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Arbor Statement on FDA DA Decision

Arbor supports the U.S. Food and Drug Administration’s decision to require manufacturers of certain dopamine agonists (DAs) to add new information to their products’ labels to clarify that patients may experience psychiatric adverse events including impulse control disorders (ICDs), hallucinations, psychotic-like behavior and mania while taking these products for Restless Legs Syndrome (RLS).

The association between DAs and impulse control disorders (ICDs), hallucinations, and psychotic-like behavior had been previously acknowledged in patients taking DAs for Parkinson’s disease. The FDA’s decision reinforces findings of individual case reports suggesting that the risk of impulse control disorders associated with DAs used for Parkinson’s disease may also exist for patients taking dopamine agonists for RLS despite the lower dose. 

The decision was prompted by a review of two citizen petitions submitted in 2016 and 2017 focused on Parkinson’s Disease and RLS respectively.  The 2017 petition was submitted by BioMedEcon and supported by Arbor.  The FDA not only reviewed the material, including literature reports, submitted by BioMedEcon, but also conducted a literature search and reviewed FDA collected post-marketing safety data.  After their review, the FDA determined that the evidence supported Safety Labeling Changes broadening the Warnings and Precautions section for pramipexole, ropinirole and rotigotine. 

RLS affects an estimated 2% to 10% of adults in the U.S.,1,2,3,4 causes sleep interruptions2 and pain2,5 and may have serious impacts on quality of life.4,6 Arbor encourages healthcare providers to review FDA’s decision and findings, which may help inform their care of RLS patients.

Arbor 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

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.

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

Pregnancy Category C.  There are no adequate and well-controlled studies with Horizant in pregnant women. In nonclinical studies in rat and rabbits, administration of gabapentin enacarbil was developmentally toxic when administered to pregnant animals at doses and gabapentin exposures greater than those used clinically. Horizant should be used during pregnancy only if potential benefit justifies potential risk to fetus.

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 gabapentin products. Because of the potential for adverse reactions in nursing infants from Horizant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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.

References

  1. Phillips B, Hening W, Britz P, Mannino D. Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest. 2006;129(1):76-80.
  2. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165(11):1286-1292.
  3. 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.
  4. McCrink L, Allen RP, Wolowacz S, Sherrill B, Connolly M, Kirsch J.Predictors of health-related quality of life in sufferers with restless legs syndrome: a multi-national study.Sleep Med. 2007 Jan;8(1):73-83.
  5. Hornyak M, Sohr M, Busse M, Study G. Evaluation of painful sensory symptoms in restless legs syndrome: experience from two clinical trials. Sleep Med. 2011;12(2):186-189.
  6. 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.