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

Contraindications

Rotigotine contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible individuals.

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.

Dosing

Treatment is initiated with 2 mg/24 hours once daily and the patch is applied at the same time every day. Titration is done in 2 mg/24 hours increments each week until optimal effect is observed, up to 6 mg/24 hours.

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.

Interactions

No drug interactions have been reported. Particularly, there is no pharmacokinetic interaction between transdermal rotigotine and oral levodopa-carbidopa as determined in an open-label phase I study on patients with restless legs syndrome (04). It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rotigotine.

Adverse effects

Rotigotine may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. The most often reported side effects in clinical trials were nausea, application site reactions, somnolence, dizziness, headache, vomiting, and insomnia. Hallucinations were reported in 2.0% of patients treated with rotigotine.

Management. Application site reactions are localized and can be managed by rotation of the site of application. The side effects of rotigotine as a dopamine agonist can be managed by adjusting the amount of drug or discontinuing the drug if this does not suffice.