Generic Name: GABAPENTIN
Brand Name: Gabapentin
- Substance Name(s):
7 Concentrations increased by morphine; may need dose adjustment (5.4, 7.2) 7.1 Other Antiepileptic Drugs Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly co-administered antiepileptic drugs [see Clinical Pharmacology (12.3)].
7.2 Opioids Hydrocodone Co-administration of gabapentin with hydrocodone decreases hydrocodone exposure [see Clinical Pharmacology (12.3)].
The potential for alteration in hydrocodone exposure and effect should be considered when gabapentin is started or discontinued in a patient taking hydrocodone.
Morphine When gabapentin is administered with morphine, patients should be observed for signs of CNS depression, such as somnolence, sedation and respiratory depression [see Clinical Pharmacology (12.3)] .
7.3 Maalox ® (aluminum hydroxide, magnesium hydroxide) The mean bioavailability of gabapentin was reduced by about 20% with concomitant use of an antacid (Maalox ® ) containing magnesium and aluminum hydroxides.
It is recommended that gabapentin be taken at least 2 hours following Maalox administration [see Clinical Pharmacology (12.3)].
7.4 Drug/Laboratory Test Interactions Because false positive readings were reported with the Ames N-Multistix SG ® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.
10 A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8,000 mg/kg.
Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation.
Acute oral overdoses of gabapentin up to 49 grams have been reported.
In these cases, double vision, slurred speech, drowsiness, lethargy, and diarrhea were observed.
All patients recovered with supportive care.
Coma, resolving with dialysis, has been reported in patients with chronic renal failure who were treated with gabapentin.
Gabapentin can be removed by hemodialysis.
Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.
If overexposure occurs, call your poison control center at 1-800-222-1222.
11 The active ingredient in gabapentin capsules, USP is gabapentin, USP, which has the chemical name 1-(aminomethyl)cyclohexaneacetic acid.
The molecular formula of gabapentin is C 9 H 17 NO 2 and the molecular weight is 171.24.
The structural formula of gabapentin is: Gabapentin, USP is a white to off-white crystalline solid with a pK a1 of 3.7 and a pK a2 of 10.7.
It is freely soluble in water and both basic and acidic aqueous solutions.
The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is –1.25.
Each gabapentin, USP capsule contains 100 mg, 300 mg, or 400 mg of gabapentin and the following inactive ingredients: magnesium stearate, pregelatinized starch (corn), starch (corn) and talc.
The 100 mg capsule shell contains gelatin, sodium lauryl sulfate and titanium dioxide.
The 300 mg capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, and iron oxide yellow.
The 400 mg capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, FD&C Yellow No.6 and FD&C Blue No.1.
14 14.1 Postherpetic Neuralgia Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in two randomized, double-blind, placebo-controlled, multicenter studies.
The intent-to-treat (ITT) population consisted of a total of 563 patients with pain for more than 3 months after healing of the herpes zoster skin rash (Table 6).
Controlled PHN Studies: Duration, Dosages, and Number of Patients Study Study Duration Gabapentin (mg/day) a Target Dose Patients Receiving Gabapentin Patients Receiving Placebo 1 8 weeks 3600 113 116 2 7 weeks 1800, 2400 223 111 Total 336 227 a Given in 3 divided doses (TID) Each study included a 7-or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose).
Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days.
Dosages were then to be titrated in 600 to 1,200 mg/day increments at 3-to 7-day intervals to the target dose over 3 to 4 weeks.
Patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).
A mean pain score during baseline of at least 4 was required for randomization.
Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication).
Both studies demonstrated efficacy compared to placebo at all doses tested.
The reduction in weekly mean pain scores was seen by Week 1 in both studies, and were maintained to the end of treatment.
Comparable treatment effects were observed in all active treatment arms.
Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses.
Figures 1 and 2 show pain intensity scores over time for Studies 1 and 2.
Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1 Figure 2.
Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2 The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score compared to baseline) was calculated for each study (Figure 3).
Proportion of Responders (patients with ≥ 50% reduction in pain score) at Endpoint: Controlled PHN Studies 10 10 10 14.2 Epilepsy for Partial Onset Seizures (Adjunctive Therapy) The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures.
Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age).
The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients).
In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period.
Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the “responder rate”) and a derived measure called response ratio, a measure of change defined as (T -B)/(T + B), in which B is the patient’s baseline seizure frequency and T is the patient’s seizure frequency during treatment.
Response ratio is distributed within the range -1 to +1.
A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values.
A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency.
The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated.
One study compared gabapentin 1,200 mg/day, in three divided doses with placebo.
Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant.
Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance.
A second study compared primarily gabapentin 1,200 mg/day, in three divided doses (N=101), with placebo (N=98).
Additional smaller gabapentin dosage groups (600 mg/day, N=53; 1,800 mg/day, N=54) were also studied for information regarding dose response.
Responder rate was higher in the gabapentin 1,200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant.
The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1,800 mg group (26%) was statistically significantly superior to the placebo rate.
Response ratio was better in the gabapentin 1,200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224).
A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1,800 mg/day group (-0.222) than in the 1,200 mg/day group, with the 1,800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared gabapentin 900 mg/day, in three divided doses (N=111), and placebo (N=109).
An additional gabapentin 1,200 mg/day dosage group (N=52) provided dose-response data.
A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%).
Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1,200 mg/day gabapentin (-0.184) compared to placebo.
Analyses were also performed in each study to examine the effect of gabapentin on preventing secondarily generalized tonic-clonic seizures.
Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses.
There were several response ratio comparisons that showed a statistically significant advantage for gabapentin compared to placebo and favorable trends for almost all comparisons.
Analysis of responder rate using combined data from all three studies and all doses (N=162, gabapentin; N=89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures.
In two of the three controlled studies, more than one dose of gabapentin was used.
Within each study, the results did not show a consistently increased response to dose.
However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4).
Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients ≥ 12 Years of Age with Partial Seizures In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo-assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis).
Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist.
There was no consistent pattern indicating that age had any effect on the response to gabapentin.
There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups.
A fourth study in pediatric patients age 3 to 12 years compared 25 to 35 mg/kg/day gabapentin (N=118) with placebo (N=127).
For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079).
For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%).
A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N=38) with placebo (N=38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline).
Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures.
There were no statistically significant differences between treatments in either the response ratio or responder rate.
16 /STORAGE AND HANDLING Gabapentin capsules, USP are supplied as follows: 100 mg capsules: White-White, opaque hard gelatin capsules printed with “IP 101” on both cap and body.
They are available as follows: Box of 10×10 UD 100 NDC 63739-591-10 300 mg capsules: Buff-Buff, opaque hard gelatin capsules printed with “IP 102” on both cap and body.
They are available as follows: Boxes of 10×10 UD 100 NDC 63739-236-10 400 mg capsules: Light caramel-Light caramel, opaque hard gelatin capsules printed with “IP 103” on both cap and body.
They are available as follows: Boxes of 10×10 UD 100 NDC 63739-984-10 Store gabapentin capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Dispense in tight (USP), child-resistant containers.
RECENT MAJOR CHANGES
Warnings and Precautions, Respiratory Depression (5.7) 04/2020
8.5 Geriatric Use The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older.
There was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage.
Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function.
However, other factors cannot be excluded.
The types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.
Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients [see Dosage and Administration (2.4) , Adverse Reactions (6), and Clinical Pharmacology (12.3)].
DOSAGE FORMS AND STRENGTHS
3 Capsules: 100 mg: white-white, opaque hard gelatin capsules printed with “IP 101” on both cap and body.
300 mg: buff-buff, opaque hard gelatin capsules printed with “IP 102” on both cap and body.
400 mg: light caramel-light caramel, opaque hard gelatin capsules printed with “IP 103” on both cap and body.
Capsules: 100 mg, 300 mg, and 400 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanisms by which gabapentin produces its analgesic and antiepileptic actions are unknown.
Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation.
In vitro studies have shown that gabapentin binds with high-affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.
INDICATIONS AND USAGE
1 Gabapentin capsules are indicated for: Management of postherpetic neuralgia in adults Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy Gabapentin capsules are indicated for: Postherpetic neuralgia in adults (1) Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy (1)
8.4 Pediatric Use Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established.
Safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established [see Clinical Studies (14.2) ].
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as gabapentin, during pregnancy.
Encourage women who are taking gabapentin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
Risk Summary There are no adequate data on the developmental risks associated with the use of gabapentin in pregnant women.
In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically [see Data].
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % to 4% and 15% to 20%, respectively.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data Animal data When pregnant mice received oral doses of gabapentin (500 mg, 1000 mg, or 3000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses.
The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3600 mg/kg on a body surface area (mg/m 2 ) basis.
In studies in which rats received oral doses of gabapentin (500 mg to 2000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses.
The lowest dose tested is similar to the MRHD on a mg/m 2 basis.
When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60 mg, 300 mg, or 1,500 mg/kg).
The lowest dose tested is less than the MRHD on a mg/m 2 basis.
In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans).
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.
8.2 Lactation Risk Summary Gabapentin is secreted in human milk following oral administration.
The effects on the breastfed infant and on milk production are unknown.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gabapentin and any potential adverse effects on the breastfed infant from gabapentin or from the underlying maternal condition.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): Discontinue if alternative etiology is not established (5.1) Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately (5.2) Driving Impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior (5.6) Respiratory depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants or in the setting of underlying respiratory impairment.
Monitor patients and adjust dosage as appropriate (5.7) Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Monitor for such events (5.8) 5.1 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 gabapentin.
Some of these reactions have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present.
This disorder is variable in its expression, and other organ systems not noted here may be involved.
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.
5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment.
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 or angioedema.
5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive.
Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment.
Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect.
The duration of driving impairment after starting therapy with gabapentin is unknown.
Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of gabapentin is unknown.
Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ] , patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks.
5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1,800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia.
In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.
During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3,600 mg per day: i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness.
Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin.
Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy.
In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [ see Drug Interactions (7.2) ].
5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.
In the placebo-controlled epilepsy studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs.
0.5% in patients receiving placebo (2 of 378).
Among the 2,074 patients > 12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus.
Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications.
Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin.
5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing gabapentin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.7 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.
When the decision is made to co-prescribe gabapentin with another CNS depressant, particularly an opioid, or to prescribe gabapentin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose.
The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin).
5.8 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions.
The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity).
Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.
In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs.
1.3% (placebo-treated patients); hostility 5.2% vs.
1.3%; hyperkinesia 4.7% vs.
2.9%; and thought disorder 1.7% vs.
One of these reactions, a report of hostility, was considered serious.
Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder.
One placebo-treated patient (0.4%) withdrew due to emotional lability.
5.9 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)] .
The clinical significance of this finding is unknown.
Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin.
Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.
5.10 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2,203 epilepsy patients treated (2,103 patient-years of exposure) with gabapentin.
Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.
This represents an incidence of 0.0038 deaths per patient-year.
Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy).
Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Administration Information Inform patients that gabapentin is taken orally with or without food.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Prior to initiation of treatment with gabapentin, instruct patients 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 [see Warnings and Precautions (5.1) ].
Anaphylaxis and Angioedema Advise patients to discontinue gabapentin and seek medical care if they develop signs or symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.2) ] .
Dizziness and Somnolence and Effects on Driving and Operating Heavy Machinery Advise patients that gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression.
Other drugs with sedative properties may increase these symptoms.
Accordingly, although patients’ ability to determine their level of impairment can be unreliable, advise them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely.
Inform patients that it is not known how long this effect lasts [see Warnings and Precautions (5.3) and Warnings and Precautions (5.4) ] .
Suicidal Thinking and Behavior Counsel the patient, their caregivers, and families that AEDs, including gabapentin, may increase the risk of suicidal thoughts and behavior.
Advise patients of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Instruct patients to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.6) ].
Use in Pregnancy Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1) and (8.2) ].
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)].
This product’s label may have been updated.
For full prescribing information, please visit www.amneal.com.
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Manufactured by: Amneal Pharmaceuticals Pvt.
Ahmedabad 382220, INDIA Or Manufactured by: Amneal Pharmaceuticals Pvt.
Oral Solid Dosage Unit Ahmedabad 382213, INDIA Distributed by: McKesson Corporation 4971 Southridge Blvd, Suite 101 Memphis, TN 38141 Rev.
DOSAGE AND ADMINISTRATION
2 Postherpetic Neuralgia (2.1) Dose can be titrated up as needed to a dose of 1,800 mg/day Day 1: Single 300 mg dose Day 2: 600 mg/day (i.e., 300 mg two times a day) Day 3: 900 mg/day (i.e., 300 mg three times a day) Epilepsy with Partial Onset Seizures ( 2.2 ) Patients 12 years of age and older: starting dose is 300 mg three times daily; may be titrated up to 600 mg three times daily Patients 3 to 11 years of age: starting dose range is 10 to 15 mg/kg/day, given in three divided doses; recommended dose in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses; the recommended dose in patients 5 to 11 years of age is 25 to 35 mg/kg/day, given in three divided doses.
The recommended dose is reached by upward titration over a period of approximately 3 days Dose should be adjusted in patients with reduced renal function ( 2.3 , 2.4 ) 2.1 Dosage for Postherpetic Neuralgia In adults with postherpetic neuralgia, gabapentin capsules may be initiated on Day 1 as a single 300 mg dose, on Day 2 as 600 mg/day (300 mg two times a day), and on Day 3 as 900 mg/day (300 mg three times a day).
The dose can subsequently be titrated up as needed for pain relief to a dose of 1,800 mg/day (600 mg three times a day).
In clinical studies, efficacy was demonstrated over a range of doses from 1,800 mg/day to 3,600 mg/day with comparable effects across the dose range; however, in these clinical studies, the additional benefit of using doses greater than 1,800 mg/day was not demonstrated.
2.2 Dosage for Epilepsy with Partial Onset Seizures Patients 12 years of age and above The starting dose is 300 mg three times a day.
The recommended maintenance dose of gabapentin capsules is 300 mg to 600 mg three times a day.
Dosages up to 2,400 mg/day have been well tolerated in long-term clinical studies.
Doses of 3,600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated.
Administer gabapentin three times a day using 300 mg or 400 mg capsules.
The maximum time between doses should not exceed 12 hours.
Pediatric Patients Age 3 to 11 years The starting dose range is 10 mg/kg/day to 15 mg/kg/day, given in three divided doses, and the recommended maintenance dose reached by upward titration over a period of approximately 3 days.
The recommended maintenance dose of gabapentin capsules in patients 3 to 4 years of age is 40 mg/kg/day, given in three divided doses.
The recommended maintenance dose of gabapentin capsules in patients 5 to 11 years of age is 25 mg/kg/day to 35 mg/kg/day, given in three divided doses.
Gabapentin may be administered as the oral solution, capsule, or tablet, or using combinations of these formulations.
Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study.
The maximum time interval between doses should not exceed 12 hours.
2.3 Dosage Adjustment in Patients with Renal Impairment Dosage adjustment in patients 12 years of age and older with renal impairment or undergoing hemodialysis is recommended, as follows (see dosing recommendations above for effective doses in each indication): TABLE 1.
Gabapentin Capsules Dosage Based on Renal Function Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥ 60 900 to 3,600 300 TID 400 TID 600 TID 800 TID 1,200 TID > 30 to 59 400 to 1,400 200 BID 300 BID 400 BID 500 BID 700 BID > 15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 a 100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg) b Hemodialysis 125 b 150 b 200 b 250 b 350 b TID = Three times a day; BID = Two times a day; QD = Single daily dose a For patients with creatinine clearance < 15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
b Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table.
Creatinine clearance (CLCr) is difficult to measure in outpatients.
In patients with stable renal function, creatinine clearance can be reasonably well estimated using the equation of Cockcroft and Gault: The use of gabapentin capsules in patients less than 12 years of age with compromised renal function has not been studied.
formula 2.4 Dosage in Elderly Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients.
2.5 Administration Information Administer gabapentin capsules orally with or without food.
Gabapentin capsules should be swallowed whole with water.
If the gabapentin capsules dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber).