Arbor has long recognized the need for effective treatment options for Restless Legs Syndrome (RLS) and support for the patients who suffer from it. We are pleased to support The Updated Algorithm for The Management of RLS developed by the Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation (RLSF) and published in the July 2021 issue of the Mayo Clinic Proceedings. Unless contraindicated, alpha-2-delta ligands are first-line agents for the treatment of chronic persistent RLS, with dopamine agonists moved to second-line.
Chronic persistent RLS is defined as restless legs symptoms that are frequent and troublesome enough to require daily treatment, usually occurring on average at least twice a week and resulting in moderate or severe distress. This type of RLS affects an estimated 1.5 percent to 2.7 percent of patients in the U.S.1,2 It also may cause sleep disturbances, and may result in reduced quality of life.3 Arbor encourages providers to review the RLSF practice recommendations to help inform care of their RLS patients.
The updated recommendations were informed, in part, by a deeper understanding of the potential risks associated with prolonged use of dopamine agonists, which physicians often use in the treatment of RLS. Specifically, dopamine agonists have been demonstrated to carry an increase in the risk of augmentation, or worsening of the symptoms of RLS, and a risk for development of impulse control disorders, such as pathologic gambling, impulsive shopping or hypersexuality.3
In 2019, the U.S. Food and Drug Administration (FDA) mandated that manufacturers of certain dopamine agonists add new information to their products’ labels to clarify that patients may experience psychiatric adverse events, including impulse control disorders, hallucinations, psychotic-like behavior and mania while taking these products for RLS.4 Alpha-2-delta ligands do not carry these warnings on their labels and have been proven to be an effective treatment option for adults with moderate to severe RLS.
Arbor Pharmaceuticals manufactures Horizant®(gabapentin enacarbil) Extended-Release Tablets for adults with moderate to severe primary Restless Legs Syndrome (RLS). Horizant (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. As 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. Anyone considering prescribing Horizant must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Monitor for suicidal thoughts or behaviors. RLS patients treated with Horizant reported similar rates of psychiatric disorders for both placebo and the 600mg indicated dose, these were depression (<1%) and decreased libido (<1%); both were noted to be dose related. Side effects of depression and decreased libido increased at the 1200mg doses to 3% and 2% respectively.
For Important Safety Information about Horizant, please see below.
Important Safety Information for HORIZANT®(gabapentin enacarbil) Extended-Release Tablets
HORIZANT® (gabapentin enacarbil) Extended-Release Tablets are 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.
HORIZANT® (gabapentin enacarbil) Extended-Release Tablets are indicated for the management of postherpetic neuralgia (PHN) in adults.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Effects on Driving
HORIZANT may cause significant driving impairment. The duration of driving impairment after starting therapy is unknown. Patients should not drive until they have enough experience on HORIZANT to know if it impairs their driving. Patients’ ability to assess their driving competence and degree of somnolence caused by HORIZANT can be imperfect.
Somnolence/Sedation and Dizziness
HORIZANT causes somnolence/sedation and dizziness. Patients should not drive or operate other complex machinery until they have enough experience on HORIZANT to know if it impairs their ability to perform these tasks.
Lack of Interchangeability With Gabapentin
HORIZANT is not interchangeable 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. The safety and effectiveness of HORIZANT in patients with epilepsy have not been studied.
Suicidal Behavior and Ideation
HORIZANT 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. As 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. Anyone considering prescribing HORIZANT must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Patients, 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 of self-harm. Behaviors of concern should be reported immediately to healthcare providers.
There 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
Drug 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, and/or lymphadenopathy, 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.
Discontinuation of HORIZANT
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.
In an oral carcinogenicity study, gabapentin enacarbil increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats. The clinical significance of this finding is unknown.
The most common adverse reactions for patients with RLS (incidence >10% and at least 2 times the rate of placebo) were somnolence/sedation and dizziness.
The most common adverse reactions for patients with PHN (incidence >10% and greater than placebo) were dizziness, somnolence, and headache.
Gabapentin enacarbil is released faster from HORIZANT Extended-Release tablets in the presence of alcohol. Consumption of alcohol is not recommended when taking HORIZANT.
HORIZANT taken in conjunction with morphine causes increased somnolence/sedation, dizziness, and nausea.
USE IN SPECIAL POPULATIONS
Pregnancy and Lactation
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.
It is not known whether gabapentin derived from HORIZANT is secreted in human milk; however, gabapentin is secreted into human milk following oral administration of other gabapentin products. There are no data on the effects of gabapentin on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HORIZANT and any potential adverse effects on the breastfed infant from HORIZANT or from the underlying maternal condition.
Safety and effectiveness of HORIZANT in pediatric patients have not been studied.
Clinical trials of HORIZANT for the treatment of RLS did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger individuals. Because elderly patients are more likely to have a decreased renal function, the frequency of dosing may need to be adjusted based on calculated creatinine clearance in these patients.
Gabapentin is known to be almost exclusively excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. The dose of Horizant should be adjusted in patients with renal impairment based upon creatinine clearance. HORIZANT is not recommended for treatment of RLS in patients receiving hemodialysis.
For additional safety information, please see accompanying complete Prescribing Information for HORIZANT.
You are encouraged to report side effects of prescription drugs to Arbor Pharmaceuticals, LLC Medical Information at 1-866-516-4950 or to the FDA at https://www.fda.gov/medwatch or call 1-800-FDA-1088.
- Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 2011;26(1):114-120.
- Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: prevalence and characteristics. Sleep Med. 2010; 11: 31-37
- Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman, JW. The Management of Restless Legs Syndrome: An Updated Algorithm, Mayo Clin Proc. 2021;96(7):1921-1937
- Letter from CDER to Public Citizen. U.S. Food and Drug Administration. 2019. Available at: https://www.regulations.gov/document/FDA-2017-P-3486-0016. Last accessed July 9, 2021.
HORIZANT is a registered trademark of Arbor Pharmaceuticals, LLC © 2021 Arbor Pharmaceuticals, LLC All rights reserved. PP-HOR-US-0696