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Gabapentin Enacarbil

Pronunciation

(gab a PEN tin en a KAR bil)

Index Terms

  • GSK 1838262
  • Solzira
  • XP13512

Dosage Forms

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

Tablet Extended Release, Oral:

Horizant: 300 mg, 600 mg

Brand Names: U.S.

  • Horizant

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

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.

Absorption

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

Distribution

Vd: 76 L

Excretion

Urine (94%); feces (5%)

Time to Peak

5-6 hours

Half-Life Elimination

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

Protein Binding

3%

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.

Hemodialysis

Gabapentin is significantly removed by hemodialysis. A dose reduction is recommended for patients on hemodialysis being treated for PHN; use is not recommended for patients being treated for RLS

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.

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); increasing to 1200 mg daily provided no additional benefit and increased side effects

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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

No dosage adjustment provided in manufacturer’s labeling.

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

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

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Dimethindene: 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 (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. 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

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

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. 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 [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. 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: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: 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%), sedation (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% (Limited to important or life-threatening): Decreased libido, feeling abnormal, increased creatine phosphokinase (gabapentin)

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:

• Renal impairment: Use with caution in patients with renal impairment; dose adjustment is needed.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

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

Suicidality (eg, suicidal thoughts, depression, behavioral changes)

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, nausea, weight gain, or insomnia. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), confusion, severe loss of strength and energy, muscle pain, muscle weakness, severe dizziness, passing out, blurred vision, change in balance, angina, shortness of breath, excessive weight gain, swelling of arms or legs, bruising, bleeding, chills, pharyngitis, enlarged lymph nodes, agitation, irritability, panic attacks, or mood changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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