Drug Safety-related Labeling Changes (SrLC)

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NEURONTIN (NDA-020882)

(GABAPENTIN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/25/2025 (SUPPL-60)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including NEURONTIN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Suicidal behavior and ideation have also been reported in patients after discontinuation of NEURONTIN [see Warnings and Precautions (5.6)]. 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.

…

5.6 Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid Discontinuation

Additions and/or revisions underlined:

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

When NEURONTIN is being discontinued, the dose should be tapered over at least a one-week period.

After discontinuation of short-term and long-term treatment with gabapentin, withdrawal symptoms have been observed in some patients [see Adverse Reactions (6.2) and Drug Abuse and Dependence (9.3)]. Suicidal behavior and ideation have also been reported in patients after discontinuation of NEURONTIN [see Warnings and Precautions (5.5)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.6)]

• Status Epilepticus [see Warnings and Precautions (5.7)]

  6.2 Postmarketing Experience

  Additions and/or revisions underlined:

  …

  There are postmarketing reports of withdrawal symptoms after discontinuation of gabapentin. Reported adverse reactions include, but are not limited to, seizures, depression, suicidal ideation and behavior, agitation, confusion, disorientation, psychotic symptoms, anxiety, insomnia, nausea, pain, sweating, tremor, headache, dizziness, and malaise [see Warnings and Precautions (5.6)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Postmarketing data suggest that extended gabapentin use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone [see Clinical Considerations]. Although there is at least one report of neonatal withdrawal syndrome in an infant exposed to gabapentin alone during pregnancy, there are no comparative epidemiologic studies evaluating this association. Therefore, whether exposure to gabapentin alone late in pregnancy may cause withdrawal signs and symptoms is not known.

…

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to NEURONTIN and opioids for signs and symptoms of neonatal withdrawal and manage accordingly.

…

Data from a cohort study of over 200,000 Medicaid-eligible pregnancies with prescription opioid exposure in the last 45 days of pregnancy found that the risk of neonatal drug withdrawal was greater in pregnancies with combined exposure to gabapentin and opioids compared to pregnancies with exposure to opioids alone.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Suicidal Thinking and Behavior

 

Counsel the patient, their caregivers, and families that AEDs, including NEURONTIN, 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 (5.5)]. Also, inform patients who plan to or have discontinued NEURONTIN that suicidal thoughts and behavior can appear even after the drug is stopped.

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

NEURONTIN can cause serious side effects including:

1. Suicidal Thoughts. Like other antiepileptic drugs, NEURONTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. This can happen while you take NEURONTIN as well as after stopping NEURONTIN.

   …

   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.

• Do not stop taking NEURONTIN without talking to your healthcare provider first. If you stop taking NEURONTIN suddenly, you may develop side effects.

  …

           

07/12/2024 (SUPPL-57)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NEURONTIN, during pregnancy. Encourage women who are taking NEURONTIN 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

The totality of available data from published prospective and retrospective cohort studies pertaining to gabapentin use during pregnancy has not indicated an increased risk of major birth defects or miscarriage. There are important methodological limitations hindering interpretation of these studies [see Data]. 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].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Human Data

An observational study based on routinely collected data from administrative and medical registers in Denmark, Finland, Norway, and Sweden, compared the prevalence of major congenital malformations in approximately 1,500 pregnancies exposed to gabapentin monotherapy in the first trimester to pregnancies unexposed to antiepileptics (n=2,995,816) and pregnancies exposed to lamotrigine monotherapy in the first trimester (n=7,582). The adjusted prevalence ratios in a pooled analysis were 1.00 (95% CI: 0.80-1.24) compared to pregnancies unexposed to antiepileptics and 1.29 (95% CI: 1.00-1.67) compared to pregnancies exposed to lamotrigine monotherapy in the first trimester.

Data from another observational study in the US based on Medicaid data, which compared the risk for major congenital malformations in more than 4,600 pregnancies exposed to gabapentin during the first trimester to unexposed pregnancies (n=1,753,865), estimated an adjusted relative risk of 1.07 (95% CI: 0.94-1.21).

The data from these observational studies should be interpreted with caution due to the potential for exposure misclassification, outcome misclassification, and residual confounding, including by underlying disease.

Animal Data

…

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 ?2? subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label

12/16/2020 (SUPPL-50)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Opioids

(Additions and/or revisions underlined)

Respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids (e.g., morphine, hydrocodone, oxycodone, buprenorphine) [see Warnings and Precautions (5.7)].

Hydrocodone

Coadministration of NEURONTIN with hydrocodone decreases hydrocodone exposure [see Clinical Pharmacology (12.3)]. The potential for alteration in hydrocodone exposure and effect should be considered when NEURONTIN 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)].

04/02/2020 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7         Respiratory Depression

(Newly added subsection)

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 NEURONTIN with another CNS depressant, particularly an opioid, or to prescribe NEURONTIN to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating NEURONTIN at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including NEURONTIN).

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in greater detail in other sections:

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

• Anaphylaxis and Angioedema

• Somnolence/Sedation and Dizziness

• Withdrawal Precipitated Seizure, Status Epilepticus

• Suicidal Behavior and Ideation

• Respiratory Depression

6.2               Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postmarketing use of NEURONTIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary disorders: jaundice

Investigations: elevated creatine kinase, elevated liver function tests Metabolism and nutrition disorders: hyponatremia

Musculoskeletal and connective tissue disorder: rhabdomyolysis Nervous system disorders: movement disorder

Psychiatric disorders: agitation

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

Skin and subcutaneous tissue disorders: angioedema, bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking NEURONTIN with opioids or other CNS depressants, or in the setting of underlying respiratory impairment.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NEURONTIN, during pregnancy. Encourage women who are taking NEURONTIN 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 NEURONTIN 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.

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, 1000, 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 on a body surface area (mg/m2) basis.

In studies in which rats received oral doses of gabapentin (500 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/m2 basis.

When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The lowest dose tested is less than the MRHD on a mg/m2 basis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

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 NEURONTIN and any potential adverse effects on the breastfed infant from NEURONTIN or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness of NEURONTIN 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

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.

MEDICATION GUIDE

(Additions and/or revisions underlined)

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

4.    Serious breathing problems. Serious breathing problems can occur when NEURONTIN 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 NEURONTIN or when the dose is increased. Get help right away if breathing problems occur.

  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 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 NEURONTIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking NEURONTIN. You and your healthcare provider will decide if you should take NEURONTIN while you are pregnant.

o   Pregnancy Registry: If you become pregnant while taking NEURONTIN, 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. NEURONTIN can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take NEURONTIN.

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 NEURONTIN.

10/18/2017 (SUPPL-47)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NEURONTIN, during pregnancy. Encourage women who are taking NEURONTIN 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 NEURONTIN 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.

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

…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/m2) basis.

In studies in which rats …The lowest dose tested is similar to the MRHD on a mg/m2 basis.

When pregnant rabbits…The lowest dose tested is less than the MRHD on a mg/m2 basis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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 NEURONTIN and any potential adverse effects on the breastfed infant from NEURONTIN or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What should I tell my healthcare provider before taking NEURONTIN? Before taking NEURONTIN, tell your healthcare provider if you:

• are pregnant or plan to become pregnant.

  • Pregnancy Registry: If you become pregnant while taking NEURONTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry…

03/24/2017 (SUPPL-45)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Psychiatric disorders: agitation