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Gabapentin enacarbil: Drug information

Gabapentin enacarbil: Drug information
(For additional information see "Gabapentin enacarbil: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Horizant
Pharmacologic Category
  • Anticonvulsant, Miscellaneous
Dosing: Adult

Note: For patients with respiratory disease, initiate therapy at the lowest dose (FDA 2019).

Postherpetic neuralgia: Oral: Initial: 600 mg once daily in the morning for 3 days, then increase to 600 mg twice daily; increasing to >1.2 g daily provided no additional benefit and increased side effects.

Restless legs syndrome: Oral: 300 to 600 mg once daily at ~5:00 pm (AAN [Winkelman 2016]; Silber 2021).

Dosing: Kidney Impairment: Adult

Note: Estimation of renal function for the purpose of drug dosing should be done using the Cockcroft-Gault formula.

PHN:

CrCl 30-59 mL/minute: Initial: 300 mg every morning for 3 days, then increase to 300 mg twice daily. May increase to 600 mg twice daily as needed based on tolerability and efficacy. When discontinuing, reduce current dose to once daily in the morning for 1 week.

CrCl 15-29 mL/minute: Initial: 300 mg in the morning on day 1 and on day 3; then increase to 300 mg once daily. May increase to 300 mg twice daily if needed based on tolerability and efficacy. When discontinuing, if current dose is 300 mg twice daily, reduce to 300 mg once daily for 1 week. If current dose is 300 mg once daily, no taper is needed.

CrCl <15 mL/minute: 300 mg every other day in the morning; may increase dose to 300 mg once daily if needed based on tolerability and efficacy. When discontinuing, no taper is needed.

CrCl <15 mL/minute and on hemodialysis: 300 mg following every dialysis. May increase to 600 mg following every dialysis if needed based on tolerability and efficacy. When discontinuing, no taper is needed.

RLS:

CrCl 30-59 mL/minute: Initial dose: 300 mg daily; increase to 600 mg daily as needed

CrCl 15-29 mL/minute: 300 mg daily

CrCl <15 mL/minute: 300 mg every other day

CrCl <15 mL/minute and on hemodialysis: Use is not recommended.

Dosing: Hepatic Impairment: Adult

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Older Adult

Initiate therapy at the lowest dose (FDA 2019). Refer to adult dosing. Note: A starting dose of 300 mg once daily for the treatment of restless leg syndrome in patients >65 years of age has been recommended (Garcia-Borreguero 2016).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release, Oral:

Horizant: 300 mg, 600 mg

Generic Equivalent Available: US

No

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022399s010lbl.pdf#page=27, must be dispensed with this medication.

Administration: Adult

Oral: Tablet should be swallowed whole; do not break, chew, cut, or crush. Administer with food.

Restless legs syndrome: Administer at ~5:00 pm daily.

Use: Labeled Indications

Postherpetic neuralgia: Management of postherpetic neuralgia.

Restless legs syndrome: Treatment of moderate to severe restless legs syndrome.

Medication Safety Issues
Sound-alike/look-alike issues:

Gabapentin enacarbil may be confused with gabapentin, gemfibrozil

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (when used for neuropathic pain) among its list of drugs that have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Percentages reported are for restless leg syndrome (RLS) 600 mg daily and postherpetic neuralgia (PHN) 1200 mg daily.

>10%: Nervous system: Dizziness (13% to 17%), drowsiness (RLS: ≤20%; PHN: ≤10%), headache (10% to 12%), sedated state (RLS: ≤20%; PHN: ≤10%)

1% to 10%:

Cardiovascular: Peripheral edema (6%)

Endocrine & metabolic: Weight gain (3%)

Gastrointestinal: Flatulence (≤3%), increased appetite (≤2%), nausea (6% to 8%), xerostomia (≤3%)

Nervous system: Balance impairment (<2%), depression (<2%), disorientation (<2%), fatigue (≤6%), insomnia (PHN: 3%), intoxicated feeling (<2%), irritability (≤4%), lethargy (<2%), vertigo (<2%)

Neuromuscular & skeletal: Asthenia (≤6%)

Ophthalmic: Blurred vision (≤2%)

<1%, postmarketing, and/or case reports: Breast hypertrophy (gabapentin), bullous pemphigoid (gabapentin), decreased libido, drug reaction with eosinophilia and systemic symptoms (gabapentin), feeling abnormal, gynecomastia (gabapentin), increased creatine phosphokinase in blood specimen (gabapentin), respiratory depression (FDA Safety Alert, December 19, 2019), suicidal ideation (gabapentin), suicidal tendencies (gabapentin)

Contraindications

There are no contraindications listed within the manufacturer’s labeling.

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 that require mental alertness (eg, operating machinery, driving).

• Multiorgan hypersensitivity: Potentially serious, sometimes fatal multiorgan hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms) has been reported with some antiseizure 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.

• Respiratory effects: Serious, life-threatening, and fatal respiratory depression may occur in patients taking gabapentin enacarbil; risk may be increased with conditions such as chronic obstructive pulmonary disease, in the elderly, and with the concomitant use of opioids and other CNS depressants. Initiate at the lowest dose and monitor patients for symptoms of respiratory depression and sedation in patients with underlying respiratory disease (FDA 2019).

• Suicidal ideation: Pooled analysis of trials involving gabapentin and other antiseizure medications (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 health care 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.

• Respiratory disease: Gabapentin enacarbil may cause respiratory depression; use caution and initiate with the lowest recommended dose in patients with respiratory compromise (FDA 2019).

Special populations:

• Elderly: Gabapentin may cause respiratory depression; use caution and initiate with the lowest recommended dose in elderly patients (FDA 2019).

Other warnings/precautions:

• Appropriate use: Restless legs syndrome: 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 receiving twice daily doses or patients with restless legs syndrome (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).

Metabolism/Transport Effects

None known.

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. Risk X: Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

Food Interactions

Ethanol may cause rapid release of gabapentin enacarbil from the extended release tablet. Management: Avoid ethanol.

Pregnancy Considerations

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 enacarbil in pregnant women for the treatment of restless legs syndrome (Picchietti 2015); use should be avoided (Garcia-Borreguero 2016).

Refer to Gabapentin monograph for information related to gabapentin exposure during pregnancy.

Breastfeeding Considerations

It is not known if gabapentin is present in breast milk following maternal use of gabapentin enacarbil; however, gabapentin is present in breast milk following administration of other dosage forms.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Current guidelines note there is insufficient evidence to recommend gabapentin enacarbil in breastfeeding women for the treatment of restless legs syndrome (Picchietti 2015).

Refer to Gabapentin monograph for additional information related to gabapentin exposure in breastfeeding women.

Dietary Considerations

Take with food.

Monitoring Parameters

Renal function (baseline and as clinically indicated); suicidality (eg, suicidal thoughts, depression, behavioral changes)

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 degradation 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 restless legs syndrome are unknown.

Pharmacokinetics

Absorption: Mediated by active transport via proton-linked monocarboxylate transporter, MCT-1

Distribution: Vd: 76 L

Protein binding: <3%

Bioavailability: With food: ~75%; Fasting: 42% to 65%

Metabolism: Prodrug hydrolyzed primarily in the intestines to gabapentin (active metabolite)

Time to peak, plasma: With food: 7.3 hours; Fasting: 5 hours

Half-life elimination: 5-6 hours

Excretion: Urine (94%); feces (5%)

Pharmacokinetics: Additional Considerations

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.

Pricing: US

Tablet, controlled release (Horizant Oral)

300 mg (per each): $18.09

600 mg (per each): $18.09

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Regnite (JP)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Attal N, Cruccu G, Baron R, et al, "EFNS Guidelines on the Pharmacological Treatment of Neuropathic Pain: 2010 Revision," Eur J Neurol, 2010, 17(9):1113-e88. [PubMed 20402746]
  2. Backonja MM, Canafax DM, and Cundy KC, "Efficacy of Gabapentin Enacarbil vs Placebo in Patients With Postherpetic Neuralgia and a Pharmacokinetic Comparison With Oral Gabapentin," Pain Med, 2011, 12(7):1098-108. [PubMed 21627766]
  3. Bogan RK, Bornemann MA, Kushida CA, et al, “Long-term Maintenance Treatment of Restless Legs Syndrome With Gabapentin Enacarbil: A Randomized Controlled Study,” Mayo Clin Proc, 2010, 85(6):512-21. [PubMed 20511481]
  4. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1-11. doi: 10.1016/j.sleep.2016.01.017. [PubMed 27448465]
  5. Garcia-Borreguero D, Stillman P, Benes H, et al, “Algorithms for the Diagnosis and Treatment of Restless Legs Syndrome in Primary Care,” BMC Neurology, 2011, 11(28): 2-13. [PubMed 21352569]
  6. Horizant (gabapentin enacarbil) [prescribing information]. Atlanta, GA: Arbor Pharmaceuticals LLC; April 2020.
  7. Kushida CA, Becker PM, Ellenbogen AL, et al, “Randomized, Double-Blind, Placebo-Controlled Study of XP13512/GSK1838262 in Patients With RLS,” Neurology, 2009, 72(5):439-46. [PubMed 19188575]
  8. Kushida CA, Walters AS, Becker P, et al, “A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of XP13512/GSK1838262 in the Treatment of Patients With Primary Restless Legs Syndrome,” Sleep, 2009, 32(2):159-68. [PubMed 19238802]
  9. Mehrizi M, Fontem RF, Gearhart TR, Pascuzzi RM. Medications and myasthenia gravis (a reference for health care professionals). Indianapolis, In: Indiana University School of Medicine (Department of Neurology); 2012. https://www.myasthenia.org/portals/0/draft_medications_and_myasthenia_gravis_for_MGFA_website_8%2010%2012.pdf. Accessed July 31, 2019.
  10. Picchietti DL, Hensley JG, Bainbridge JL, et al. Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation. Sleep Med Rev. 2015;22:64-77. [PubMed 25553600]
  11. Silber MH. Treatment of restless legs syndrome and periodic limb movement disorder in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 16, 2021.
  12. US Food and Drug Administration (FDA). FDA Drug Safety Communication. MedWatch. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR). https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin. Published December 19, 2019. Accessed April 3, 2020.
  13. Vignatelli L, Billiard M, Clarenbach P, et al, “EFNS Guidelines on Management of Restless Leg Syndrome and Periodic Limb Movement Disorder in Sleep,” Eur J Neurol, 2006, 13(10):1049-65. [PubMed 16987157]
  14. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585-2593. doi:10.1212/WNL.0000000000003388 [PubMed 27856776]
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