Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

HORIZANT (NDA-022399)

(GABAPENTIN ENACARBIL)

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

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04/25/2025 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Suicidal Behavior and Ideation

Additions and/or revisions underlined:

HORIZANT (gabapentin enacarbil) is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs 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 gabapentin [see Warnings and Precautions (5.5)].

…

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

Additions and/or revisions underlined:

Abrupt or rapid discontinuation of gabapentinoids may increase the risk for seizures.

When discontinuing HORIZANT, patients with RLS receiving 600 mg or less once daily can discontinue the drug without tapering. If the recommended dose is exceeded, the dose should be reduced to 600 mg daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure.

In patients with PHN receiving HORIZANT twice daily, the dose should be reduced to once daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure, see Table 2 [see Dosage and Administration (2.4)].

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 been reported after discontinuation of gabapentin [see Warnings and Precautions (5.4)].

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 (5.5)]
Respiratory Depression [see Warnings and Precautions (5.6)]
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 (5.5)].

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. 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 [see Clinical Considerations].

…

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 HORIZANT and opioids for signs and symptoms of neonatal withdrawal and manage accordingly.

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

PATIENT COUNSELING INFORMATION

Additions revisions underlined:

…

Suicidal Behavior and Ideation

Patients, their caregivers, and families should be counseled that HORIZANT may increase the risk of suicidal thoughts and behavior, and should be advised 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 (5.4)]. Also, inform patients who plan to or have discontinued HORIZANT that suicidal thoughts and behavior can appear even after the drug is stopped.

…

Use in Pregnancy

Instruct patients to notify their healthcare provider if they are pregnant or intend to become pregnant during therapy and to notify their healthcare provider if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1) and (8.2)].

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is the most important information I should know about HORIZANT? HORIZANT can cause serious side effects:

…

2. HORIZANT may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. This can happen while you take HORIZANT or after stopping HORIZANT.

…

For more information about HORIZANT, go to www.HORIZANT.com or call 1-800- 461-7449.

…

04/17/2020 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

(Additions and/or revisions underlined)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. HORIZANT is a prodrug of gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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. Because this disorder is variable in its expression, 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. HORIZANT should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described in more detail in the Warnings and Precautions section of the label:

Effects on Driving
Somnolence/Sedation and Dizziness
Suicidal Behavior and Ideation
Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Respiratory Depression

6.2 Postmarketing Experience

(Subsection title revised; Additions and/or revisions underlined)

The following adverse reactions have been reported in patients receiving gabapentin and have been identified during postapproval use of HORIZANT. 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: breast enlargement, gynecomastia, elevated creatine kinase, bullous pemphigoid.

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

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no adequate data on the developmental risk associated with the use of HORIZANT in pregnant women. In nonclinical studies in rats and rabbits, administration of gabapentin enacarbil was developmentally toxic when administered to pregnant animals at doses and gabapentin exposures greater than those used clinically.

In the US 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 rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased at the 2 highest doses and fetal body weights were decreased at the high dose. The no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) represents approximately 2 times the gabapentin exposure associated with the maximum recommended human dose (MRHD) of 1,200 mg/day gabapentin enacarbil on an area under the curve (AUC) basis.

When pregnant rabbits were administered gabapentin enacarbil (oral doses of 200, 500, or 2,500 mg/kg/day) throughout the period of organogenesis, embryofetal mortality was increased and fetal body weights were decreased at the high dose. The no-effect dose for embryofetal developmental toxicity in rabbits (500 mg/kg/day) represents approximately 9 times the gabapentin exposure associated with the MRHD of 1,200 mg/day gabapentin enacarbil on an AUC basis.

When female rats were administered gabapentin enacarbil (oral doses of 200, 1,000, or 5,000 mg/kg/day) throughout the pregnancy and lactation periods, offspring growth and survival were decreased at the two highest doses. The no-effect dose for pre- and post-natal developmental toxicity in rats is approximately 2 times the MRHD on an AUC basis.

In reproductive and developmental studies of gabapentin, developmental toxicity was observed at all doses tested. Increased incidences of hydroureter and/or hydronephrosis were observed in rat offspring following treatment of pregnant animals in studies of fertility and general reproductive performance, embryofetal development, and peri- and post-natal development. Overall, a no-effect dose was not established. In mice, treatment of pregnant animals with gabapentin during the period of organogenesis resulted in delayed fetal skeletal ossification at all but the lowest dose tested.

When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses of gabapentin tested.

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.

8.2 Lactation

(PLLR conversion)

Risk Summary

It is not known whether gabapentin derived from HORIZANT is secreted in human milk;

however, gabapentin is secreted into human milk following oral administration of other gabapentin products. There are no data on the effects of gabapentin on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HORIZANT and any potential adverse effects on the breastfed infant from HORIZANT or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Effects on Driving

Patients should be told that HORIZANT may cause a significant driving impairment. Accordingly, they should be advised not to drive a car until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to drive, although patients’ ability to determine their level of impairment can be unreliable. Patients should be told that it is not known how long this effect lasts.

Somnolence/Sedation and Dizziness

Patients should be told that HORIZANT can cause significant somnolence and dizziness. This typically resolves within several weeks of initiating treatment. Accordingly, they should be told

not to operate dangerous machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to operate dangerous machinery safely.

Suicidal Behavior and Ideation

Behaviors of concern should be reported immediately to healthcare providers.

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 concurrent respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs.

Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Patients should be instructed that multiorgan hypersensitivity reactions may occur with HORIZANT. Patients should contact their physician immediately if they experience any signs or symptoms of these conditions.

Lack of Interchangeability With Gabapentin

Patients should be advised that doses of HORIZANT and other gabapentin products are not interchangeable.

Dosing Instructions

Instruct patients to take HORIZANT only as prescribed.
Instruct patients to swallow tablets whole and do not cut, crush, or chew tablets.
Instruct patients to take HORIZANT with food.
For Restless Legs Syndrome, 600 mg HORIZANT should be taken once daily at about 5 PM. If the dose is not taken at the recommended time, the patient should take the next dose at about 5 PM the following day.
For Postherpetic Neuralgia, the starting dose is 600 mg HORIZANT in the morning for 3 days. Starting on day 4, 600 mg HORIZANT should be taken twice daily. If the dose is not taken at the recommended time, the next dose should be taken at the time of next scheduled dose.

Instruct patients about how to discontinue HORIZANT.

Alcohol

Advise patients to avoid alcohol when taking HORIZANT

04/02/2020 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 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 central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe HORIZANT with another CNS depressant, particularly an opioid, or to prescribe HORIZANT to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating HORIZANT at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including HORIZANT).

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

Somnolence/sedation and dizziness
Respiratory Depression

6.2 Adverse Events Associated With Gabapentin

The following adverse events have been reported in patients receiving gabapentin, either in clinical trials or postmarketing: breast enlargement, gynecomastia, and elevated creatine kinase, bullous pemphigoid.

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

17 PATIENT COUNSELING INFORMATION

17.4 Respiratory Depression

(Newly added subsection)

MEDICATION GUIDE

(Extensive changes; please refer to label)