, higher doses may also increase the incidence of adverse events (see ADVERSE REACTIONS).
Maintenance: Daily maintenance doses should be given in three equally divided doses, and the maximum time between doses in a three times daily schedule should not exceed 12 hours to prevent breakthrough convulsions. It is not necessary to monitor gabapentin plasma concentrations in order to optimize pms-GABAPENTIN therapy. Further, as there are no drug interactions with commonly used antiepileptic drugs, pms-GABAPENTIN may be used in combination with these drugs without concern for alteration of plasma concentrations of either gabapentin or other antiepileptic drugs.
Discontinuation of Treatment, Dose Reduction or Initiation of Adjunctive Antiepileptic Therapy: If pms-GABAPENTIN dose is reduced, discontinued or substituted with an alternate anticonvulsant or an alternate anticonvulsant is added to pms-GABAPENTIN therapy, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber (see PRECAUTIONS).
Special Patient Populations: Geriatrics and Renal Impairment: Due to the primarily renal excretion of pms-GABAPENTIN, the following dosage adjustments are recommended for elderly patients with declining renal function, patients with renal impairment and patients undergoing hemodialysis (see Dosing Considerations as previously mentioned; PHARMACOLOGY: Pharmacokinetics: Special Populations and Conditions under ACTIONS). (See Table 5.)

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Pediatrics: pms-GABAPENTIN (gabapentin) is not indicated for use in children under 18 years of age (see INDICATIONS/USES; Use in Children (<18 years of age) under PRECAUTIONS).
Hepatic Impairment: Because gabapentin is not metabolized to a significant extent in humans, no studies have been performed in patients with hepatic impairment.
Missed Dose: Physicians should instruct their patients that if a dose is missed, the next one should be taken as soon as possible. However, if it is within 4 hours of the next dose, the missed dose is not to be taken and the patient should return to the regular dosing schedule. To avoid breakthrough convulsions the maximum time between doses should not exceed 12 hours.

Symptoms of Overdosage: Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 grams ingested at one time. In these cases, dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy and mild diarrhea were observed. All patients recovered with supportive care.
Overdoses of gabapentin, particularly in combination with other CNS depressant medications, including opioids, can result in coma and death.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8,000 mg/kg. Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.
Treatment of Overdosage: 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.
Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, reduce toxicity from overdoses.
In managing overdosage, consider the possibility of multiple drug involvement.
For management of a suspected drug overdose, contact the regional Poison Control Centre.

Hypersensitivity: pms-GABAPENTIN (gabapentin) is contraindicated in patients who have demonstrated hypersensitivity to the drug or to any of the components of the formulation.

Life-threatening Respiratory Depression: Concomitant use of pms-GABAPENTIN with opioids may result in respiratory depression, profound sedation, syncope, and death.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.

General: pms-GABAPENTIN (gabapentin) is not considered effective in the treatment of absence seizures and should therefore be used with caution in patients who have mixed seizure disorders that include absence seizures.
Discontinuation of Treatment with pms-GABAPENTIN: As with other anticonvulsant agents, abrupt withdrawal is not recommended because of the possibility of increased seizure frequency. There have been post-marketing reports of adverse events such as anxiety, insomnia, nausea, pain and sweating following abrupt discontinuation of treatment (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS). When in the judgement 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 (a longer period may be needed at the discretion of the prescriber).
Neurologic: Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been post-marketing reports of agitation, 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 (see Dosing Considerations and Special Patient Populations under DOSAGE & ADMINISTRATION).
Respiratory Depression: Gabapentin has been associated with central nervous system (CNS) depression including sedation, somnolence, loss of consciousness as well as serious cases of respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing these severe adverse effects. Concomitant use of CNS depressants with gabapentin is also a contributing factor.
Concomitant Use with Opioids: Concomitant use of opioids with gabapentin potentiates the risk of respiratory depression, profound sedation, syncope, and death. Gabapentin concentrations may also increase in patients receiving concomitant opioid (see INTERACTIONS).
Patients who require concurrent treatment with opioids or other CNS depressants should be observed carefully for signs and symptoms of CNS depression, and the dose of gabapentin or opioid should be reduced accordingly.
Psychomotor Impairment: Patients with uncontrolled epilepsy should not drive or handle potentially dangerous machinery. Patients taking pms-GABAPENTIN should not drive until they have gained sufficient experience to assess whether pms-GABAPENTIN impairs the ability to drive. During clinical trials, the most common adverse reactions observed were somnolence, ataxia, fatigue, and nystagmus. Patients should be advised to refrain from activities requiring mental alertness or physical coordination until they are sure that pms-GABAPENTIN does not affect them adversely.
Carcinogenesis and Mutagenesis: Gabapentin produced an increased incidence of acinar cell adenomas and carcinomas in the pancreas of male rats, but not female rats or in mice, in oncogenic studies with doses of 2,000 mg/kg which resulted in plasma concentrations 14 times higher than those occurring in humans at a dose of 2400 mg/day. The relevance of these pancreatic acinar cell tumours in male rats to humans is unknown, particularly since tumours of ductal rather than acinar cell origin are the predominant form of human pancreatic cancer (see PHARMACOLOGY: TOXICOLOGY: Carcinogenesis and Mutagenesis under ACTIONS).
Dependence/Tolerance: The abuse and dependence potential of gabapentin has not been evaluated in human studies. Cases of abuse and dependence have been reported in the post-marketing database. These individuals were taking higher than recommended doses of gabapentin for unapproved uses. Most of the individuals described in these reports had a history of polysubstance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. As with any CNS active drug, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of abuse or misuse of pms-GABAPENTIN (e.g., development of tolerance, self-dose escalation, and drug-seeking behavior).
There are rare post-marketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not indicated. Such symptoms included agitation, disorientation and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. Most of these individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
Hypersensitivity: Serious Dermatological Reactions: There have been post-marketing reports of Stevens-Johnson syndrome (SJS) and Erythema multiforme (EM) in patients during treatment with gabapentin. Should signs and symptoms suggest SJS or ER, gabapentin should be discontinued immediately (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS).
There have been reports in the post-marketing experience of hypersensitivity including systemic reactions and cases of urticaria and angioedema (see Post-Market Adverse Drug Reactions under ADVERSE REACTIONS).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome 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.
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
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.
Psychiatric: Suicidal Ideation and Behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.
All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.
There were 43,892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.
Monitoring and Laboratory Tests: Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. Gabapentin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or other antiepileptic drugs.
Use in Pregnancy: Based on animal data, gabapentin may cause fetal harm (see PHARMACOLOGY: TOXICOLOGY: Reproduction Studies under ACTIONS). In non-clinical studies in mice, rats and rabbits, gabapentin was developmentally toxic (e.g., increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses lower than the maximum recommended human dose (MRHD) of 3,600 mg/day on a body surface area (mg/m²) basis.
Teratogenic Potential: Gabapentin crosses the human placental barrier. Although there are no adequate and well-controlled studies in pregnant women, congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use; both, from literature and Pregnancy Registries. Since the potential risk for humans is uncertain, gabapentin should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus. If women decide to become pregnant while taking pms-GABAPENTIN, the use of this product should be carefully re-evaluated.
Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking pms-GABAPENTIN enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://aedpregnancyregistry.org/.
Use in Lactation: Gabapentin is excreted in human milk. There are no controlled studies on the effects of gabapentin on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants, a decision should be made as to whether to discontinue nursing or to discontinue pms-GABAPENTIN, taking into account the benefit of the drug to the mother.
Use in Children (< 18 years of age): The safety and efficacy in patients under the age of 18 have not been established.
Safety data in 39 patients between the ages of 12 and 18 years included in the double-blind, placebo-controlled trials showed that, at doses of 900 to 1,200 mg/day, the incidence of adverse events in this group of patients was similar to that observed in older individuals.
In controlled clinical trials involving patients, 3 to 12 years of age (N = 323), psychiatric adverse events such as emotional lability, hostility, hyperkinesia and thought disorder were reported at a higher frequency in patients treated with gabapentin compared to placebo.
Use in the Elderly (> 65 years of age): Systematic studies in geriatric patients have not been conducted. Adverse clinical events reported among 59 patients over the age of 65 years treated with gabapentin did not differ from those reported for younger individuals. The small number of individuals evaluated and the limited duration of exposure limits the strength of any conclusions reached about the influence of age, if any, on the kind and incidence of adverse events associated with the use of gabapentin. As gabapentin is eliminated primarily by renal excretion, dosage adjustment may be required in elderly patients because of declining renal function (see Dosing Considerations under DOSAGE & ADMINISTRATION; PHARMACOLOGY: PHARMACOKINETICS: Special Populations and Conditions under ACTIONS).

Pregnant Women: Based on animal data, gabapentin may cause fetal harm (see PHARMACOLOGY: TOXICOLOGY: Reproduction Studies under Actions). In non-clinical studies in mice, rats and rabbits, gabapentin was developmentally toxic (e.g., increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses lower than the maximum recommended human dose (MRHD) of 3,600 mg/day on a body surface area (mg/m²) basis.
Teratogenic Potential: Gabapentin crosses the human placental barrier. Although there are no adequate and well-controlled studies in pregnant women, congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use; both, from literature and Pregnancy Registries. Since the potential risk for humans is uncertain, gabapentin should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus. If women decide to become pregnant while taking pms-GABAPENTIN, the use of this product should be carefully re-evaluated.
Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking pms-GABAPENTIN enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://aedpregnancyregistry.org/.
Nursing Women: Gabapentin is excreted in human milk. There are no controlled studies on the effects of gabapentin on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants, a decision should be made as to whether to discontinue nursing or to discontinue pms-GABAPENTIN, taking into account the benefit of the drug to the mother.

Adverse Drug Reaction Overview: Commonly Observed Adverse Events: The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs, not seen at an equivalent frequency in placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, nystagmus and tremor (see Table 6).
Adverse Events Leading to Discontinuation of Treatment: Approximately 6.4% of the 543 patients who received gabapentin in the placebo-controlled studies withdrew due to adverse events. In comparison, approximately 4.5% of the 378 placebo-controlled participants withdrew due to adverse events during these studies. The adverse events most commonly associated with withdrawal were somnolence (1.2%), ataxia (0.8%), fatigue, nausea and/or vomiting and dizziness (all at 0.6%).
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Incidence in Controlled Clinical Trials: Adults: Multiple doses of gabapentin were administered to 543 subjects with partial seizures in placebo controlled clinical trials of 12 weeks duration. In these studies, either gabapentin (at doses of 600, 900, 1,200 or 1,800 mg/day) or placebo was added to the patient's current antiepileptic drug therapy. Treatment-emergent signs and symptoms that occurred in at least 1% of patients participating in these studies are listed in Table 6. (See Table 6.)

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Dose-Related Treatment Emergent Adverse Events: Among the treatment-emergent adverse events occurring in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. Patients treated with 1,800 mg/day (n = 54, from one controlled study) experienced approximately a two-fold increase, as compared to patients on lower doses of 600 to 1,200 mg/day (n = 489, from several controlled studies), in the incidence of nystagmus (20.4%), tremor (14.8%), rhinitis (13%), peripheral edema (7.4%), coordination abnormal, depression and myalgia (all at 5.6%). Adverse events were usually mild to moderate in intensity, with a median time to resolution of 2 weeks. Data from long-term, open, uncontrolled studies shows that gabapentin treatment does not result in any new or unusual adverse events.
Other Adverse Drug Reactions Observed in All Clinical Trials: Adverse events that occurred in at least 1% of the 2,074 individuals who participated in all clinical trials, only some of which were placebo-controlled, are described as follows. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing as follows. The frequencies presented represent the proportion of the 2,074 patients exposed to gabapentin who experienced an event of the type cited on at least one occasion while receiving gabapentin. All reported events are included except those already listed in Table 6, those too general to be informative, and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
Body as a Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect.
Cardiovascular: Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis.
Digestive: Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.
Endocrine: Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance.
Hematologic and Lymphatic: Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin's lymphoma, bleeding time increased.
Musculoskeletal: Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.
Nervous: Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, suicide attempt, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction, suicide.
Respiratory: Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema.
Dermatological: Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.
Urogenital: Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain.
Special Senses: Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.
Post-Market Adverse Drug Reactions: Sudden, unexplained deaths in patients with epilepsy have been reported where a causal relationship to treatment with gabapentin has not been established.
Post-marketing adverse events that have been reported, which may have no causal relationship to gabapentin are as follows: agitation, anaphylactic reaction, angioedema, blood creatine phosphokinase increased, blood glucose abnormal, drug rash with eosinophilia and systemic symptoms, fall, gynaecomastia, hepatic function abnormal, hepatitis, hepatitis cholestatic, hepatitis fulminant, hyperglycemia, hypoglycemia, hypersensitivity, hyponatremia, jaundice, loss of consciousness, pancreatitis, pulmonary oedema, renal failure acute, rhabdomyolysis, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia), Stevens-Johnson syndrome.
Adverse events following the abrupt discontinuation of gabapentin have also been reported during post-marketing experience. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.

Overview: In vitro studies were performed 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%) observed with isoform CYP2A6. No inhibition was observed with any of the other isoforms tested at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C_max at 3,600 mg/day). Gabapentin is not an inducer of cytochrome P₄₅₀ enzymes.
At plasma concentrations associated with doses up to 3600 mg/day (C_max 11.6 mcg/mL), the highest recommended daily dose, a metabolically-based interaction between gabapentin and a drug whose clearance is dependent upon the major cytochrome P450 enzymes is unlikely.
Gabapentin is not metabolized to a significant extent in humans and does not interfere with the metabolism of commonly administered antiepileptic drugs (see Drug-Drug Interactions: Antiepileptic agents as follows). Gabapentin also shows a low level of binding to plasma proteins (approximately 3%) and is eliminated solely by renal excretion as unchanged drug (see ACTIONS). Consequently, there have been few drug interactions described in which the pharmacokinetics of gabapentin or other co-administered drugs were affected to an appreciable extent.
Drug-Drug Interactions: The drug interaction data described in this subsection were obtained from studies involving healthy adults and adult patients with epilepsy: Antiepileptic Agents: There is no interaction between gabapentin and phenytoin, valproic acid, carbamazepine, or phenobarbital. Consequently, pms-GABAPENTIN may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or the other antiepileptic drugs.
Hydrocodone: Co-administration of single doses of gabapentin (125 mg to 500 mg; N = 48) and hydrocodone (10 mg; N = 50) decreased the C_max and AUC values of hydrocodone in a dose-dependent manner relative to administration of hydrocodone alone. The C_max and AUC values for hydrocodone were 2% and 4% lower, respectively, after administration of 125 mg gabapentin and 16% and 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increased gabapentin AUC values by 14%. The magnitude of interaction with higher doses of gabapentin is not known.
Morphine: A literature article reported that when a 60 mg controlled release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule in healthy volunteers (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine in this study. Because this was a single dose study, the magnitude of the interaction at steady state and at higher doses of gabapentin are not known.
Naproxen: In healthy adult volunteers (N = 18), the co-administration of single doses of naproxen sodium capsules (250 mg) and gabapentin (125 mg) increased the amount of gabapentin absorbed by 12% to 15%. Gabapentin did not affect naproxen pharmacokinetic parameters in this study. These doses are lower than the therapeutic doses for both drugs. Therefore, the magnitude of interaction at steady state and within the recommended dose ranges of either drug is not known.
Oral Contraceptives: Co-administration of gabapentin with the oral contraceptive norethindrone does not influence the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Antacids: Co-administration of gabapentin with an aluminum and magnesium-based antacid reduces gabapentin bioavailability by up to 20%. Although the clinical significance of this decrease is not known, co-administration of similar antacids and gabapentin is not recommended.
Cimetidine: A slight decrease in renal excretion of gabapentin observed when it is co-administered with cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine has not been evaluated.
Probenecid: Renal excretion of gabapentin is unaltered by probenecid.
Pharmacodynamic: Opioids, Benzodiazepines and Alcohol: Gabapentin appears to be additive in the impairment of cognitive and gross motor function caused by opioids, benzodiazepines and alcohol.
In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking gabapentin alone or in combination with other CNS depressants, including in patients with substance use disorders.
Drug-Food Interactions: pms-GABAPENTIN is given orally with or without food.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Interactions: For urinary protein determination the sulfosalicylic acid precipitation procedure is recommended, as false positive readings were reported with the Ames N-Multistix SG dipstick test, when gabapentin or placebo was added to other anticonvulsant drugs.

Store between 15°C and 30°C.

Anticonvulsants / Drugs for Neuropathic Pain

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

POM