Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release, Oral:
Horizant: 300 mg, 600 mg
Pharmacology
Mechanism of Action
Gabapentin enacarbil is a prodrug of gabapentin. Gabapentin is structurally related to GABA. However, it does not bind to GABAA or GABAB receptors, and it does not appear to influence synthesis or uptake of GABA. High affinity gabapentin binding sites have been located throughout the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. This channel appears to be located presynaptically, and may modulate the release of excitatory neurotransmitters. These effects on RLS are unknown.
Pharmacokinetics/Pharmacodynamics
Absorption
Mediated by active transport via proton-linked monocarboxylate transporter, MCT-1
Distribution
Vd: 76 L
Metabolism
Prodrug hydrolyzed primarily in the intestines to gabapentin (active metabolite)
Excretion
Urine (94%); feces (5%)
Time to Peak
Plasma: With food: 7.3 hours; Fasting: 5 hours
Half-Life Elimination
5-6 hours
Protein Binding
<3%
Use in Specific Populations
Special Populations: Renal Function Impairment
In moderate and severe renal impairment, clearance was decreased to 3 and 1 L/hour, respectively, compared with 5-7 L/hour in nonrenal impairment patients.
Use: Labeled Indications
Treatment of moderate-to-severe restless leg syndrome (RLS); management of postherpetic neuralgia (PHN)
Contraindications
There are no contraindications listed within the manufacturer’s labeling.
Dosage and Administration
Dosing: Adult
Postherpetic neuralgia (PHN): Oral: Initial: 600 mg once daily in the morning for 3 days, then increase to 600 mg twice daily; increasing to >1200 mg daily provided no additional benefit and increased side effects
Restless legs syndrome (RLS): Oral: 600 mg once daily (at ~5:00 pm)
Dosing: Geriatric
Refer to adult dosing. Note: A starting dose of 300 mg once daily for the treatment of restless leg syndrome in patients >65 years has been recommended (Garcia-Borreguero 2016).
Administration
Tablet should be swallowed whole; do not break, chew, cut, or crush. Administer with food.
Restless leg syndrome: Administer at ~5:00 pm daily.
Dietary Considerations
Take with food.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture. Do not remove from original container.
Drug Interactions
Alcohol (Ethyl): May enhance the CNS depressant effect of Gabapentin Enacarbil. Alcohol (Ethyl) may increase the absorption of Gabapentin Enacarbil. Specifically, the rate of absorption may be enhanced, as alcohol may speed the release of drug from the extended-release tablet. Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification
Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Adverse Reactions
Percentages reported are for restless leg syndrome (RLS) 600 mg daily and postherpetic neuralgia (PHN) 1200 mg daily.
>10%: Central nervous system: Drowsiness (RLS: ≤20%; PHN: ≤10%), sedated state (RLS: ≤20%; PHN: ≤10%), dizziness (13% to 17%), headache (10% to 12%)
1% to 10%:
Cardiovascular: Peripheral edema (PHN: 6%; RLS: <1%)
Central nervous system: Fatigue (6%), irritability (≤4%), insomnia (PHN: 3%), equilibrium disturbance (<2%), depression (<2%), disorientation (<2%), intoxicated feeling (<2%), lethargy (<2%), vertigo (<2%)
Endocrine & metabolic: Weight gain (2% to 3%)
Gastrointestinal: Nausea (6% to 8%), flatulence (≤3%), xerostomia (≤3%), increased appetite (≤2%)
Ophthalmic: Blurred vision (≤2%)
<1%, postmarketing, and/or case reports: Breast hypertrophy (gabapentin), decreased libido, feeling abnormal, gynecomastia (gabapentin), increased creatine phosphokinase in blood specimen (gabapentin), respiratory depression (FDA Safety Alert, Dec 19, 2019)
Warnings/Precautions
Concerns related to adverse effects:
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
- Multiorgan hypersensitivity: Potentially serious, sometimes fatal multiorgan hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) has been reported with some antiepileptic drugs, including gabapentin. Monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, cardiac, and/or hematologic systems; fever, rash, and eosinophilia may also be present. Discontinue immediately if suspected.
- Suicidal ideation: Pooled analysis of trials involving gabapentin and other antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Gabapentin enacarbil is a prodrug of gabapentin and may also increase patient’s risk. Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
- Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).
- Renal impairment: Use with caution in patients with renal impairment; dose adjustment is needed.
Other warnings/precautions:
- Appropriate use: Restless legs syndrome (RLS): Not recommended for use in patients who are required to sleep during the day and remain awake during the night.
- Discontinuation of therapy: To avoid the potential for withdrawal seizure, dose reduction is recommended for patients with postherpetic neuralgia (PHN) receiving twice daily doses or patients with RLS receiving daily doses >600 mg (daily doses of ≤600 mg can be discontinued without tapering in patients with RLS).
- Product interchangeability: Gabapentin enacarbil (Horizant) and other gabapentin products are not interchangeable due to differences in formulation, indications and pharmacokinetics.
- Tumorigenic potential: Rat studies demonstrated an association with pancreatic adenocarcinoma (clinical implication unknown).
Monitoring Parameters
Renal function (baseline and as clinically indicated); suicidality (eg, suicidal thoughts, depression, behavioral changes)
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were observed in animal reproduction studies. Gabapentin enacarbil is the prodrug of gabapentin; bioavailability following gabapentin enacarbil is increased in comparison to gabapentin (Backonja 2011). Current guidelines note there is insufficient evidence to recommend gabapentin encarbil in pregnant women for the treatment of restless leg syndrome (Picchietti 2015).
Refer to Gabapentin monograph for information related to gabapentin exposure during pregnancy.
Patient Education
What is this drug used for?
- It is used to treat restless leg syndrome.
- It is used to treat painful nerve diseases.
- It may be given to you for other reasons. Talk with the doctor.
Frequently reported side effects of this drug
- Headache
- Nausea
- Trouble sleeping
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
- Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion
- Trouble breathing
- Slow breathing
- Shallow breathing
- Blue/gray skin discoloration
- Confusion
- Severe loss of strength and energy
- Muscle pain
- Muscle weakness
- Blurred vision
- Chest pain
- Shortness of breath
- Excessive weight gain
- Swelling of arms or legs
- Bruising
- Bleeding
- Chills
- Sore throat
- Swollen gland
- Severe fatigue
- Severe dizziness
- Passing out
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
