Gabapentin: Package Insert and Label Information (Page 4 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis
Gabapentin was administered orally to mice and rats in 2-year carcinogenicity studies. No evidence of drug-related carcinogenicity was observed in mice treated at doses up to 2000 mg/kg/day. At 2000 mg/kg, the plasma gabapentin exposure (AUC) in mice was approximately 2 times that in humans at the MRHD of 3600 mg/day. In rats, increases in the incidence of pancreatic acinar cell adenoma and carcinoma were found in male rats receiving the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. At 1000 mg/kg, the plasma gabapentin exposure (AUC) in rats was approximately 5 times that in humans at the MRHD.
Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting 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 demonstrate mutagenic or genotoxic potential in in vitro (Ames test, HGPRT forward mutation assay in Chinese hamster lung cells) and in vivo (chromosomal aberration and micronucleus test in Chinese hamster bone marrow, mouse micronucleus, unscheduled DNA synthesis in rat hepatocytes) assays.
Impairment of Fertility No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg. At 2000 mg/kg, the plasma gabapentin exposure (AUC) in rats is approximately 8 times that in humans at the MRHD.

14 CLINICAL STUDIES

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).

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 1200 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.

gabapentin-fig1
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Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1

gabapentin-fig2
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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).

gabapentin-fig3
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Figure 3. Proportion of Responders (patients with ≥ 50% reduction in pain score) at Endpoint: Controlled PHN Studies

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 1200 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 1200 mg/day, in three divided doses (N=101), with placebo (N=98). Additional smaller gabapentin dosage groups (600 mg/day, N=53; 1800 mg/day, N=54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 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 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 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 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 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 1200 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 1200 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).

gabapentin-fig4
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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 – 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 HOW SUPPLIED/STORAGE AND HANDLING

Gabapentin capsules USP are supplied as follows:

300 mg capsules :

Yellow hard gelatin capsules imprinted “215” on body with blue ink, available in:

NDC: 70518-1760-00

NDC: 70518-1760-01

NDC: 70518-1760-02

NDC: 70518-1760-03

PACKAGING: 30 in 1 BLISTER PACK

PACKAGING: 90 in 1 BOTTLE PLASTIC

PACKAGING: 60 in 1 BOTTLE PLASTIC

PACKAGING: 30 in 1 BOTTLE PLASTIC

Storage

Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature].

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION

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

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)].

70518-2921-00

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)] .

Respiratory Depression

Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant CNS depressants (such as opioid analgesics) or those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs.

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.dailymed.nlm.nih.gov.

Trademarks are the property of their respective owners.

Repackaged By / Distributed By: RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

MEDICATION GUIDE

Gabapentin Capsules USP

(GA ba PEN tin)

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

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

Stopping gabapentin suddenly can cause serious problems.

Gabapentin can cause serious side effects including:

1. Suicidal Thoughts. Like other antiepileptic drugs, gabapentin may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

· thoughts about suicide or dying

· attempts to commit suicide

· new or worse depression

· new or worse anxiety

· feeling agitated or restless

· panic attacks

· trouble sleeping (insomnia)

· new or worse irritability

· acting aggressive, being angry, or violent

· acting on dangerous impulses

· an extreme increase in activity and talking (mania)

· other unusual changes in behavior or mood

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

· Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

· Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop taking gabapentin without first talking to a healthcare provider.

· Stopping gabapentin suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

· Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

2. Changes in behavior and thinking – Using gabapentin in children 3 to 12 years of age can cause emotional changes, aggressive behavior, problems with concentration, restlessness, changes in school performance, and hyperactivity.

3. Gabapentin may cause serious or life-threatening allergic reactions that may 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 gabapentin. You may or may not have a rash with an allergic reaction caused by gabapentin. Call a healthcare provider right away if you have any of the following symptoms:

· skin rash

· hives

· difficulty breathing

· fever

· swollen glands that do not go away

· swelling of your face, lips, throat, or tongue

· yellowing of your skin or of the whites of the eyes

· unusual bruising or bleeding

· severe fatigue or weakness

· unexpected muscle pain

· frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking gabapentin.

4. Serious breathing problems. Serious breathing problems can occur when gabapentin is taken with other medicines that can cause severe sleepiness or decreased awareness, or when it is taken by someone who already has breathing problems. Watch for increased sleepiness or decreased breathing when starting gabapentin or when the dose is increased. Get help right away if breathing problems occur.

What is gabapentin?

Gabapentin is a prescription medicine used to treat:
·Pain from damaged nerves (postherpetic pain) that follows healing of shingles (a painful rash that comes after a herpes zoster infection) in adults.
· Partial seizures when taken together with other medicines in adults and children 3 years of age and older with seizures .
Who should not take gabapentin?

Do not take gabapentin if you are allergic to gabapentin or any of the other ingredients in gabapentin. See the end of this Medication Guide for a complete list of ingredients in gabapentin.

What should I tell my healthcare provider before taking gabapentin?

Before taking gabapentin, tell your healthcare provider if you:

· have or have had kidney problems or are on hemodialysis

· have or have had depression, mood problems, or suicidal thoughts or behavior

· have diabetes · have breathing problems

· are pregnant or plan to become pregnant. It is not known if gabapentin can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking gabapentin. You and your healthcare provider will decide if you should take gabapentin while you are pregnant.

o Pregnancy Registry: If you become pregnant while taking gabapentin, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. You can enroll in this registry by calling 1-888-233-2334.

· are breast-feeding or plan to breast-feed. Gabapentin can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take gabapentin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take any opioid pain medicine (such as oxycodone), any medicines for anxiety (such as lorazepam) or insomnia (such as zolpidem), or any medicines that make you sleepy.

You may have a higher chance for dizziness, sleepiness, or breathing problems if these medicines are taken with gabapentin.

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

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take gabapentin?

· Take gabapentin exactly as prescribed. Your healthcare provider will tell you how much gabapentin to take.

o Do not change your dose of gabapentin without talking to your healthcare provider.

o Take gabapentin capsules with water.

If you take too much gabapentin, call your healthcare provider or your local Poison Control Center right away at 1-800-222-1222.

What should I avoid while taking gabapentin?

· Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking gabapentin without first talking with your healthcare provider. Taking gabapentin with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.

· Do not drive, operate heavy machinery, or do other dangerous activities until you know how gabapentin affects you. Gabapentin can slow your thinking and motor skills.

What are the possible side effects of gabapentin?

Gabapentin may cause serious side effects including:

See “What is the most important information I should know about gabapentin?”

· problems driving while using gabapentin. See “What I should avoid while taking gabapentin?”

· sleepiness and dizziness, which could increase the occurrence of accidental injury, including falls

· The most common side effects of gabapentin include:

· lack of coordination

· feeling tired

· viral infection

· fever

· feeling drowsy

· jerky movements

· nausea and vomiting

· difficulty with coordination

· difficulty with speaking

· double vision

· tremor

· unusual eye movement

· swelling, usually of legs and feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of gabapentin. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store gabapentin?

· Store gabapentin Capsules between 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature].

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

General information about the safe and effective use of gabapentin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use gabapentin for a condition for which it was not prescribed. Do not give gabapentin to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about gabapentin. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about gabapentin that was written for healthcare professionals.

What are the ingredients in gabapentin?

Active ingredient: Gabapentin USP

Inactive ingredients in the capsules: anhydrous lactose, cornstarch, and talc. The 100-mg capsule shell also contains: gelatin, sodium lauryl sulfate, and titanium dioxide.

The 300-mg capsule shell also contains: gelatin, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

The 400-mg capsule shell also contains: gelatin, sodium lauryl sulfate, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propyl glycol, strong ammonia solution, and titanium dioxide.

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

Repackaged By / Distributed By: RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

DRUG: Gabapentin

GENERIC: Gabapentin

DOSAGE: CAPSULE

ADMINSTRATION: ORAL

NDC: 70518-1760-0

NDC: 70518-1760-1

NDC: 70518-1760-2

NDC: 70518-1760-3

COLOR: yellow

SHAPE: CAPSULE

SCORE: No score

SIZE: 19 mm

IMPRINT: 215

PACKAGING: 30 in 1 BLISTER PACK

PACKAGING: 90 in 1 BOTTLE PLASTIC

PACKAGING: 60 in 1 BOTTLE PLASTIC

PACKAGING: 30 in 1 BOTTLE PLASTIC

ACTIVE INGREDIENT(S):

  • GABAPENTIN 300mg in 1

INACTIVE INGREDIENT(S):

  • STARCH, CORN
  • ANHYDROUS LACTOSE
  • TALC
  • GELATIN
  • SODIUM LAURYL SULFATE
  • TITANIUM DIOXIDE
  • FERRIC OXIDE YELLOW
Remedy_Label
(click image for full-size original)
MM2
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MM3
(click image for full-size original)
MM4
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GABAPENTIN gabapentin capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70518-1760(NDC:67877-223)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GABAPENTIN (GABAPENTIN) GABAPENTIN 300 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN
ANHYDROUS LACTOSE
TALC
GELATIN
SODIUM LAURYL SULFATE
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
Product Characteristics
Color yellow (yellow) Score no score
Shape CAPSULE (Capsule) Size 19mm
Flavor Imprint Code 215
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:70518-1760-0 30 CAPSULE in 1 BLISTER PACK None
2 NDC:70518-1760-1 90 CAPSULE in 1 BOTTLE, PLASTIC None
3 NDC:70518-1760-2 60 CAPSULE in 1 BOTTLE, PLASTIC None
4 NDC:70518-1760-3 30 CAPSULE in 1 BOTTLE, PLASTIC None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090858 01/01/2019
Labeler — REMEDYREPACK INC. (829572556)

Revised: 06/2021 REMEDYREPACK INC.

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