Side Effects of Horizant (gabapentin enacarbil)

Horizant (gabapentin enacarbil) is an anticonvulsant used to treat restless leg syndrome (RLS) and postherpetic neuralgia. It is a prodrug of the anticonvulsant gabapentin, which means it is first converted to gabapentin in the body before it has its effects. 

The mechanism of action of gabapentin in treating restless leg syndrome (RLS) or postherpetic neuralgia is not known. Gabapentin structurally resembles the neurotransmitter gamma aminobutyric acid (GABA). 

It is possible this similarity is related to gabapentin's mechanism of action. In animal models used for testing the anti-seizure and anti-pain (analgesic) activities of drugs, gabapentin prevents seizures and reduces pain-related responses. 

Common side effects of Horizant include

• dizziness,
• drowsiness,
• loss of coordination,
• fatigue,
• drowsiness,
• significant driving impairment,
• fluid retention,
• hostility,
• nausea and vomiting,
• weight gain,
• joint pain,
• motion sickness,
• blurred vision, and
• viral infections.

Serious side effects of Horizant include

• increased risk of suicidal thinking and behavior,
• unusual fever,
• swollen glands,
• yellowing skin/eyes (jaundice),
• unusual tiredness,
• dark urine,
• changes in the amount of urine, and
• chest pain. 

Drug interactions of Horizant include alcohol, which increases the amount of Horizant released into the body. Alcohol should not be used with Horizant. Combining Horizant with morphine significantly increases the occurrence of sedation and dizziness over either drug alone. 

Safety of Horizant use in pregnancy has not been established. Horizant is secreted in human breast milk. Nursing mothers should only use Horizant if necessary. Consult your doctor before breastfeeding.

The most common side effects of gabapentin enacarbil are:

• dizziness,
• somnolence,
• ataxia,
• fatigue, and
• drowsiness.

Gabapentin enacarbil may cause significant driving impairment. Fluid retention, hostility, nausea and vomiting also occur. Other adverse events associated with gabapentin enacarbil include:

• weight gain,
• joint pain,
• motion sickness,
• blurred vision, and
• viral infections.

Gabapentin enacarbil is converted to gabapentin, which is an anti-seizure medication. Anti-seizure medications have been associated with an increased risk of suicidal thinking and behavior.

Anyone considering the use of anti-seizure drugs must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

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

• Somnolence/sedation and dizziness
• Respiratory Depression

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In all controlled and uncontrolled trials across various patient populations, more than 2,300 patients have received Horizant orally in daily doses ranging from 600 to 3,600 mg.

Restless Legs Syndrome

• The exposure to Horizant in 1,201 patients with RLS included 613 exposed for at least 6 months and 371 exposed for at least 1 year.
• Horizant in the treatment of RLS was studied primarily in placebo-controlled trials (n = 642), and in long-term follow-up studies.
• The population with RLS ranged from 18 to 82 years of age, with 60% being female and 95% being Caucasian.
• The safety of Horizant in doses ranging from 600 to 2,400 mg has been evaluated in 515 patients with RLS in 3 double-blind, placebo-controlled, 12-week clinical trials.
• The 600-mg dose was studied in 2 of the 3 studies. Eleven out of 163 (7%) patients treated with 600 mg of Horizant discontinued treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received placebo.
• The most commonly observed adverse reactions (≥5% and at least 2 times the rate of placebo) in these trials for the 600-mg dose of Horizant were somnolence/sedation and dizziness (see Table 4).
• Table 4 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with RLS treated with Horizant and numerically greater than placebo.

Table 4: Incidence of Adverse Reactions in 12-Week RLS Studies Reported in ≥2% of Patients Treated With 600 or 1,200 mg of Horizant and Numerically Greater Than Placebo

Adverse reactions reported in these three 12-week studies in <2% of patients treated with 600 mg of Horizant and numerically greater than placebo were

• balance disorder,
• blurred vision,
• disorientation,
• feeling drunk,
• lethargy, and
• vertigo.

The following adverse reactions were dose-related:

• somnolence/sedation,
• dizziness,
•  feeling drunk,
• libido decreased,
• depression,
• headache,
• peripheral edema, and
• vertigo.

Postherpetic Neuralgia

• The exposure to Horizant in 417 patients with PHN included 207 patients exposed for at least 3 months.
• Overall, the mean age of patients in the PHN studies ranged from 61 to 64 years of age across dose groups; the majority of patients were male (45% to 61%) and Caucasian (80% to 98%).
• The safety of Horizant in doses ranging from 1,200 to 3,600 mg has been evaluated in 417 patients with PHN in 3 clinical studies.
• The principal efficacy study evaluating the efficacy and safety of Horizant in the management of PHN was a 12-week, double-blind, multicenter study comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo.
• Six out of 107 (6%) patients treated with 1,200 mg of Horizant discontinued treatment due to adverse events compared with 12 of the 95 (13%) patients who received placebo.
• The most commonly observed adverse reactions (≥10% and greater than placebo) in this trial for the 1,200 mg dose of Horizant were dizziness, somnolence, and headache (see Table 5).
• Table 5 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with PHN treated with Horizant 1,200 mg/day and numerically greater than placebo.

Table 5: Incidence of Adverse Reactions (in At Least 2% of Patients Treated With 1,200 mg/day of Horizant and Numerically Greater Than the Placebo Rate) Reported in All Patients in the 12-Week PHN Study

The following adverse reactions were also reported as ≥2% at 2,400 mg/day and/or 3,600 mg/day and appeared to be dose-related but were <2% at 1,200 mg/day:

• balance disorder,
• confusional state,
• depression,
• dry mouth,
• flatulence,
• increased appetite,
• irritability, and
• vertigo.

Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship.

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.

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.

Gabapentin enacarbil is released faster from Horizant Extended-Release tablets in the presence of alcohol. Consumption of alcohol is not recommended when taking Horizant.

Morphine

• Horizant taken in conjunction with morphine causes increased somnolence/sedation, dizziness, and nausea when compared with either drug alone.

Drug Abuse And Dependence

Controlled Substance

Horizant, a prodrug of gabapentin, is not a scheduled drug.

Abuse

• Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta, or kappa), or cannabinoid 1 receptor sites.
• A small number of postmarketing cases report gabapentin misuse and abuse.
• These individuals were taking higher than recommended doses of gabapentin for unapproved uses.
• Most of the individuals described in these reports had a history of polysubstance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
• When prescribing products that deliver gabapentin, carefully evaluate patients for a history of drug abuse and observe them for signs and symptoms of gabapentin misuse or abuse (e.g., development of tolerance, self dose escalation, and drug-seeking behavior).

Dependence

• There are rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved.
• Such symptoms included agitation, disorientation, and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin.
• Most of these individuals had a history of poly-substance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
• The dependence and abuse potential of gabapentin has not been evaluated in human studies.