Horizant
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Horizant Prescribing Information
HORIZANT is indicated for:
- treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. ()
1.1 Treatment of Restless Legs SyndromeHORIZANT®is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults.
HORIZANT is not recommended for patients who are required to sleep during the daytime and remain awake at night.
- management of postherpetic neuralgia (PHN) in adults. ()
1.2 Management of Postherpetic NeuralgiaHORIZANT is indicated for the management of postherpetic neuralgia (PHN) in adults.
HORIZANT Extended-Release Tablets, 300 mg, are white to off-white, oval-shaped tablets debossed with "GS TF7" and 600 mg, are white to off-white, oval-shaped tablets debossed with "GS LFG". Both the 300 mg and 600 mg tablets may contain occasional black/grey spots.
Pregnancy: Based on animal data, may cause fetal harm. (
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
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
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.
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.
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
None.
- Driving impairment: Warn patients not to drive until they have gained sufficient experience with HORIZANT to assess whether it will impair their ability to drive. ()
5.1 Effects on DrivingHORIZANT may cause significant driving impairment
[see Clinical Studies (14.3)]. The duration of driving impairment after starting therapy with HORIZANT is unknown. Patients taking HORIZANT should not drive until they have gained sufficient experience to assess whether HORIZANT impairs their ability to drive. However, 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 HORIZANT, can be imperfect. Whether the impairment is related to somnolence[see Warnings and Precautions (5.2)]or other effects of HORIZANT is unknown. - Somnolence/sedation and dizziness: May impair the patient's ability to operate complex machinery. ()
5.2 Somnolence/Sedation and DizzinessHORIZANT causes somnolence/sedation and dizziness (see Tables 4and 5). Patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to perform these tasks.
During the controlled trials in patients with RLS, somnolence/sedation was reported in 20% of patients treated with 600 mg of HORIZANT per day compared with 6% of patients receiving placebo. In those patients treated with HORIZANT who reported somnolence, the somnolence persisted during treatment in about 30%. In the remaining patients, symptoms resolved within 3 to 4 weeks. Dizziness was reported in 13% of patients receiving 600 mg of HORIZANT per day compared with 4% of patients receiving placebo. In those patients treated with HORIZANT who reported dizziness, symptoms persisted during treatment in about 20%. Somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of HORIZANT per day. Dizziness led to withdrawal in 1% of patients receiving 600 mg of HORIZANT per day. The incidence of these adverse reactions was greater in the patients receiving 1,200 mg per day.
During the 12-week, controlled study in patients with PHN, somnolence was reported in 10% of patients treated with 1,200 mg of HORIZANT per day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of HORIZANT per day compared with 1% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported somnolence (10%), the somnolence persisted during treatment in about 27%. In the remaining patients, symptoms resolved within 4 to 5 weeks. Dizziness was reported in 17% of patients receiving 1,200 mg of HORIZANT per day compared with 15% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported dizziness, symptoms persisted during treatment in about 6%. Somnolence led to withdrawal in <1% of patients receiving 1,200 mg of HORIZANT per day compared with 2% of patients receiving placebo. Dizziness led to withdrawal in 2% of patients receiving 1,200 mg of HORIZANT per day compared with 3% of patients receiving placebo.
- HORIZANT is not substitutable with other gabapentin products. ()
5.3 Lack of Substitutability With GabapentinHORIZANT is not substitutable with other gabapentin products because of differing pharmacokinetic profiles. The same dose of HORIZANT results in different plasma concentrations of gabapentin relative to other gabapentin products
[see Clinical Pharmacology (12.3)].The safety and effectiveness of HORIZANT in patients with epilepsy have not been studied.
- Suicidal thoughts or behaviors: HORIZANT is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behaviors. Monitor for suicidal thoughts or behaviors. ()
5.4 Suicidal Behavior and IdeationHORIZANT (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 ]. Because HORIZANT is a prodrug of gabapentin, HORIZANT also increases this risk. 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 (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk [adjusted relative risk 1.8, 95% confidence interval (CI): 1.2, 2.7] of suicidal thinking or behavior compared with 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 with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 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 1 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 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3. 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 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 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 HORIZANT 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 HORIZANT increases 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.
- Abrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms, or suicidal behavior and ideation have been observed after discontinuation. ()
5.5 Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid DiscontinuationAbrupt 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 ].After discontinuation of short-term and long-term treatment with gabapentin, withdrawal symptoms have been observed in some patients
[see Adverse Reactions and Drug Abuse and Dependence ]. Suicidal behavior and ideation have been reported after discontinuation of gabapentin[see Warnings and Precautions ]. - Respiratory depression: May occur with HORIZANT when used with concomitant central nervous system (CNS) depressants or in the setting of concurrent respiratory impairment. Monitor patients and adjust dosage as appropriate ().
5.6 Respiratory DepressionThere 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).
The following clinically significant adverse reactions are described in more detail in the
- Effects on Driving[see]
5.1 Effects on DrivingHORIZANT may cause significant driving impairment
[see Clinical Studies (14.3)]. The duration of driving impairment after starting therapy with HORIZANT is unknown. Patients taking HORIZANT should not drive until they have gained sufficient experience to assess whether HORIZANT impairs their ability to drive. However, 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 HORIZANT, can be imperfect. Whether the impairment is related to somnolence[see Warnings and Precautions (5.2)]or other effects of HORIZANT is unknown. - Somnolence/Sedation and Dizziness[see]
5.2 Somnolence/Sedation and DizzinessHORIZANT causes somnolence/sedation and dizziness (see Tables 4and 5). Patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to perform these tasks.
During the controlled trials in patients with RLS, somnolence/sedation was reported in 20% of patients treated with 600 mg of HORIZANT per day compared with 6% of patients receiving placebo. In those patients treated with HORIZANT who reported somnolence, the somnolence persisted during treatment in about 30%. In the remaining patients, symptoms resolved within 3 to 4 weeks. Dizziness was reported in 13% of patients receiving 600 mg of HORIZANT per day compared with 4% of patients receiving placebo. In those patients treated with HORIZANT who reported dizziness, symptoms persisted during treatment in about 20%. Somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of HORIZANT per day. Dizziness led to withdrawal in 1% of patients receiving 600 mg of HORIZANT per day. The incidence of these adverse reactions was greater in the patients receiving 1,200 mg per day.
During the 12-week, controlled study in patients with PHN, somnolence was reported in 10% of patients treated with 1,200 mg of HORIZANT per day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of HORIZANT per day compared with 1% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported somnolence (10%), the somnolence persisted during treatment in about 27%. In the remaining patients, symptoms resolved within 4 to 5 weeks. Dizziness was reported in 17% of patients receiving 1,200 mg of HORIZANT per day compared with 15% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported dizziness, symptoms persisted during treatment in about 6%. Somnolence led to withdrawal in <1% of patients receiving 1,200 mg of HORIZANT per day compared with 2% of patients receiving placebo. Dizziness led to withdrawal in 2% of patients receiving 1,200 mg of HORIZANT per day compared with 3% of patients receiving placebo.
- Suicidal Behavior and Ideation[see]
5.4 Suicidal Behavior and IdeationHORIZANT (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 ]. Because HORIZANT is a prodrug of gabapentin, HORIZANT also increases this risk. 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 (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk [adjusted relative risk 1.8, 95% confidence interval (CI): 1.2, 2.7] of suicidal thinking or behavior compared with 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 with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 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 1 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 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3. 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 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 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 HORIZANT 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 HORIZANT increases 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.
- Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid Discontinuation[see]
5.5 Increased Risk of Seizures and Other Adverse Reactions with Abrupt or Rapid DiscontinuationAbrupt 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 ].After discontinuation of short-term and long-term treatment with gabapentin, withdrawal symptoms have been observed in some patients
[see Adverse Reactions and Drug Abuse and Dependence ]. Suicidal behavior and ideation have been reported after discontinuation of gabapentin[see Warnings and Precautions ]. - Respiratory Depression[see]
5.6 Respiratory DepressionThere 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).
- Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity[see]
5.7 Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan HypersensitivityDrug 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.