Rotigotine

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 07.29.2021
Released 09.07.2007
Expires For CME 07.29.2024

Rotigotine

Author: K K Jain MD†

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Rotigotine

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Introduction

Historical note and terminology

Dopamine agonists have been shown to be effective in delaying levodopa-induced dyskinesia in early Parkinson disease, but intermittent administration of short-acting dopaminergic agents can predispose Parkinson disease patients to motor fluctuations. Rotigotine, a non-ergot dopamine D2 agonist, has antiparkinsonian effects when infused intravenously, and a transdermal preparation is now available as rotigotine constant delivery system (CDS), which allows a constant delivery of the drug. This is a significant development in the treatment of Parkinson disease. In addition to an improved safety profile and symptomatic effectiveness, transdermal rotigotine can simplify treatment for physicians as well as patients. It is particularly useful for patients with dysphagia who have difficulty swallowing oral medications. It was approved in the United States by the FDA in 2007.

Pharmacology

Rotigotine, also known as N-0923, {(-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthelenol HCl}, is a novel, non-ergoline dopamine receptor agonist formulated into a silicone-based transdermal system. The chemical structure and receptor affinity profile resembles that of dopamine.

Pharmacodynamics. The precise mechanism of action of rotigotine as a treatment for Parkinson disease is unknown although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen region of the brain. Administration of a slow-release formulation of rotigotine to conscious rats with microdialysis probes implanted intrastriatally resulted in consistent decrease of dopamine levels to 20% of the control level, suggesting that the sustained administration of rotigotine provides stable extracellular drug levels in the striatum, which provides continuous stimulation of dopamine receptors (24). Rotigotine has been shown to improve motor deficits in animal models of Parkinson disease when administered transdermally. Subchronic administration of rotigotine in experimental studies on rats has been shown to increase the expression of brain-derived neurotrophic factor in the cortex and hippocampus, suggesting that it may exert its medical effect in part through improving brain-derived neurotrophic factor function in the brain (01).

Pharmacokinetics. Rotigotine is administered once a day in the form of an adhesive matrix patch, which is applied to the skin. The patch leads to an optimized release of the active principle and steady concentrations of the substance in the blood. On average, approximately 45% of the rotigotine from the patch is released within 24 hours. There is no characteristic peak concentration observed. The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo.

Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decrease with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. Rotigotine is extensively metabolized by the liver via multiple pathways and pharmacokinetics is not affected by cytochrome P inhibitors.

A study in healthy male subjects using 2 different forms of administration, continuous infusion and transdermal application, showed that plasma concentration-time profiles of unchanged rotigotine during and after infusion and during and after patch administration were comparable (08). Absolute bioavailability of transdermally applied rotigotine was 37%.

Rotigotine transdermal patch can provide “around the clock” treatment for moderate to severe restless legs syndrome (38). Integrated analysis of 3 pharmacokinetic trials in healthy subjects as well as in patients with early-stage Parkinson disease has shown that once daily transdermal patch generates stable mean steady-state 24-hour plasma concentrations (16).

Alternative methods of drug delivery. In experimental studies efficient intranasal delivery of rotigotine to the brain has been demonstrated by using a formulation with biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles, which were surface-modified with lactoferrin (03). Distribution of rotigotine in the brain showed a higher concentration in the striatum, indicating targeted delivery of rotigotine for the treatment of Parkinson disease.

Some challenges remain in other routes of rotigotine administration such as oral, parenteral, and pulmonary whereby resolving these challenges will be beneficial to patients as they are less invasive and comfortable in terms of administration. Rotigotine can also be formulated as an extended-release microsphere for injection (28).

Clinical trials

Numerous clinical trials have been conducted with transdermal rotigotine since 2001 and have involved more than 2000 patients. Earlier trials showed that significant reductions in levodopa dose were achieved with rotigotine as compared to placebo in patients with Parkinson disease. Similar results were seen in the later PREFER study (26). Two controlled trials of rotigotine in early Parkinson disease showed promise in treating motor dysfunction in early Parkinson disease (32; 40). The safety and effectiveness of rotigotine CDS, as compared to a placebo, was tested in a double-blind, randomized, placebo-controlled trial over a period of 3 months. A significant and dose-related improvement of motor symptoms and activities of daily life was demonstrated. These endpoints were measured using 2 subscales of the Unified Parkinson's Disease Rating Scale. Rotigotine CDS was generally well tolerated. In a phase 3, 24-week clinical trial, patients on rotigotine showed significant improvement on a scale that measures mental abilities and the ability to perform basic motor skills and daily living activities. Clinical trials demonstrate the efficacy of rotigotine in early and advanced Parkinson disease, with important implications for treatment of nonmotor symptoms of Parkinson disease (30). A randomized, double-blind, multicenter, placebo-controlled study showed that rotigotine transdermal system consistently demonstrated statistically significant and clinically relevant efficacy over placebo in patients with early Parkinson disease and was well tolerated (23). Another randomized, double-blind, controlled study of rotigotine versus placebo and ropinirole showed that rotigotine had a similar efficacy to ropinirole (19). A randomized, double-blind, placebo-controlled trial on patients with early-stage Parkinson disease in Japan has shown that rotigotine, at doses up to 16 mg/24 hours, is well tolerated and improves function (29).

Analysis of the results of RECOVER, a prospective randomized controlled trial of rotigotine transdermal system showed improvement of nonmotor symptoms in patients with Parkinson disease such as fatigue, depression, anhedonia, and apathy (35).

A meta-analysis of 6 randomized controlled trials has shown that rotigotine improves the symptoms of Parkinson disease, but it is also associated with a higher incidence of application site reactions as compared with placebo (43).

Use of rotigotine for restless legs syndrome has been supported by a controlled clinical trial (31). Following 6 weeks' double-blind treatment, patients suffering from moderate to severe restless legs syndrome received open-label rotigotine at dosages of 1 to 3 mg/24 hours, which was well tolerated with sustained efficacy for 5 years (15). A meta-analysis of randomized clinical trials suggests that rotigotine is significantly more effective than placebo for the treatment of restless legs syndrome (14).

In a randomized, double-blind trial of patients with Parkinson disease, improvement produced by rotigotine in the total score of multidomain nonmotor symptoms was not superior to placebo (02). Adverse events more frequently reported with rotigotine were nausea, application site reactions, somnolence, and headache.

A randomized, double-blind, placebo-controlled, parallel-group study has demonstrated that rotigotine improves sleep quality and stability in Parkinson disease by increasing REM, which may be due to its direct effect on both D1 and D2 receptors (33). A meta-analysis of randomized, placebo-controlled trials showed that rotigotine transdermal patch effectively improved neuropsychiatric symptoms and quality of life in patients with Parkinson disease (39). In a randomized clinical trial rotigotine treatment did not significantly affect global cognition in patients with mild to moderate Alzheimer disease but improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living (25).

A multicenter, randomized, double-blind study of the effect of rotigotine versus placebo showed no significant difference in change of depression at 6 months between rotigotine and placebo, but trait anxiety was significantly improved (06).

Indications

Rotigotine transdermal system is indicated for the treatment of Parkinson disease and moderate-to-severe primary restless legs syndrome.

Off-label uses

	• Transdermal dopaminergic stimulation with rotigotine has been used to treat Parkinsonian akinetic crisis (10).
	• An open-label study showed that transdermal rotigotine was a well tolerated and effective treatment in patients with sleep disorders of advanced Parkinson disease (05).
	• Results of a double-blind, randomized, placebo-controlled study suggest a beneficial role of dopaminergic modulation by rotigotine on visual search and selective attention in patients with hemispatial neglect following stroke (21).
	• Because of the role of dopamine in both amyloid beta formation as well as in progression of cognitive decline, effects of the dopamine agonist rotigotine on cortical excitability and on central cholinergic transmission is being investigated in cases of Alzheimer disease. Rotigotine increases cortical excitability and central cholinergic transmission, indicating the potential use of dopaminergic drugs for preventing cognitive decline in Alzheimer disease (27).
	• An observational study has shown that low doses of rotigotine are well tolerated and effective in antipsychotic drug-induced parkinsonism (12).
	• It could be another therapeutic option in the treatment of chronic drug-resistant cluster headache (13).
	• It may be used to treat apathy in limbic autoimmune encephalitis (18).
	• In a randomized study rotigotine produced short-term improvement in periodic limb movements and symptoms of restless legs syndrome in patients on hemodialysis (11). A meta-analysis of several studies shows considerable efficacy of rotigotine in alleviating the frequency of periodic limb movements in sleep (41).
	• In an open-label comparative study transdermal patch of rotigotine attenuated freezing of gait in patients with Parkinson disease, whereas 2 other nonergot dopamine receptor agonists -- pramipexole LA and ropinirole -- did not alter freezing of gait scores (22).
	• Long-term treatment with low doses of rotigotine is well tolerated and may improve cognitive functions in patients with progressive supranuclear palsy (36).

Goals and duration of treatment

Continuous transdermal delivery of rotigotine is intended to avoid the peaks and valleys inherent with oral dopamine agonists, which cause patients to experience side effects during the peaks and disease symptoms during the valleys. Steady-state plasma concentrations are achieved within 2 to 3 days of daily dosing. Onset of benefits begins as early as the second week after the start of treatment. Although long-acting drugs such as rotigotine are theoretically less likely to cause dopamine dysregulation–a potentially serious side effect of dopamine agonists–there are no published data on this issue. Rotigotine transdermal patch favors compliance along with other advantages of constant drug delivery, such as reduced emergence of motor complications (34). Rotigotine transdermal patch was associated with high compliance in patients with Parkinson disease under conditions of clinical practice (37). In routine clinical practice, treatment with rotigotine transdermal patch is associated with a reduction of other prescribed medications for Parkinson disease and with an improvement in quality of sleep (09). In open extensions of clinical trials, rotigotine was generally well tolerated for up to approximately 6 years in patients with early-stage Parkinson disease, and the reported adverse events were like those in previous studies with typical dopaminergic side effects and application site reactions (20). After more than a decade of clinical use, rotigotine transdermal patch is now an established, once-daily dopamine agonist preparation for use in short- as well as long-term treatment of Parkinson disease and is particularly useful for patients with gastrointestinal disturbances as an alternative to oral medications (17). A study was undertaken to determine the rate of successful continuation of the rotigotine patch for 1 year after initiation and the reasons for discontinuation as well as the oral dopamine agonist dose before and after switching to rotigotine patch treatment (42). Results showed that continuation rates were 38.5% in the overnight group, 61.5% in the cross-titration group, 35.3% in the add-on group, and 50.9% in the de novo group. The findings suggest that it is not how the rotigotine patch is introduced but the use of an equivalent dose of dopamine agonist formulations that affects the continuation rate of the rotigotine patch. The most common reason for discontinuation in all groups was skin reactions. It is recommended that a rotigotine patch with an equivalent dose should be considered when switching from oral dopamine agonists.

Special considerations

Rotigotine should be used with caution in patients, especially those at risk for cardiovascular disease, because of the potential for symptomatic hypotension, syncope, elevated heart rate, elevated blood pressure, fluid retention, and/or weight gain. No dosage adjustment is required in patients with hepatic or renal insufficiency. No dose adjustments are required for transdermal rotigotine in subjects with impaired renal function including those patients with different stages of chronic renal insufficiency and those who are on hemodialysis (07).

Pediatric. The safety and effectiveness of rotigotine in pediatric patients have not been established.

Geriatric. Rotigotine is well tolerated in elderly patients.

Pregnancy. Rotigotine given to pregnant rats during organogenesis resulted in increased fetal death at all doses. No information is available about the use of rotigotine in human pregnancy, which is unlikely in patients with Parkinson disease.

Studies in rats have shown that rotigotine and its metabolites are excreted in breast milk. It is not known whether rotigotine is excreted in human breast milk. Because of the possibility that rotigotine may be excreted in human milk, and because of the potential for adverse reactions in nursing infants, 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.

Anesthesia. No interactions of rotigotine with anesthetics have been reported. Rotigotine should be discontinued for at least 24 hours before anesthesia and can be resumed in the postanesthetic period after the patient has recovered from nausea. This is a general precaution with dopamine agonists, as they tend to induce nausea and vomiting as side effects. Perioperative administration of rotigotine is feasible and efficacious with no safety issues.

References

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22: Ikeda K, Hirayama T, Takazawa T, Kawabe K, Iwasaki Y. Transdermal patch of rotigotine attenuates freezing of gait in patients with Parkinson's disease: an open-label comparative study of three non-ergot dopamine receptor agonists. Intern Med 2016;55(19):2765-9. PMID 27725534
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Rotigotine

Also Relevant

Neuropharmacology
Parkinson disease
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Rotigotine

Rotigotine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

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Rotigotine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Acupuncture

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

This is an article preview.
Start a Free Account
to access the full version.