Neurontin (Gabapentin) for Epilepsy and Nerve Pain: Uses, Dosage, Side Effects, Interactions, Warnings (2023)

drug description

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describe

The active ingredient in NEURONTIN capsules, tablets and oral solution is gabapentin, which has the chemical name 1-(aminomethyl)cyclohexanoacetic acid.

The molecular formula for gabapentin is C₉H_{number 17}No₂Molecular weight 171.24. The structural formula of gabapentin is:

Gabapentin is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. It is easily soluble in water as well as in alkaline and acidic aqueous solutions. The logarithm of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.

Each Neurontin capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following inactive ingredients: lactose, corn starch, talc, gelatin, titanium dioxide, FD&C Blue No. 2, iron oxide yellow (300 mg and 400 mg only) and iron oxide red (400 mg only).

Each Neurontin tablet contains 600 mg or 800 mg of gabapentin and the following inactive ingredients: Poloxamer 407, copovidone, corn starch, magnesium stearate, hydroxypropyl cellulose, talc, and candelilla wax

Neurontin oral solution contains 250 mg of gabapentin (50 mg/mL) and the following inactive ingredients per 5 mL: glycerin, xylitol, purified water, strawberry fennel artificial cool flavor.

Indications and Dosage

Clues

neuron^®Indicated for:

• Treatment of postherpetic neuralgia in adults
• For the adjunctive treatment of partial-onset seizures (with or without secondary generalized seizures) in adults and children with epilepsy 3 years of age and older

Dosage and administration

Dosage for postherpetic neuralgia

For adults with postherpetic neuralgia, NEURONTIN can be started on day 1 with a single dose of 300 mg, followed by 600 mg/day (300 mg twice daily) on day 2 and 900 mg on day 3/day (300 mg each time). several times a day). The dose can then be titrated to 1800 mg/day (600 mg 3 times a day) as needed for pain relief. In clinical studies, efficacy was demonstrated at doses ranging from 1800 mg/day to 3600 mg/day, with comparable results across the dose range; however, these clinical studies used doses greater than 1800 mg/day No additional benefits were demonstrated .

Dosage for partial-onset seizures

Patients 12 years of age and older

The starting dose is 300 mg 3 times a day. The recommended maintenance dose of NEURONTIN is 300 mg to 600 mg three times a day. Doses up to 2400 mg/day have been well tolerated in long-term clinical studies. A dose of 3600 mg/day has also been administered to a small number of patients over a relatively short period of time and has been well tolerated. NEURONTIN is taken as 300 mg or 400 mg capsules or 600 mg or 800 mg tablets three times a day. The maximum interval between doses should not exceed 12 hours.

Pediatric patients aged 3 to 11 years

The starting dose ranges from 10 mg/kg/day to 15 mg/kg/day in 3 divided doses and is titrated up to the recommended maintenance dose over approximately 3 days. The recommended maintenance dose of NEURONTIN in patients 3 to 4 years of age is 40 mg/kg/day in three divided doses. The recommended maintenance dose of NEURONTIN for patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day in three divided doses. NEURONTIN may be administered as an oral solution, capsule, or tablet, or as a combination of these formulations. Doses up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The maximum time between two doses should not exceed 12 hours.

Dose adjustment in patients with renal impairment

Dosage adjustments are recommended for patients 12 years of age and older with renal impairment or undergoing hemodialysis as follows (see dosage recommendations above for effective doses for each indication):

Table 1. NEURONTIN Dosage Based on Renal Function

Creatinine clearance (CLCr) is difficult to measure in outpatients. In patients with stable renal function, creatinine clearance can be reasonably estimated using the Cockcroft and Gault equation:

The use of NEURONTIN has not been studied in patients younger than 12 years of age with impaired renal function.

Elderly Dosage

Since elderly patients are more prone to reduced renal function, care should be taken in dose selection and dose adjustment should be based on creatinine clearance values ​​in these patients.

administrative information

Take NEURONTIN by mouth with or without food.

NEURONTIN capsules should be swallowed whole with water.

Advise patients that if they split a NEURONTIN 600 mg or 800 mg tablet scored in half, they should take the unused half as their next dose. Unused halves within 28 days of splitting a scored tablet should be discarded.

If the dose of NEURONTIN is reduced, discontinued, or replaced by an alternative drug, it should be done gradually over at least 1 week (longer periods may be required at the discretion of the prescribing physician).

how to provide

Dosage Form and Specification

capsule

• 100 mg: White hard gelatin capsule with "PD" printed on the body and "Neurontin/100 mg" printed on the cap
• 300 mg: Yellow hard gelatin capsule with "PD" imprinted on the body and "Neurontin/300 mg" imprinted on the cap
• 400 mg: orange hard gelatin capsule with "PD" printed on the body and "Neurontin/400 mg" printed on the cap

tablet

• 600 mg: white oval film-coated tablet debossed with "NT" and "16" on one side
• 800 mg: white oval film-coated tablet debossed with "NT" and "26" on one side

drinking liquid

• 250 mg/5 mL (50 mg/mL), clear colorless to slightly yellow solution

storage and handling

neuron(gabapentin) capsules, tablets, and oral solution are supplied as follows:

100 mg capsule

white hard gelatin capsule imprinted with "PD" on body and "Neurontin/100 mg" on cap; may be used for:

100 bottles:National Data Center0071-0803-24

300 mg capsules

yellow hard gelatin capsule imprinted "PD" on body and "Neurontin/300 mg" on cap; may be used for:

100 bottles:National Data Center0071-0805-24
Unit dose 50 tablets:National Data Center0071-0805-40

400 mg capsules

orange hard gelatin capsule imprinted "PD" on body and "Neurontin/400 mg" on cap; may be used for:

100 bottles:National Data Center0071-0806-24
Unit dose 50 tablets:National Data Center0071-0806-40

Tablet 600 mg

white oval film-coated tablet debossed with "NT" and "16" on one side; can be used for:

Tablet 800 mg

white oval film-coated tablet debossed with "NT" and "26" on one side; can be used for:

100 bottles:National Data Center0071-0401-24p

Each 5 mL oral solution contains 250 mg

Colorless to pale yellow clear solution, each 5 mL oral solution contains 250 mg gabapentin, can be used for:

Glass bottles containing 470 mL:National Data Center0071-2012-23
Bottles containing 470 mL:National Data Center0071-2012-44,National Data Center0071-2012-47

Store NEURONTIN tablets and capsules at 25°C (77°F), the allowable temperature range is 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store NEURONTIN oral solution in the refrigerator at 2°C to 8°C (36°F to 46°F).

Distributor: Pfizer, Parke-Davis, Division of Pfizer Inc, NY, NY 10017. Revision Date: July 2022

side effect

side effect

The following serious side effects are discussed in more detail elsewhere:

• Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity [seeWarnings and precautions]
• Anaphylaxis and angioedema [seeWarnings and precautions]
• Drowsiness/sedation and dizziness [seeWarnings and precautions]
• Withdrawal seizures, status epilepticus [seeWarnings and precautions]
• Suicidal behavior and ideation [seeWarnings and precautions]
• respiratory depression [seeWarnings and precautions]
• Neuropsychiatric Adverse Effects (Pediatric Patients 3 to 12 years of age) [seeWarnings and precautions]
• Sudden and unexplained death in a patient with epilepsy [seeWarnings and precautions]

Clinical trial experience

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect those observed in clinical practice.

postherpetic neuralgia

The most common adverse reactions associated with NEURONTIN in adults were dizziness, somnolence, and peripheral edema, which were not observed in patients receiving placebo.

In two controlled trials for postherpetic neuralgia, 16% of 336 patients receiving NEURONTIN and 9% of 227 patients receiving placebo discontinued treatment due to adverse events. The adverse reactions most commonly leading to discontinuation in NEURONTIN-treated patients were dizziness, somnolence, and nausea.

Table 3 lists adverse reactions that occurred in at least 1% of patients with postherpetic neuralgia treated with NEURONTIN in placebo-controlled trials, and adverse reactions occurred more frequently in the NEURONTIN group than in the placebo group.

Table 3. Adverse reactions from pooled placebo-controlled trials of postherpetic neuralgia

Other reactions, which occurred in more than 1% of patients but were as common or more common in the placebo group, included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu-like syndrome.

There were no clinically significant differences between men and women in the type and frequency of adverse events. Because few patients were reported with a race other than white, there are insufficient data to support a statement about the racial distribution of adverse events.

Partial-onset epilepsy (adjunctive therapy)

The most common adverse reactions of NEURONTIN in combination with other antiepileptic drugs in patients >12 years of age were somnolence, dizziness, ataxia, fatigue, and nystagmus, while the same adverse reactions were not observed in placebo-treated patients.

The most common adverse reactions of NEURONTIN in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age were viral infection, fever, nausea and/or vomiting, lethargy, and hostility [seeWarnings and precautions].

Of 2074 patients >12 years of age treated with NEURONTIN in premarketing clinical trials, approximately 7% of patients and approximately 7% of 449 pediatric patients aged 3 to 12 years discontinued treatment due to adverse events. The most common withdrawal-related adverse events in patients over 12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0, 6%) and dizziness (0.6%). . The most common withdrawal-related adverse events in pediatric patients were mood instability (1.6%), hostility (1.3%), and hyperkinesia (1.1%).

Table 4 lists adverse reactions that occurred in at least 1% of NEURONTIN-treated epileptic patients >12 years of age in placebo-controlled trials and were quantitatively more frequent in the NEURONTIN group. In these studies, NEURONTIN or placebo was added to patients' current antiepileptic drug therapy.

Table 4. Adverse events in additional placebo-controlled trials in patients with epilepsy older than 12 years

Among adverse reactions that occurred in at least 10% of patients treated with NEURONTIN, somnolence and ataxia appeared to show a positive dose-response relationship.

The overall incidence and type of adverse reactions were similar in men and women receiving NEURONTIN. In patients receiving NEURONTIN or placebo, the incidence of adverse events increased slightly with age. Since only 3% (28/921) of patients in the placebo-controlled studies were identified as non-white (black or other), there are insufficient data to support the statement that adverse events are racially distributed.

Table 5 lists adverse reactions that occurred in at least 2% of NEURONTIN-treated epilepsy patients aged 3 to 12 years who participated in placebo-controlled trials and were more common in the NEURONTIN group.

Table 5. Adverse events 2#3 in an additional placebo-controlled trial in pediatric patients with epilepsy, 3 to 12 years

Other reactions, which occurred in more than 2% of pediatric patients aged 3 to 12 years but occurred equally or more frequently in the placebo group, included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, cough and otitis media.

after purchase experience

The following side effects have been observed with postmarketing use of NEURONTIN. Because these reactions are reported voluntarily from populations of uncertain size, it is not always possible to reliably estimate their frequency or demonstrate a causal relationship to drug exposure.

Diseases of the liver and bile ducts:jaundice

research:Elevated creatine kinase, elevated liver function tests

Metabolic and Nutritional Disorders:Hyponatremia

Musculoskeletal and connective tissue disorders:Rhabdomyolysis

Diseases of the nervous system:movement disorder

mental illness:agitation

Reproductive system and breast disorders:Breast enlargement, changes in libido, ejaculation disorders and anorgasmia

Skin and subcutaneous tissue disorders:Angioedema [seeWarnings and precautions], bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome.

There have been postmarketing reports of life-threatening or fatal respiratory depression in patients receiving NEURONTIN with opioids or other CNS depressants or in patients with underlying respiratory disorders [seeWarnings and precautions].

Adverse effects have also been reported after abrupt discontinuation of gabapentin. The most common reactions were anxiety, insomnia, nausea, pain and sweating.

drug interactions

drug interactions

opioids

Respiratory depression, sedation, and sometimes death have been reported with the concomitant use of gabapentin with opioids (eg, morphine, hydrocodone, oxycodone, buprenorphine) [seeWarnings and precautions].

Hydrocodone

Coadministration of NEURONTIN with hydrocodone decreases hydrocodone exposure [seeClinical Pharmacology]. When initiating or discontinuing NEURONTIN in a patient receiving hydrocodone, the potential for altered hydrocodone exposure and effects should be considered.

morphine

When gabapentin is coadministered with morphine, patients should be monitored for signs of CNS depression such as lethargy, sedation, and respiratory depression [seeClinical Pharmacology].

other antiepileptic drugs

Gabapentin is not significantly metabolized and does not interfere with the metabolism of commonly used antiepileptic drugs [seeClinical Pharmacology].

Acid resistant mold^®(aluminum hydroxide, magnesium hydroxide)

The mean bioavailability of gabapentin was reduced by approximately 20% when coadministered with antacids (Maalox)^®) containing magnesium and aluminum hydroxides. Gabapentin is recommended to be taken at least 2 hours after administration of Maalox [seeClinical Pharmacology].

Drug/lab test interactions

Because the Ames N-Multistix SG reports false positive readings^®When gabapentin is added to other antiepileptic drugs, a more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of protein in the urine.

Substance abuse and dependence

controlled substance

Gabapentin is not a scheduled drug.

abuse

Abuse is the intentional, non-therapeutic use of a substance, even once, to achieve a desired psychological or physical effect. Abuse is the intentional use of a drug by a person for therapeutic purposes in a manner other than as prescribed by a health care provider or as an over-the-counter drug.

Gabapentin has no affinity for benzodiazepines, opioids (mu, delta, or kappa), or cannabinoid receptor 1 sites. Abuse and misuse of gabapentin have been reported in the postmarketing context and in the published literature. Most of the individuals described in these reports had a history of polysubstance abuse. Some of these people received higher than recommended doses of gabapentin for unapproved uses. When prescribing NEURONTIN, carefully assess patients for a history of substance abuse and observe them for signs and symptoms of gabapentin abuse or misuse (eg, self-escalation and drug-seeking behavior). The abuse potential of gabapentin has not been evaluated in human studies.

depends

Physical dependence is a condition resulting from physiological adaptations to repeated drug use, manifested by signs and symptoms of withdrawal after abrupt discontinuation or significant reduction in drug dosage. There have been rare post-marketing reports of people experiencing withdrawal symptoms shortly after stopping higher than recommended doses of gabapentin for conditions for which it is not approved. These symptoms included restlessness, disorientation, and confusion after gabapentin was abruptly discontinued, but resolved after gabapentin was restarted. The dependence potential of gabapentin has not been evaluated in human studies.

Warnings and precautions

warn

contained in"Precautions"part

Precautions

Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with NEURONTIN. Some of these reactions are fatal or life-threatening, usually (but not limited to) presenting with fever, rash, and/or lymphadenopathy involving other organ systems such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling with an acute viral infection. Eosinophilia is often present. Expression in this disease is variable and other organ systems not listed here may be involved.

It's worth noting that early signs of an allergy, such as fever or swollen lymph nodes, can occur even if the rash isn't obvious. Patients should be evaluated immediately if such signs or symptoms occur. NEURONTIN should be discontinued if no alternative cause of symptoms or signs can be identified.

Anaphylaxis and Angioedema

NEURONTIN may cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms of reported cases include difficulty breathing, swelling of the lips, throat and tongue, and low blood pressure that requires emergency treatment. Instruct patients to discontinue NEURONTIN and seek immediate medical attention if signs or symptoms of anaphylaxis or angioedema develop.

Effects on driving and operating heavy machinery

Patients receiving NEURONTIN should not drive until they have gained enough experience to assess whether NEURONTIN impairs their ability to drive. A driving performance study using a prodrug of gabapentin (gabapentin etacabil, extended-release tablets) showed that gabapentin can cause serious driving impairment. Prescribers and patients should be aware that patients' ability to assess their ability to drive and to assess the degree of drowsiness caused by NEURONTIN may be imperfect. The duration of impaired driving after initiation of NEURONTIN treatment is unknown. Is the disorder associated with somnolence [seeDrowsiness/sedation and dizziness] or other effects of NEURONTIN are unknown.

In addition, NEURONTIN may cause drowsiness and dizziness [seeDrowsiness/sedation and dizziness], patients should be advised not to operate complex machinery until they have sufficient experience with NEURONTIN to assess whether NEURONTIN will impair their ability to perform such tasks.

Drowsiness/sedation and dizziness

In a controlled epilepsy trial with NEURONTIN 1800 mg daily in patients over 12 years of age, somnolence, dizziness, and ataxia were more common in patients receiving NEURONTIN compared with placebo: that is, 19% in the drug group, compared with 19 percent on placebo. club. Drowsiness occurred in 9% of the placebo group, dizziness in 17% of the drug group, 7% of the placebo group, ataxia in 13% of the drug group and 6% of the placebo group. % developed disorder. Somnolence, ataxia, and fatigue were common adverse events leading to discontinuation of NEURONTIN in patients older than 12 years of age in these trials, with 1.2%, 0.8%, and 0.6% of patients discontinuing treatment. treatment due to these events, respectively.

In controlled trials in patients with postherpetic neuralgia, the incidence of somnolence and dizziness was higher in patients receiving NEURONTIN at doses up to 3600 mg daily compared to placebo: i.e. NEURONTIN-treated 21% of treated patients, in compared to 5% of patients treated with NEURONTIN. Somnolence was reported in % of placebo-treated patients, 28% of NEURONTIN-treated patients, and 8% of placebo-treated patients. Dizziness and somnolence were the most common adverse reactions leading to discontinuation of NEURONTIN.

Because of the potential for synergy, patients should be carefully monitored for signs of central nervous system (CNS) depression, such as somnolence and sedation, when NEURONTIN is administered with other drugs with sedative properties. In addition, patients requiring concomitant morphine therapy may experience increased gabapentin concentrations and may require dose adjustment [seedrug interactions].

withdrawal seizures, status epilepticus

Antiepileptic drugs should not be stopped abruptly because of a possible increase in seizure frequency.

In placebo-controlled epilepsy studies in patients >12 years of age, the incidence of status epilepticus was 0.6% (3 of 543) in NEURONTIN-treated patients compared to 0.6% in placebo-treated patients 0.5 % (2 of 378 cases). In all epilepsy studies (controlled and uncontrolled), among 2074 patients >12 years of age receiving NEURONTIN, 31 (1.5%) had status epilepticus. Fourteen of the patients had no history of status epilepticus before treatment or while taking other drugs. Because there are insufficient historical data, it cannot be determined whether treatment with NEURONTIN is associated with a higher or lower incidence of status epilepticus than would be expected in a similar population not treated with NEURONTIN.

suicidal behavior and ideation

Antiepileptic drugs (AEDs), including NEURONTIN, can increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients receiving any AED for any indication should be monitored for the development or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

A pooled analysis of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of these AEDs had approximately twice the risk of suicide (adjusted relative risk 1.8, 95% CI: 1, 2, 2,7 ) compared to the thinking or behavior of patients randomized to placebo. In these trials with a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation was 0.43% in 27,863 AED-treated patients and 0.24% in 16,029 placebo-treated patients, meaning that the incidence of suicidal behavior or ideation increased by approximately 1 case. Suicidal thoughts or behaviors were reported for every 530 patients treated. There were four suicides in the trial patients who received the drug and none in the placebo patients, but this number was too small to draw conclusions about the drug's effect on suicide.

The increased risk of suicidal thoughts or behaviors with AED use was observed as early as one week after initiation of AED medication and persisted throughout the treatment period evaluated. The risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed as most trials included in the analysis were 24 weeks or less in duration.

The risk of drug-related suicidal thoughts or behavior was generally consistent across the data analyzed. The finding of increased risk for AEDs with different mechanisms of action and a range of indications suggests that this risk applies to all AEDs used for any indication. The risk did not differ significantly by age (5-100 years) in the clinical trials analyzed. Table 2 shows the absolute and relative risks by indication for all AEDs evaluated.

Table 2 Risk of antiepileptic drug indications in the pooled analysis

The relative risk of suicidal ideation or behavior was higher in epilepsy clinical trials than in psychiatric or other disorder clinical trials, but absolute risk differences were similar for epilepsy and psychiatric indications.

Anyone considering prescribing NEURONTIN or any other AED must balance the risk of suicidal thoughts or behavior against the risk of an untreated medical condition. Epilepsy and many other conditions treated with AEDs are associated with an increased risk of morbidity and mortality and suicidal thoughts and behaviors. If suicidal thoughts and behaviors develop during treatment, prescribers should consider whether a particular patient experiencing these symptoms may be related to the disorder being treated.

Patients, their caregivers, and their families should be advised that AEDs increase the risk of suicidal thoughts and behaviors and to be alert for the onset or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the development of suicidal thoughts, behaviors or thoughts of self-harm. Disturbing behavior should be reported to a health care provider immediately.

respiratory depression

Evidence from case reports, human studies, and animal studies indicate that gabapentin can cause serious, life-threatening, or fatal events when administered with CNS depressants, including opioids, or in the presence of underlying respiratory disorders, respiratory depression. When deciding to prescribe NEURONTIN with another CNS depressant (especially an opioid) or to prescribe NEURONTIN in patients with underlying respiratory disorders, monitor patients for symptoms of respiratory depression and sedation and consider starting NEURONTIN at a low dose. Treatment of respiratory depression may include close monitoring, supportive measures, and reduction or withdrawal of CNS depressants, including NEURONTIN.

Neuropsychiatric Adverse Effects (Pediatric Patients 3 to 12 years of age)

The use of gabapentin in pediatric patients with epilepsy aged 3 to 12 years is associated with the development of CNS-related adverse events. The most important of these can be broken down into the following categories: 1) emotional instability (mainly conduct problems), 2) hostility, including aggressive behavior, 3) thought disorders, including concentration problems and changes in school performance, and 4) movement Hyperactivity ( mainly restlessness and hyperactivity). In patients treated with gabapentin, most responses were mild to moderate in intensity.

In controlled epilepsy clinical trials in pediatric patients aged 3 to 12 years, the incidence of these adverse reactions was: mood instability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients), hostility 5, 2% vs. 1.3% Hyperkinesia was 4.7% and 2.9%, respectively; thought disorder was 1.7% and 0%, respectively. One of the reactions was a report of hostility, which was deemed serious. Emotional lability and hyperkinesia were reported in 1.3% of patients, and hostility and thought disturbances were reported in 0.9% of gabapentin-treated patients who discontinued gabapentin therapy. One placebo patient (0.4%) withdrew due to emotional instability.

oncogenic potential

In an oral carcinogenesis study, gabapentin increased the incidence of pancreatic acini tumors in rats [seeNon-Clinical Toxicology]. The clinical significance of this finding is unclear. Clinical experience during the premarket development of gabapentin has not provided a direct method for evaluating its tumorigenic potential in humans.

In an adjunctive epilepsy clinical study with 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal gland, 1 non-Hodgkin's lymphoma, 1 endometrial carcinoma in situ ) and 11 patients (9 brain, 1 breast, 1 prostate) during or within 2 years of discontinuation of NEURONTIN Pre-existing tumor progression. Without knowledge of the background incidence and relapse in a similar population not receiving NEURONTIN, it is impossible to know whether the incidence in this cohort was affected by treatment.

Sudden unexplained death in a patient with epilepsy

During premarket development of NEURONTIN, 8 sudden and unexplained deaths were reported in 2203 patients with epilepsy (2103 patient-years of exposure) treated with NEURONTIN.

Some of these may represent seizure-related deaths in which seizures were not observed, such as at night. This means 0.0038 deaths per patient per year. Although this rate exceeded expectations in a healthy age- and sex-matched population, it was within the estimated range for the incidence of sudden unexplained death in epilepsy patients not receiving NEURONTIN (range 0.0005 in the general epilepsy population to 0.0005 in epileptic patients). 0.003). Similar to the clinical trial population in the NEURONTIN program, 0.005 in patients with refractory epilepsy). Therefore, whether these data are reassuring or cause further concern depends on the comparability of the populations reported in the NEURONTIN cohort and the precision of the estimates provided.

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Medication Guide）.

administrative information

Inform patients that NEURONTIN can be taken by mouth with meals or alone. Advise patients that if a 600 mg or 800 mg tablet is split in half, the unused half should be taken as the next dose. Advise patients to discard unused halves within 28 days of breaking a tablet.

Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity

Before starting treatment with NEURONTIN, inform patients that a rash or other allergic signs or symptoms (such as fever or swollen lymph nodes) may indicate a serious medical event and that patients should report any such event to their physician immediately [see .Warnings and precautions].

Anaphylaxis and Angioedema

Advise patients to discontinue NEURONTIN and seek medical attention if they develop signs or symptoms of anaphylaxis or angioedema [seeWarnings and precautions].

Dizziness, drowsiness and their effects on driving and operating heavy machinery

Advise patients that NEURONTIN may cause dizziness, drowsiness, and other signs and symptoms of central nervous system depression. Other drugs that have a sedative effect can make these symptoms worse. Therefore, although patients' ability to determine the extent of their injury may be unreliable, it is recommended that they not drive a car or operate other complex machinery until they have sufficient experience with NEURONTIN to judge whether it adversely affects mental and/or sports performance. Advise patients that it is not known how long this effect lasts [seeWarnings and precautionsandWarnings and precautions].

suicidal thoughts and behavior

Advise patients, caregivers, and families that AEDs, including NEURONTIN, may increase the risk of suicidal thoughts and behaviors. Advise patients to be alert for the onset or worsening of depressive symptoms, any unusual changes in mood or behavior, or the development of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients to promptly report behaviors of concern to their health care provider [seeWarnings and precautions].

respiratory depression

Inform patients of the risk of respiratory depression. Include information that patients who use concomitant CNS depressants (such as opioid analgesics) or have underlying respiratory dysfunction are at greatest risk. Teach patients how to recognize respiratory depression and advise them to seek immediate medical attention if respiratory depression occurs [seeWarnings and precautions].

use during pregnancy

Instruct patients to tell their doctor if they become pregnant or plan to become pregnant during treatment and to tell their doctor if they are breast-feeding or plan to breast-feed during treatment [seeuse in certain populations].

Non-Clinical Toxicology

Carcinogenesis, mutation, reduced fertility

carcinogenesis

In a 2-year carcinogenicity study, gabapentin was administered orally to mice and rats. No evidence of drug-related carcinogenesis was observed in mice at doses up to 2000 mg/kg/day. At a dose of 2000 mg/kg, mouse plasma gabapentin exposure (AUC) was approximately twice the human MRHD of 3600 mg/day. In rats, an increased incidence of adenomas and carcinomas from pancreatic adenomas was found in male rats given the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. At 1000 mg/kg, rat plasma gabapentin exposure (AUC) was approximately 5 times the human MRHD.

Gabapentin stimulates DNA synthesis in rat pancreatic cells in studies aimed at investigating the mechanism of gabapentin-induced pancreatic carcinogenesis in ratsin vitroThus, it probably acts as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.

mutagenesis

Gabapentin did not exhibit mutagenic or genotoxic potentialin vitro(Ames test, Chinese hamster lung cell HGPRT forward mutation assay) andlive(Chromosomal abnormalities and micronucleus assay in Chinese hamster bone marrow, mouse micronucleus, unscheduled DNA synthesis in rat hepatocytes).

reduced fertility

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg. At 2000 mg/kg, rat plasma gabapentin exposure (AUC) was approximately 8 times the human MRHD.

use in certain populations

Pregnant

Pregnancy exposure registry

There is a pregnancy exposure registry that tracks pregnancy outcomes in women exposed to antiepileptic drugs (AEDs) such as NEURONTIN during pregnancy. Women taking NEURONTIN during pregnancy are encouraged to register with the North American Antiepileptic Drug (NAAED) Pregnancy Registry at toll-free 1-888-233-2334 or visit http://www.aedpregnancyregistry.org/.

Risk summary

There are insufficient data on the developmental risks associated with the use of NEURONTIN in pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities and increased fetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically.data].

In the general US population, the estimated historical risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The historical risk of major birth defects and miscarriage in specific populations is unknown.

data

animal data

When pregnant mice received oral doses of gabapentin (500, 1000 or 3000 mg/kg/day) during organogenesis, embryotoxicity (increased frequency of skeletal variants) was observed at the two highest doses. The no-effect dose (500 mg/kg/day) for mouse embryo-developmental toxicity was below the maximum recommended human dose (MRHD) of 3600 mg (mg/m2) for body surface area²) Base.

In studies of gabapentin administered orally (500 to 2000 mg/kg/day) during pregnancy in rats, adverse effects on offspring development (increased frequency of hydroureter and/or hydronephrosis) were observed at all doses of gabapentin. The lowest dose tested was similar to the MRHD (mg/m²Base.

When pregnant rabbits were treated with gabapentin during organogenesis, increased fetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). Lowest dose tested below the MRHD (mg/m)²Base.

In one published study, gabapentin (400 mg/kg/day). Gabapentin causes a marked reduction in neuronal synapse formation in intact mouse brains, as well as abnormal neuronal synapse formation in a mouse synapse repair model. Gabapentin has been shown toin vitroInterference with the activity of the α2δ subunit of voltage-gated calcium channels, a receptor involved in synaptogenesis in neurons. The clinical significance of these findings is unclear.

Breastfeeding

Risk summary

Gabapentin is excreted in human milk after oral administration. Effects on nursing infants and milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NEURONTIN and any adverse effects of NEURONTIN or the mother's underlying condition on the nursing infant.

Pediatric use

The safety and efficacy of NEURONTIN in the treatment of postherpetic neuralgia in children have not been established.

The safety and efficacy of adjunctive therapy for partial-onset seizures in pediatric patients less than 3 years of age have not been established [seeclinical research].

use in the elderly

In controlled clinical trials in patients with postherpetic neuralgia, a total of 336 patients were treated with NEURONTIN, of whom 102 (30%) were 65 to 74 years of age and 168 (50%) were 75 years of age or older. Patients 75 years of age and older had a greater therapeutic effect than younger patients who received the same dose. Since gabapentin is almost entirely eliminated by renal excretion, the greater treatment effect seen in patients aged ≥75 years may be a result of increased gabapentin exposure at a given dose due to age-related decline in renal function. However, other factors cannot be ruled out. The type and frequency of adverse events were similar between age groups, with the exception of peripheral edema and ataxia, the frequency of which increased with age.

Clinical studies of NEURONTIN for the treatment of epilepsy did not include sufficient numbers of people aged 65 and over to determine whether they responded differently from younger people. Other reported clinical experience has not identified differences in response between elderly and younger patients. In general, dose selection in elderly patients should be cautious, usually starting at the low end of the dose range, reflecting reduced hepatic, renal, or cardiac function and a higher incidence of concomitant disease or other drug therapy.

The drug is known to be primarily excreted by the kidneys, and patients with impaired renal function may be at greater risk of toxicity from this drug. Since elderly patients are more susceptible to reduced renal function, care should be taken in dose selection and dose adjustment should be based on creatinine clearance values ​​in these patients [seeDosage and administration,Unwanted actions, andClinical Pharmacology].

Renal failure

Adult patients with impaired renal function may require dose adjustment [seeDosage and administrationandClinical Pharmacology]. Pediatric patients with renal failure have not been studied.

Patients undergoing hemodialysis require dose adjustment [seeDosage and administrationandClinical Pharmacology].

Overdose and contraindications

excess

Symptoms of acute poisoning in animals include disorientation, dyspnea, drooping eyelids, sedation, and lethargy or excitement.

Acute oral overdose with NEURONTIN has been reported. Symptoms include double vision, tremors, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported in overdose with NEURONTIN alone or in combination with other CNS depressants.

Gabapentin can be removed by dialysis.

In case of overexposure, call Poison Control: 1-800-222-1222.

Contraindications

NEURONTIN is contraindicated in patients with hypersensitivity to the drug or its components.

Clinical Pharmacology

Clinical Pharmacology

Mechanism

The exact mechanism by which gabapentin produces its analgesic and antiepileptic effects is unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA), but has no effect on GABA binding, uptake, or degradation.in vitroStudies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-gated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unclear.

Pharmacokinetics

All pharmacological effects following administration of gabapentin are attributed to the activity of the parent compound; gabapentin is not significantly metabolized in humans.

oral bioavailability

The bioavailability of gabapentin is not dose proportional, ie, bioavailability decreases with increasing dose. The bioavailability of gabapentin was approximately 60%, 47%, 34%, 33% and 27% after three daily doses of 900, 1200, 2400, 3600 and 4800 mg, respectively. Food had only minor effects on the rate and extent of gabapentin absorption (14% increase in AUC and Cmax).

distribute

Less than 3% of circulating gabapentin is bound to plasma proteins. The apparent volume of distribution of gabapentin after intravenous administration of 150 mg was 58 ± 6 L (mean ± SD). In epileptic patients, steady-state concentrations (Cmin) of gabapentin in CSF are approximately 20% of the corresponding plasma concentrations.

eliminate

Gabapentin is eliminated from the systemic circulation as an unchanged drug by renal excretion. Gabapentin is not significantly metabolized in humans.

The half-life of gabapentin is 5 to 7 hours and does not vary with dose or with multiple doses. Gabapentin elimination rate constant, plasma clearance and renal clearance are proportional to creatinine clearance. In elderly patients and patients with reduced renal function, the plasma clearance of gabapentin is reduced. Gabapentin can be removed from plasma by hemodialysis.

Specific populations

age

The effect of age was studied in people aged 20-80 years. The apparent oral clearance (CL/F) of gabapentin decreases with age, from approximately 225 mL/min in subjects under 30 years of age to approximately 125 mL/min in subjects over 70 years of age. Renal clearance (CLr) and body surface area-adjusted CLr also decreased with age; however, renal clearance of gabapentin decreased with age, largely due to decreased renal function. [LookDosage and administrationanduse in certain populations].

genus

Although no formal studies have been conducted to compare the pharmacokinetics of gabapentin in men and women, the pharmacokinetic parameters appear to be similar in men and women and there are no significant gender differences.

Race

Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily excreted by the kidney and there are no significant racial differences in creatinine clearance, pharmacokinetic differences by race are not expected.

Pediatrics

The pharmacokinetics of gabapentin were determined after doses of approximately 10 mg/kg in 48 pediatric subjects aged between 1 month and 12 years. Peak plasma concentrations were similar between age groups, occurring 2 to 3 hours after dosing. In general, exposures (AUC) in pediatric subjects 1 month to less than 5 years of age were approximately 30% lower than those observed in children 5 years of age and older. Thus, oral clearance rates normalized to body weight were higher in younger children. Apparent oral clearance of gabapentin is similar to creatinine clearance. The elimination half-life of gabapentin averaged 4.7 hours and was similar in all age groups studied.

A population pharmacokinetic analysis was performed in 253 pediatric subjects aged 1 month to 13 years. Patients receive 3 times a day at a dose of 10 to 65 mg/kg. Apparent oral clearance (CL/F) is directly proportional to creatinine clearance and this relationship is similar at single dose and steady state. Oral clearance was higher in children younger than 5 years compared to children 5 years and older when normalized for body weight. Clearance rates in infants younger than 1 year vary widely. Normalized CL/F values ​​observed in pediatric patients 5 years of age and older were consistent with those observed in adults after a single dose. The oral volume of distribution normalized by body weight was constant across the age range.

These pharmacokinetic data suggest that an effective daily dose of 40 mg/kg/day in children with epilepsy aged 3 and 4 years should be equivalent to that achieved in patients aged 5 years and older receiving 30 mg/kg gabapentin. Plasma concentrations were similar to mean plasma concentrations. kg/day [seeDosage and administration].

Adult patients with renal failure

Subjects (N=60) with renal impairment (mean creatinine clearance range 13-114 mL/min) received a single oral dose of gabapentin 400 mg. The mean half-life of gabapentin ranged from approximately 6.5 hours (patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min), and the renal clearance of gabapentin was approximately 90 mL/min (> 60 mL/min ) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min [seeDosage and administrationanduse in certain populations]. Pediatric patients with renal failure have not been studied.

hemodialysis

In a study of adult subjects with anuria (N=11), the apparent elimination half-life of gabapentin was approximately 132 hours on non-dialysis days; during dialysis, the apparent half-life of gabapentin decreased to 3.8 hours. Thus, hemodialysis has a significant effect on the elimination of gabapentin in anuric subjects [seeDosage and administrationanduse in certain populations].

liver disease

Because gabapentin is not metabolized, it has not been studied in patients with hepatic impairment.

drug interactions

• in vitrostudy
  in vitroThe study aimed 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 exogenous metabolism. Slight inhibition (14% to 30%) of the CYP2A6 isoform was observed only at the highest concentration tested (171 mcg/mL, 1 mM). No inhibition was observed for any of the other subtypes tested at gabapentin concentrations as high as 171 mcg/mL (approximately 15 times the Cmax of 3600 mg/day).
• livestudy
  The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy.

Phenytoin

Gabapentin had no effect on steady-state plasma trough levels in the single-dose (400 mg) and multiple-dose (400 mg 3 times daily) NEURONTIN study in epileptic patients (N=8) who maintained phenytoin monotherapy for at least 2 months H concentration of phenytoin and phenytoin had no effect on the pharmacokinetics of gabapentin.

carbamazepine

Steady-state trough concentrations of carbamazepine and carbamazepine 10, 11 epoxide were unaffected by coadministration of gabapentin (400 mg 3 times daily, N=12). Likewise, gabapentin pharmacokinetics were not altered by carbamazepine administration.

Valproic acid

Mean serum valproic acid trough concentrations at steady state did not differ before and during gabapentin coadministration (400 mg three times daily, N = 17), nor were gabapentin pharmacokinetic parameters affected by valproic acid.

Phenobarbital

Steady-state pharmacokinetic parameter estimates for phenobarbital or gabapentin (300 mg three times daily, N=12) were the same whether the drugs were administered alone or together.

naphthalene

Coadministration of naproxen sodium capsules (250 mg) with NEURONTIN (125 mg) (N=18) appeared to increase the absorption of gabapentin by 12% to 15%. Gabapentin had no effect on the pharmacokinetic parameters of naproxen. These doses were lower than the therapeutic doses of both drugs. The extent to which the two drugs interact within the recommended dose range is unknown.

Hydrocodone

Coadministration of NEURONTIN (125 to 500 mg, N=48) decreased the Cmax and AUC values ​​of hydrocodone (10 mg, N=50) in a dose-dependent manner relative to hydrocodone alone; AUC values ​​were decreased by 3% to 4% and by 21% to 22% after administration of 500 mg NEURONTIN, respectively. The mechanism of this interaction is unclear. Hydrocodone increased gabapentin AUC by 14%. The extent of the interaction at other doses is unknown.

morphine

One literature reported a 44% increase in mean gabapentin AUC when 60 mg controlled-release morphine capsules were administered 2 hours before NEURONTIN 600 mg capsules (N=12) compared to gabapentin without morphine. Morphine pharmacokinetic parameter values ​​were not affected by administration of NEURONTIN 2 hours after morphine. The extent of the interaction at other doses is unknown.

Cimetidine

With cimetidine 300 mg four times daily (N=12), the mean apparent oral clearance of gabapentin was reduced by 14% and creatinine clearance was reduced by 10%. Thus, cimetidine appears to alter the renal excretion of gabapentin and creatinine, endogenous markers of renal function. This small reduction in gabapentin excretion by cimetidine is not expected to be clinically significant. The effect of gabapentin on cimetidine was not evaluated.

oral contraceptives

Tablets containing 2.5 mg norethindrone acetate and 50 mcg ethinylestradiol were administered with or without concomitant gabapentin (400 mg 3 times daily, N=13), based on AUC and half-life. Cmax of norethindrone was increased by 13% when co-administered with gabapentin; this interaction is not expected to be clinically relevant.

Antacids (Maalox^®) (aluminum hydroxide, magnesium hydroxide)

Antacids (Maalox^®) containing magnesium hydroxide and aluminum hydroxide reduced the mean bioavailability of gabapentin (N=16) by approximately 20%. When gabapentin was administered 2 hours after antacids, bioavailability was reduced by approximately 10%.

Provenecid

Probenecid is an inhibitor of renal tubular secretion. The pharmacokinetic parameters of gabapentin without and with probenecid were comparable. This suggests that gabapentin does not undergo tubular secretion via a pathway blocked by probenecid.

clinical research

postherpetic neuralgia

NEURONTIN was evaluated in two randomized, double-blind, placebo-controlled, multicenter studies for the treatment of postherpetic neuralgia (PHN). The intention-to-treat (ITT) population included a total of 563 patients with pain persisting for more than 3 months after the shingles rash had healed (Table 6).

Table 6. Controlled PHN studies: Duration, dose and number of patients

Each study included a double-blind phase of 7 or 8 weeks (3 or 4 weeks of titration and 4 weeks of fixed dose). When patients have started treatment, titrate to a maximum of 900 mg/day gabapentin for 3 days. The dose is then titrated to the target dose over 3 to 4 weeks in increments of 600 to 1200 mg/day every 3 to 7 days. Patients record their pain in a daily diary using an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst pain). Mean pain score during the baseline period of at least 4randomize. The analysis was performed using the ITT population (all randomized patients who received at least one dose of study drug).

Both studies showed efficacy compared to placebo at all doses tested.

Both studies found a reduction in mean weekly pain scores during the first week and this continued until the end of treatment. Similar treatment effects were observed in all active treatment groups. Pharmacokinetic/pharmacodynamic models provided convincing evidence of efficacy at all doses. Figures 1 and 2 show pain intensity ratings over time for Study 1 and Study 2.

Figure 1. Mean Weekly Pain Scores (Observed Cases in the ITT Population): Study 1

Figure 2. Mean Weekly Pain Scores (Observed Cases in the ITT Population): Study 2

The proportion of responders (patients who reported at least a 50% improvement in endpoint pain score from baseline) was calculated for each study (Figure 3).

Figure 3. Proportion of endpoint responders (patients with ≥50% reduction in pain score): PHN controlled study

Partial seizures (adjunctive therapy)

The efficacy of NEURONTIN as adjunctive therapy (added to other antiepileptic drugs) was established in a multicenter, placebo-controlled, double-blind, parallel-group clinical trial in adults and pediatric patients (3 years and older).refractorySome judgments.

Efficacy data comes from three trials with 705 patients (12 years and older) and one trial with 247 pediatric patients (3 to 12 years). Enrolled patients had a history of at least 4 partial seizures per month despite taking one or more therapeutic levels of antiepileptic drugs and had a history of at least 4 partial seizures per month on their standard antiepileptic drug regimens. patient). For patients with persistent at least 2 (or, in some studies, 4) seizures per month, NEURONTIN or placebo was added to existing therapy during the 12-week treatment period. Efficacy is primarily assessed based on the percentage of patients with a reduction of 50% or moreattackFrequency from baseline to treatment ("response rate") and a derived measure called the response ratio, which is a measure of change defined as (T - B)/(T + B), where B is the baseline seizure frequency of the patient, T is the patient's seizure frequency during treatment. Response ratios range from -1 to +1. A value of zero would indicate no change, while the complete elimination of seizures would indicate a value of -1; an increase in the rate of seizures would give a positive value. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. Unless otherwise noted, the results presented below apply to all partial-onset seizures in the intent-to-treat population (all patients treated at any dose) in each study.

One study compared NEURONTIN 1200 mg/day in three doses with placebo. The response rate was 23% (14/61) in the NEURONTIN group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. The response rate in the NEURONTIN group (-0.199) was also superior to that in the placebo group (-0.044), a difference that also reached statistical significance.

The second study primarily compared NEURONTIN 1200 mg/day in three doses (N=101) with placebo (N=98). Other smaller NEURONTIN dose groups (600 mg/day, N=53, 1800 mg/day, N=54) were also studied for information on dose response. The response rate (16%) was higher in the NEURONTIN 1200 mg/day group than in the placebo group (8%), but the difference was not statistically significant. The response rate in the 600 mg group (17%) was also not significantly higher than in the placebo group, but was statistically significantly higher in the 1800 mg group (26%). The remission rate was better in the NEURONTIN 1200 mg/day group (-0.103) than in the placebo group (-0.022), however, this difference was also not statistically significant (p = 0.224). The NEURONTIN 600 mg/day group (-0.105) and the 1800 mg/day group (-0.222) had a better response than the 1200 mg/day group, with the 1800 mg/day group compared to placebo in a statistically significant group.

A third study compared NEURONTIN 900 mg/day in three divided doses (N=111) with placebo (N=109). An additional NEURONTIN 1200 mg/day dose cohort (N=52) provided dose-response data. There was a statistically significant difference in response rate in the NEURONTIN 900 mg/day group (22%) compared to the placebo group (10%). Response rates were also statistically significantly superior to NEURONTIN 900 mg/day (-0.119) compared to placebo (-0.027) and were also superior to placebo in response rates (-0.184) to 1200 mg/day of NEURONTIN dose group.

Each study was also analyzed to examine the effect of NEURONTIN in the prevention of secondary generalized tonic-clonic seizures. In all three placebo-controlled studies, patients who experienced secondary tonic-clonic seizures at baseline or during treatment were included in these analyses. Multiple response rate comparisons showed a statistically significant advantage for NEURONTIN over placebo, with almost all comparisons trending in favor.

An analysis of response rates using pooled data from all three studies and all doses (N=162, NEURONTIN; N=89, placebo) also showed that NEURONTIN was more effective than placebo in reducing the incidence of secondary generalized tonic-clonic seizures advantages.

In two of the three controlled studies, more than one dose of NEURONTIN was used. In each study, the results showed no consistent increase with dose. However, looking at all studies, a trend towards increasing efficacy with increasing doses is evident (see Figure 4).

Figure 4. Response Rates in Patients Treated with NEURONTIN, Difference from Placebo Expressed as Difference by Dose and Study: Adjuvant Therapy Study in Patients ≥ 12 Years of Age with Partial Seizures

In the plot, the size of the treatment effect, measured in YaxisThe difference in the proportion of patients in the gabapentin group and the placebo group who achieved a 50% or greater reduction in seizure frequency from baseline was plotted against the daily dose of gabapentin administered (x-axis).

Although no formal gender analysis has been performed, response estimates (response rates) from clinical trials (398 men, 307 women) suggest no significant gender differences. There was no consistent pattern showing that age had any effect on response to NEURONTIN. There were insufficient numbers of patients of races other than Caucasian to compare efficacy between racial groups.

A fourth study compared NEURONTIN at 25 – 35 mg/kg/day (N=118) with placebo (N=127) in pediatric patients aged 3 to 12 years. For all partial seizures in the intention-to-treat population, the response rate was statistically significantly better in the NEURONTIN group (-0.146) than in the placebo group (-0.079). The response rate for NEURONTIN (21%) was not significantly different from placebo (18%) in the same population.

A study of NEURONTIN 40 mg/kg/day (N=38) versus placebo in pediatric patients 1 month to 3 years of age who were receiving at least one marketed antiepileptic drug and who had received at least one drug (N=38) comparedsome judgmentsScreening period (within 2 weeks before start). Patients have up to 48 hours of baseline and up to 72 hours of double-blind videoEEGMonitoring to record and count seizures. There were no statistically significant differences in response rates or response rates between treatments.

Medication Guide

patient information

neuron
(Neuron Tin)
(gabapentin) capsules, tablets, and oral solution

What is the most important information I should know about NEURONTIN?

Do not stop taking NEURONTIN without first talking to your healthcare provider.

Stopping NEURONTIN suddenly can cause serious problems.

NEURONTIN can cause serious side effects, including:

Call your health care provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

How can I watch for early symptoms of suicidal thoughts and behaviors?

Call your health care provider between visits as needed, especially if you are concerned about symptoms.

Do not stop taking NEURONTIN without first talking to your healthcare provider.

These symptoms may be the first signs of a serious reaction. Your healthcare provider should check you to decide if you should continue taking NEURONTIN.

• Suicidal thoughts. Like other anticonvulsant drugs, NEURONTIN may cause suicidal thoughts or behavior in a very small number of people (about 1 in 5 percent).
  • thoughts of suicide or death
  • suicide attempt
  • new or worse depression;
  • new or worse anxiety
  • feeling irritable or restless
  • panic attack
  • difficulty sleeping (insomnia)
  • new or worse irritability;
  • Be aggressive, angry or violent
  • they act on a dangerous impulse
  • Extreme increases in activity and speech (maniac)
  • Other unusual changes in behavior or mood
• Pay attention to any changes in mood, behavior, thoughts, or feelings, especially sudden changes.
  • All follow-up visits are scheduled with your healthcare provider.
  • Stopping NEURONTIN suddenly can cause serious problems. Abrupt discontinuation of antiepileptic drugs in patients with epilepsyepilepsyIt can cause seizures that don't stop (status epilepticus）.
  • Suicidal thoughts or behaviors can also be caused by factors other than drugs. If you have suicidal thoughts or behavior, your healthcare provider may check for other causes.
• changes in behavior and thinking-The use of NEURONTIN in children aged 3 to 12 may cause mood changes, aggressive behavior, difficulty concentrating, restlessness, changes in school performance andADHD.
• NEURONTIN can cause serious or life-threatening allergic reactionsThis can affect your skin or other parts of your body, such as your liver or blood cells. This may cause you to be hospitalized or to stop NEURONTIN. You may or may not have a rash from an allergic reaction to NEURONTIN. Call your healthcare provider right away if you have any of the following symptoms:
  • skin rash
  • measles
  • Difficulty breathing
  • fever
  • swollen glands that do not go away
  • swelling of the face, lips, throat or tongue
  • yellowing of the skin or the whites of the eyes
  • unusual bruising or bleeding
  • severe fatigue or weakness
  • unexpected muscle pain
  • often
  • severe breathing problems.Serious breathing problems can occur when NEURONTIN is taken with other drugs that can cause severe drowsiness or decreased consciousness, or in people who already have breathing problems. When starting NEURONTIN or increasing your dose, watch for increased drowsiness or decreased breathing. If breathing problems occur, get help immediately.

What are neuroproteins?

NEURONTIN is a prescription medicine used to treat:

• Pain from nerve damage (postherpetic pain)Herpes(rash that appears after the painHerpesinfection) adults.
• Adults with seizures and children 3 years and older experience some seizures when taken with other medications.

Who should not take NEURONTIN?

Do not take NEURONTIN if you are allergic to gabapentin or any other part of NEURONTIN.

For a complete list of the ingredients of NEURONTIN, see the end of this Medication Guide.

What should I tell my healthcare provider before taking NEURONTIN?

Before taking NEURONTIN, tell your healthcare provider if:

• you have or have had kidney problems or arehemodialysis
• You have or have had depression, mood problems, or suicidal thoughts or behavior
• I haveDiabetes
• have breathing problems
• You are pregnant or planning to become pregnant. It is not known whether NEURONTIN will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking NEURONTIN. You and your healthcare provider will decide whether you should take NEURONTIN during pregnancy.
  • Pregnancy Registry:If you become pregnant while taking NEURONTIN, talk to your healthcare provider about how to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of the registry is to collect information on the safety of antiepileptic drugs during pregnancy. You can join this registry by calling 1-888-233-2334.
• are breastfeeding or plan to breastfeed. NEURONTIN passes into breast milk. You and your healthcare provider should decide how to feed your baby while you are taking NEURONTIN.

tell your healthcare provider about all the medicines you are taking,Includes prescription and over-the-counter medications, vitamins, and herbal supplements. Tell your healthcare provider specifically if you are taking any medicationsopioidsAnalgesics (egOxycodone), any medicine for anxiety (such as lorazepam) or insomnia (such as zolpidem), or any medicine that makes you sleepy.

If these drugs are taken with NEURONTIN, you may be more likely to have dizziness, drowsiness, or breathing problems.

Taking NEURONTIN with certain other medicines can cause side effects or affect how they work. Do not start or stop other medications without talking to your healthcare provider.

Know your medicines. Keep a list and show it to your healthcare provider and pharmacist when you get new medicines.

How should I take NEURONTIN?

• Take NEURONTIN exactly as prescribed. Your healthcare provider will tell you how much NEURONTIN to take.
  • Do not change your dose of NEURONTIN without talking to your healthcare provider.
  • If you take NEURONTIN tablets and split the tablet in half, you should take the unused half tablet at your next scheduled dose. Half tablets not used within 28 days of breaking should be discarded.
  • Take NEURONTIN capsules with water.
• NEURONTIN tablets can be taken with food or alone. If you are taking antacids containing aluminum and magnesium, such as Maalox^®, Mailanda^®, Rude^®, Gavicon^®, thefrom-gel^®, you should wait at least 2 hours before taking your next dose of NEURONTIN. If you take too much NEURONTIN, call your healthcare provider or local poison control center right away: 1-800-222-1222.

What should I avoid while taking NEURONTIN?

• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking NEURONTIN without talking to your doctor first. Taking NEURONTIN with alcohol or medicines that make you sleepy or dizzy may make you feel sleepy or dizzy.
• Do not drive, operate heavy machinery, or perform other hazardous activities until you know how NEURONTIN may affect you. NEURONTIN slows your thinking and motor skills.

What are the possible side effects of NEURONTIN?

NEURONTIN can cause serious side effects, including:

See "What is the most important information I should know about NEURONTIN?"

• Driving problems with NEURONTIN. See "What should I avoid while taking Neurontin?"
• Drowsiness and dizziness, which may increase the chance of accidental injury, including falls
• The most common side effects of NEURONTIN include:
  • lack of coordination
  • Viral infection
  • feeling sleepy
  • nausea and vomiting
  • difficulty speaking
  • Trembling
  • swelling, usually of the legs and feet
  • feeling tired
  • fever
  • jerky movements
  • coordination difficulty
  • Diplopia
  • abnormal eye movements

Tell your healthcare provider if you have side effects that bother you or don't go away.

These are not all the possible side effects of NEURONTIN. For more information, talk to your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You can report adverse reactions to the FDA at 1-800-FDA-1088.

How should I store NEURONTIN?

• Store NEURONTIN capsules and tablets between 68°F and 77°F (20°C to 25°C).
• Store NEURONTIN oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C).

Keep NEURONTIN and all medicines out of the reach of children.

General information on the safe and effective use of NEURONTIN

Sometimes medicines are prescribed for purposes other than those listed in the Medicines Guide. Do not use NEURONTIN for a condition for which it was not prescribed. Do not give NEURONTIN to other people, even if they have the same symptoms as you. This can harm them.

This Medication Guide summarizes the most important information about NEURONTIN. If you want more information, consult your healthcare provider. You can ask your healthcare provider or pharmacist about NEURONTIN written for healthcare professionals.

For more information, visit http://www.pfizer.com or call 1-800-438-1985.

What are the ingredients of NEURONTIN?

Active ingredients:Gabapentin

Inactive ingredients in capsules:Lactose, corn starch, talc,gelatine, Dioxide Titanium and FD&C Blue No.2.

The 300 mg capsule shell also contains: Iron oxide yellow.

The 400 mg capsule shell also contains: Iron oxide red and iron oxide yellow.

Inactive ingredients in the tablet:Poloxamer 407, Copovidone, Corn Starch, Magnesium Stearate, Hydroxypropyl Cellulose, Talc and Candelilla Wax

Inactive ingredients in oral solution:glycerin,xylitol, purified water and artificial fragrance.

This Medication Guide has been approved by the US Food and Drug Administration.