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The Management of Restless Legs Syndrome: An Updated Algorithm

2021 management algorithm

Updated RLS management algorithm

See what neurologist and RLS expert Dr. Daniel Lee has to say about The Management of Restless Legs Syndrome: An Updated Algorithm.

 
Click to expand transcript

[On-screen text: The Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation updated treatment recommendations for the management of Restless Legs Syndrome.

Mayo Clinic Proceedings published the new algorithm in its July 2021 issue.

Daniel O. Lee, MD, FAAN, FAASM
Professor, Department of Neurology, University of Kentucky College of Medicine

shares his perspective about the new treatment recommendations and what they mean for patients and healthcare providers.

Arbor Pharmaceuticals sponsored this video and compensated Dr. Lee for his time to record it.

What is Restless Legs Syndrome

Daniel O. Lee, MD, FAAN, FAASM
Professor, Department of Neurology
University of Kentucky College of Medicine

Restless Leg Syndrome is a common neurologic condition that affects one’s ability to sleep. It may potentially have a serious negative impact on the quality of life. It is characterized by the urge to move their limbs, often associated with limb discomfort. It usually occurs at rest, such as in the evening time when they try to spend some quality time with their family and loved ones, or at nighttime when they true to get some sleep. Unfortunately, the urge to move or limb discomfort only can be relieved with movement of by medications.

[On-screen text: Can you tell us about the new treatment recommendations developed by the Restless Legs Syndrome Foundation?]

Much has been changed since the last update in the management of Restless leg in 2013. The new recommendation is based on scientific evidence and also cumulative clinical experience from those experts in treating Restless Leg Syndrome. Restless Leg Syndrome has been approved by the FDA with four medication Ropinirole, Pramipexole, Rotigotine and Gabapentin Enacarbil. Therefore, any other medications we were going to be discussing in the following or being used in the treatment of Restless Leg are considered as off-label use. The new recommendation is that Restless Leg treatment should begin with Alpha-2-Delta Ligand such as Gabapentin Enacarbil, Gabapentin or Pregabalin unless non-Ergot Dopamine Agonist such as Ropinirole, Pramipexole or Rotigotine has demonstrated to be safer in certain conditions, such as moderate to severe depression, complication of obesity, gait instability, or patients having respiratory failure, or previous history of substance and polysubstance abuse. If Alpha-2-Delta Ligand is ineffective or poorly tolerated, one may consider the use of Non-Ergot Dopamine Agonist. If a patient is suffering from moderate to severe Restless Leg Syndrome for much of the night, then one may consider the use of slow-release Alpha-2-Delta ligands, such as Gabapentin Enacarbil or using Rotigotine patch if patient is not able to tolerate Gabapentin Enacarbil.

[On-screen text: What do these new treatment recommendations mean for RLS patients?]

Previously, Dopamine Agonist is considered a first line treatment for Restless Leg patient. However, as we begin to accumulate our clinical experience, more and more patient began to report to us an increase in incidence of impulse control disorder or worsening of their symptoms called augmentation, which prompted this new treatment recommendation. The good news is, because of this new recommendation, it provided a roadmap for clinician like you and be able to personalize the management of our Restless Legs patients based on their individual needs.

Arbor Disclaimer Statement

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 the following information.

HORIZANT: Important Safety Information

INDICATIONS:
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.

Respiratory Depression
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.

Tumorigenic Potential
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.

ADVERSE REACTIONS
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.

DRUG INTERACTIONS
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.

Pediatric Use
Safety and effectiveness of HORIZANT in pediatric patients have not been studied.

Geriatric Use
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.

Renal Impairment
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 complete Prescribing Information for HORIZANT at www.horizant.com.

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 www.fda.gov/medwatch or call 1-800-FDA-1088.

What changed in the updated management of RLS algorithm?

RLS management algorithm from 2013 to 2021

Alpha2-delta ligands are first-line therapy for chronic persistent RLS. Dopamine agonists are now second-line for chronic persistent RLS, which is explained in the updated management of RLS algorithm.1

Why are alpha2-delta ligands the preferred first-line treatment?1

Dopamine agonists have been a mainstay treatment option for RLS, formerly recommended as first-line treatment.2 Based on a deeper understanding of dopamine agonists, the RLS Treatment Algorithm was updated, and the dopamine agonist medication class is now considered second-line.1 As first-line RLS treatment, alpha2-delta ligands are now the preferred medication class for treating moderate to severe primary RLS.1

Alpha₂-delta ligand formula

Approach to the management of chronic persistent restless legs syndrome (RLS)1

Updated management algorithm for chronic persistent restless legs syndrome

If contraindication to calcium channel ligands (obesity and its complications, past or present moderate or severe depression, gait instability, disorders causing respiratory failure and prior history of substance use disorder):

Non-ergot dopamine agonists (pramipexole, ropinirole or rotigotine patch)

Republished under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 license: https://creativecommons.org/licenses/by-nc-nd/4.0/
  • Treatment should start with an alpha2-delta ligand (gabapentin, pregabalin, or gabapentin enacarbil) unless patient factors suggest that a nonergot dopamine agonist (pramipexole, ropinirole, or rotigotine patch) would be safer.
  • Factors favoring a dopamine agonist as initial treatment include obesity and its complications, past or present moderate or severe depression, gait instability, disorders causing respiratory failure, and previous history of substance use disorder. Alpha2-delta ligands can worsen these conditions.
  • If untreated RLS is present for much of the day and night, consider the use of slow-release preparations (gabapentin enacarbil, unless a contraindication exists, then use the rotigotine patch).
  • If alpha2-delta ligands are ineffective or poorly tolerated, change to a dopamine agonist.
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Relief for a range of RLS symptoms

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VIEW INDICATION AND FULL IMPORTANT SAFETY INFORMATION

  • Effects on DrivingHORIZANT 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 DizzinessHORIZANT 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.

Important Safety Information for HORIZANT® (gabapentin enacarbil) Extended-Release Tablets

INDICATIONS:

HORIZANT® 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® 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.

Respiratory Depression

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.

Tumorigenic Potential

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.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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.

Pediatric Use

Safety and effectiveness of HORIZANT in pediatric patients have not been studied.

Geriatric Use

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.

Renal Impairment

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.

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 www.fda.gov/medwatch or call 1-800-FDA-1088.

For additional safety information, consult the HORIZANT full Prescribing Information here.

This site is intended for US residents only.

HORIZANT is a registered trademark of Arbor Pharmaceuticals, LLC.

Trademarks, registered or otherwise, are the property of their respective owners.

© 2021 Arbor Pharmaceuticals, LLC. All rights reserved. OCT 2021. PP-HOR-US-0691