Rotigotine

Class: Nonergot-derivative Dopamine Receptor Agonists
- Antiparkinsonian Agents
VA Class: CN500
Chemical Name: 5,6,7,8-Tetrahydro-6-[propyl [2-(2-thienyl)ethyl]amino-(6S)-1-naphthalenol
Molecular Formula: C₁₉H₂₅NOS
CAS Number: 99755-59-6
Brands: Neupro

Medically reviewed by Drugs.com. Last updated on March 22, 2021.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations

Introduction

Nonergot-derivative dopamine receptor agonist.

Uses for Rotigotine

Parkinsonian Syndrome

Symptomatic management of idiopathic parkinsonian syndrome.

Efficacy demonstrated in patients with early parkinsonian syndrome not receiving concomitant levodopa therapy and in patients with advanced parkinsonian syndrome receiving concomitant levodopa therapy.

Restless Legs Syndrome

Symptomatic management of moderate-to-severe primary restless legs syndrome (RLS; also called Willis-Ekbom disease).

Nonergot-derivative dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) generally considered among the drugs of first choice for treating restless legs syndrome.

Rotigotine Dosage and Administration

Administration

Transdermal Administration

Administer percutaneously by topical application of a transdermal system (Neupro). Apply transdermal system (or “patch”) once daily at a convenient time (day or night) and at approximately the same time each day. May apply without regard to meals.

Instruct patients in the proper use and disposal of the transdermal system and advise patients to read the patient information, including the instructions for use, before beginning therapy and each time drug is refilled.

Apply transdermal system immediately after removal from its pouch and removal of the protective liner.

Apply to clean, dry, intact healthy skin on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm by firmly pressing the system with the palm of the hand for 30 seconds with the adhesive side touching the skin to ensure good contact, particularly around the edges.

Avoid application sites that are oily, irritated, or damaged; also avoid sites where the patch may be rubbed by tight clothing, under a waistband, and skin folds.

If application to a hairy area is necessary, shave hair at the application site at least 3 days prior to application; do not use creams, lotions, oils, ointments, or powders on skin where patch will be placed.

Move application site on a daily basis (i.e., from the right side to the left side, from the upper body to the lower body). Do not apply transdermal system to the same application site more than once every 14 days. (See Application Site Reactions under Cautions.)

Wear each transdermal system continuously for 24 hours. If a system becomes dislodged during period of use or if a patient forgets to change the system, apply a new system for the remainder of the day; on the following day, change the patch according to regular time schedule. May tape edges of the transdermal system in place with bandage tape if patient experiences difficulty with patch adhesion.

After handling a transdermal system, wash hands to remove any drug; avoid touching eyes or other objects prior to handwashing.

Because the backing layer of the rotigotine transdermal system contains aluminum, remove patch prior to magnetic resonance imaging (MRI) or cardioversion to avoid skin burns.

Dosage

The rotigotine transdermal system (Neupro) is labeled in terms of the approximate rate of drug delivery per 24 hours.

May use either single or multiple patches of rotigotine to achieve prescribed dosage.

Adults

Parkinsonian Syndrome

Transdermal

Early parkinsonian syndrome: Initially, 2 mg/24 hours; may increase dosage weekly by 2 mg/24 hours if tolerated and additional therapeutic effect is needed. Lowest effective dosage in clinical studies was 4 mg/24 hours. Maximum recommended dosage is 6 mg/24 hours.

Advanced parkinsonian syndrome: Initially 4 mg/24 hours; may increase dosage weekly by 2 mg/24 hours if tolerated and additional therapeutic effect needed. Recommended dosage is 8 mg/24 hours.

When discontinuing treatment in patients with parkinsonian syndrome, reduce daily dosage by a maximum of 2 mg/24 hours with a dosage reduction preferably every other day, until complete withdrawal is achieved. (See Withdrawal-emergent Hyperpyrexia and Confusion under Cautions.)

Restless Legs Syndrome

Transdermal

Initially, 1 mg/24 hours; increase dosage weekly by 1 mg/24 hours if tolerated and if additional therapeutic effect is needed, up to a maximum dosage of 3 mg/24 hours.

When discontinuing treatment, reduce daily dosage by 1 mg/24 hours preferably every other day, until complete withdrawal is achieved. (See Augmentation and Rebound in Restless Legs Syndrome and also see Withdrawal-emergent Hyperpyrexia and Confusion under Cautions.)

Prescribing Limits

Adults

Parkinsonian Syndrome

Transdermal

Early parkinsonian syndrome: 6 mg/24 hours.

Restless Legs Syndrome

Transdermal

3 mg/24 hours.

Special Populations

Hepatic Impairment

Moderate hepatic impairment: Dosage adjustment not necessary.

Severe hepatic impairment: Not studied; manufacturer does not provide specific dosage recommendations. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in patients with mild to severe renal impairment, including those receiving hemodialysis. (See Renal Impairment under Cautions.)

Geriatric Patients

Manufacturer makes no specific recommendations for dosage adjustment. (See Geriatric Use under Cautions.)

Cautions for Rotigotine

Contraindications

• Hypersensitivity to the drug or to any components in the transdermal administration system.

Warnings/Precautions

Patient Monitoring for Adverse Reactions

Monitor patients for possible adverse reactions described throughout the Cautions: Warnings/Precautions section. If any of these adverse reactions develops, dosage reduction or discontinuance of therapy may be beneficial.

Sulfite Sensitivity

Rotigotine transdermal system (Neupro) contains sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

Falling Asleep During Activities of Daily Living and Somnolence

Episodes of falling asleep while engaged in activities of daily living (e.g., driving), which sometimes resulted in accidents, have been reported. Some cases occurred as late as 1 year after initiation of transdermal rotigotine therapy. Some patients perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event; however, many experts believe that falling asleep while engaged in such activities always occurs in a setting of preexisting somnolence, although patients may not give such a history.

Somnolence commonly occurs in patients receiving transdermal rotigotine.

Concurrent use of alcohol or other CNS depressants may cause additive sedative effects. (See Specific Drugs under Interactions.)

Patients should use caution while driving, operating other machinery, or working at heights.

Continually reassess patients for drowsiness or sleepiness. Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities. Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, presence of sleep disorders).

Rotigotine generally should be discontinued if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating). If the drug is continued, advise the patient not to drive and to avoid other potentially dangerous activities. Insufficient information to establish whether dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Hallucinations/Psychotic-like Behavior

An increased risk of hallucinations, which is dose related, observed in patients with advanced parkinsonian syndrome treated with transdermal rotigotine.

Other new or worsening mental status and behavioral changes (e.g., paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, delirium), which may be severe and include psychotic-like behavior, reported during therapy or after initiating therapy or increasing the dosage. Geriatric patients with parkinsonian syndrome are at increased risk for such changes. Other antiparkinsonian agents can produce similar effects.

Do not use in patients with a major psychotic disorder. Concomitant use with antipsychotic agents may exacerbate parkinsonian symptoms and decrease its effectiveness.

If hallucinations or psychotic-like behavior occurs, reducing the dosage or discontinuing transdermal rotigotine may be beneficial.

Symptomatic Hypotension and Syncope

Transdermal rotigotine and other dopamine agonists appear to impair systemic regulation of BP, resulting in postural/orthostatic hypotension, especially during dosage escalation. Patients with parkinsonian syndrome generally have a reduced capacity to respond to orthostatic challenge.

Syncope reported in patients receiving dopamine agonists.

Use with caution in patients with severe cardiovascular disease.

Carefully monitor patients with parkinsonian syndrome or restless legs syndrome for signs and symptoms of orthostatic hypotension, particularly during dosage escalation. Inform patients of the risk of orthostatic hypotension and possible syncope during therapy. (See Advice to Patients.)

If orthostatic hypotension or syncope occurs, reducing the dosage or discontinuing the drug may be beneficial.

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, uncontrolled spending, binge eating, other intense urges) and inability to control these urges have been reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including rotigotine). Although causal relationship not established, urges stopped in some cases when dosage was reduced or the drug was discontinued.

Because patients may not recognize these behaviors as abnormal, ask patients whether they have developed new or increased gambling urges, sexual urges, uncontrolled spending, or other urges during therapy and advise them of importance of reporting such urges. Consider dosage reduction or discontinuing transdermal rotigotine if a patient develops such urges.

Elevation of BP and Heart Rate

Increases in BP and heart rate, sometimes moderate to severe, reported.

Consider possibility of BP and heart rate elevations when treating patients with cardiovascular disease with transdermal rotigotine.

Weight Gain and Fluid Retention

Weight gain and fluid retention, reported; weight gain frequently associated with the development of peripheral edema in patients with parkinsonian syndrome.

Weight gain usually well tolerated, but may cause greater difficulty in patients vulnerable to negative consequences of fluid retention such as those with significant congestive heart failure or renal insufficiency.

Dyskinesia and Concurrent Levodopa Therapy

May potentiate adverse dopaminergic effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. (See Specific Drugs under Interactions.)

Application Site Reactions

Dose-dependent application site reactions (e.g., localized erythema, edema, or pruritus limited to the patch area) reported. Most localized reactions are mild or moderate in severity and don't require dosage reduction; in more severe cases, drug discontinuance may be necessary.

Generalized (nonapplication) skin reactions (e.g., allergic rash [including erythematous, maculopapular rash, or pruritus]) reported less frequently than application site reactions.

Daily rotation of rotigotine application sites reduces the incidence of application site reactions. (See Administration under Dosage and Administration.) If a persistent application site reaction (i.e., more than a few days), an increase in severity of a reaction, or a skin reaction spreading outside the application site occurs, assess the potential risks and benefits of continued therapy in the individual patient. If a generalized skin reaction occurs, discontinue transdermal rotigotine.

Melanoma

Melanoma observed more frequently in patients with parkinsonian syndrome than in the general population. Unclear whether increased risk is due to parkinsonian syndrome or to other factors (e.g., antiparkinsonian drugs).

Monitor for melanoma on a frequent and regular basis, regardless of the indication for use. Manufacturer recommends periodic skin examinations performed by appropriately qualified individuals (e.g., dermatologists).

Augmentation and Rebound in Restless Legs Syndrome

Augmentation, a worsening of restless legs syndrome symptoms during treatment leading to an increase in overall symptom severity or earlier time of symptom onset each day, reported in patients receiving dopaminergic drugs for restless legs syndrome, including transdermal rotigotine. Risk of clinically relevant augmentation with transdermal rotigotine appears to be low.

Rebound, an exacerbation of restless legs syndrome symptoms, is considered to be an end-of-dose effect related to the half-life of the therapeutic agent. Discontinuance or wearing off of dopaminergic medications can result in rebound.

Magnetic Resonance Imaging (MRI) and Cardioversion

Because the backing layer of rotigotine transdermal system contains aluminum, remove the patch prior to MRI or cardioversion to avoid skin burns.

Heat Application

Effect of heat application to the rotigotine transdermal system not specifically studied, but has been shown to increase drug absorption several fold with other transdermal formulations. Avoid exposure of the application site to external sources of direct heat (e.g., heating pads, electric blankets, heat lamps, saunas, hot baths, hot tubs, heated water beds, hair dryers, prolonged direct sunlight. (See Advice to Patients.)

Withdrawal-emergent Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (NMS; e.g., elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, autonomic instability) reported following rapid dosage reduction, withdrawal of, or changes in antiparkinsonian therapy. Taper transdermal rotigotine dosage when discontinuing therapy as a preventative measure. (See Dosage under Dosage and Administration.)

Fibrotic Complications

Fibrotic complications, including retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and/or cardiac valvulopathy, reported with ergot-derivative dopamine receptor agonists (e.g., bromocriptine, cabergoline, pergolide [no longer commercially available in the US]); these adverse effects are believed to be related to the ergoline structure of the compounds. Not known whether nonergot-derivative dopamine agonists, including transdermal rotigotine, can also cause such fibrotic reactions.

Binding to Melanin

Binding to melanin-containing tissues (e.g., eyes) evident in the pigmented rat and monkey after a single dose of rotigotine; the binding cleared slowly over a 14-day observation period. Similar binding to melanin reported with other dopamine agonists.

Specific Populations

Pregnancy

Category C.

Lactation

Rotigotine and/or its metabolites distribute into milk in rats; not known whether distributed into human milk. Caution if used in nursing women.

Decreases prolactin secretion; could potentially inhibit lactation.

Pediatric Use

Safety and efficacy not established in pediatric patients for any indication. Pharmacokinetics in pediatric patients <18 years of age not evaluated.

Geriatric Use

No substantial differences in efficacy, safety, or pharmacokinetics of transdermal rotigotine relative to younger adults; however, possibility of greater sensitivity in some geriatric patients cannot be ruled out. (See Geriatric Patients under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Geriatric patients with parkinsonian syndrome are at increased risk for hallucinations and other psychotic-like changes during therapy with dopaminergic agents. (See Hallucinations/Psychotic-like Behavior under Cautions.)

Hepatic Impairment

No relevant changes in plasma concentrations in patients with moderate hepatic impairment (Child-Pugh class B).

Effects of severe hepatic impairment on pharmacokinetics not studied.

Renal Impairment

No relevant changes in plasma concentrations of rotigotine in individuals with mild to severe renal impairment. Exposure to conjugated rotigotine metabolites doubled in individuals with severe renal impairment not receiving dialysis. Dosage adjustment not necessary in patients with any degree of renal impairment, including those receiving dialysis.

Common Adverse Effects

Patients with early parkinsonian syndrome (not receiving concomitant levodopa): Nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, insomnia, headache, fatigue, anxiety, peripheral edema, dyspepsia.

Patients with advanced parkinsonian syndrome (receiving concomitant levodopa): Application site reactions, nausea, dyskinesia, dizziness, peripheral edema, insomnia, hallucinations.

Patients with restless legs syndrome: Application site reactions, nausea, somnolence, headache, insomnia.

Interactions for Rotigotine

In vitro studies indicate that multiple cytochrome P-450 (CYP) isoenzymes are capable of catalyzing the metabolism of rotigotine. If an individual CYP isoenzyme is inhibited, other isoenzymes can catalyze rotigotine metabolism. Clinically important pharmacokinetic interactions mediated by CYP isoenzymes are therefore unlikely.

Metabolized by multiple sulfotransferases and 2 uridine diphosphate-glucuronosyltransferases (UGT1A9 and UGT2B15).

In vitro data indicate no induction of CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 3A4.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP-450 inhibitors: No risk for inhibition of CYP1A2-, 2C9-, and 3A4-catalyzed metabolism of other drugs; low risk of inhibition of CYP2C19- and CYP2D6-catalyzed metabolism of other drugs at therapeutic rotigotine concentrations. Clinically important pharmacokinetic interactions unlikely.

CYP-450 inducers: Pharmacokinetic interactions unlikely.

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

Because rotigotine is metabolized by multiple pathways, clinically important pharmacokinetic interactions unlikely.

Specific Drugs

Rotigotine Pharmacokinetics

Absorption

Bioavailability

Following topical application, approximately 45% of rotigotine is released from the transdermal system within 24 hours.

Following topical application of single 8 mg/24 hours doses to the trunk, average lag time of approximately 3 hours (range: 1–8 hours) before detected in plasma. Peak concentrations typically occur 15–18 hours post-dose, but can occur from 4–27 hours post-dose. No characteristic peak concentration observed.

Steady-state plasma concentrations achieved within 2 to 3 days of once-daily dosing in healthy individuals.

Differences in relative bioavailability at steady state by application site ranged from less than 1% (abdomen versus hip) to 46% (shoulder versus thigh).

Food

Because administered transdermally, food should not affect absorption.

Special Populations

Mild to severe renal impairment (up to end-stage renal disease requiring hemodialysis): No relevant changes in plasma concentrations. Exposure to conjugated metabolites was doubled in individuals with severe renal impairment (Cl_cr 15 to <30 mL/min) not receiving dialysis.

Moderate hepatic impairment: No relevant changes in plasma concentrations.

Severe hepatic impairment: Not studied.

Geriatric patients: Plasma concentrations in healthy individuals and patients 65–80 years of age similar to those in younger adults. Exposure in geriatric patients >80 years of age not studied, but may be higher due to skin changes with aging.

Distribution

Extent

Distributes into milk in rats; not known whether the drug and/or its metabolites distribute into human milk.

Plasma Protein Binding

Approximately 92% to human plasma proteins in vitro; 89.5% in vivo.

Elimination

Metabolism

Extensively metabolized by conjugation and N-dealkylation.

Major metabolites in urine include rotigotine sulfate, rotigotine glucuronide, N-despropyl-rotigotine sulfate, and N-desthienylethyl-rotigotine sulfate.

Elimination Route

Approximately 71 and 23% of a single IV dose excreted in urine and feces, respectively, as metabolites; less than 1% excreted as unchanged drug in urine.

Half-life

Biphasic (after removal of patch); initial half-life of 3 hours and terminal half-life of 5–7 hours.

Actions

• Exhibits binding specificity for and intrinsic activity at dopamine D₁, D₂, D₃, D₄, and D₅ receptors, with highest affinity for D₃ subtype. Demonstrates antagonistic effects at α_2B-adrenergic receptors and agonistic effects at serotonin type 1A (5-hydroxytryptamine [5-HT_1A]) receptors, but no activity on 5-HT_2B receptors.

• Parkinsonian syndrome: Mechanism of action not fully elucidated. Appears to act by stimulating dopamine receptors (D₃, D₂, and D₁) in the caudate putamen of the brain.

• Restless legs syndrome: Precise mechanism of action unknown; appears to be related to ability to stimulate dopamine receptors.

Advice to Patients

• Importance of reading the manufacturer's patient information before beginning transdermal rotigotine therapy and each time the drug is dispensed.

• Importance of using the rotigotine transdermal system (patch) as prescribed. Importance of instructing patients to wear system continuously for 24 hours, then to remove the patch and immediately apply a new one. If a patient forgets to change a patch, they should be advised to apply a new patch as soon as possible and then replace it at the usual time the following day.

• Risk of severe allergic reactions, including allergic-type reactions in patients with sulfite sensitivity. Importance of advising patients to immediately remove the patch and seek immediate medical attention if they experience swelling of the lips or tongue, chest pain, and/or difficulty breathing or swallowing.

• Importance of advising and alerting patients of the potential for sedating effects, including somnolence and particularly the possibility of falling asleep without feeling drowsy or without warning while engaged in activities of daily living. Patients should avoid driving or engaging in other potentially dangerous activities until effects on the individual are known.

• Importance of informing patients that hallucinations or other psychotic-like behavior can occur during therapy, particularly in geriatric patients with parkinsonian syndrome.

• Risk of symptomatic (e.g., dizziness, nausea, sweating) or asymptomatic orthostatic hypotension and syncope during therapy, particularly during initial therapy and following an increase in dosage. Advise patients to avoid rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning transdermal rotigotine therapy. Advise patients to contact their clinician if they experience any signs or symptoms of lowered BP during therapy.

• Risk of increased BP or exacerbation of hypertension and increased heart rate.

• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving transdermal rotigotine and of advising them of the importance of reporting such urges.

• Risk of weight gain and fluid retention, which may manifest as peripheral edema. Patients should contact their clinician if they experience swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.

• Risk of new onset or exacerbation of dyskinesia.

• Importance of informing patients that application site reactions can occur with transdermal rotigotine and that the application site should be rotated on a daily basis. The patch should not be applied to the same application site more often than once every 14 days. Patients should report persistent application site reactions (lasting more than a few days), increases in severity, or skin reactions that spread outside the application site. If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals; such exposure may lead to changes in skin color.

• Importance of advising patients with parkinsonian syndrome that they are at higher risk of developing melanoma. Advise patients to monitor for melanoma frequently and on a regular basis when using transdermal rotigotine for any indication.

• Importance of informing patients that transdermal rotigotine may cause restless legs symptoms to have an earlier onset during the day or become worse.

• Importance of informing patients to remove the rotigotine patch before undergoing MRI or cardioversion to avoid possible skin burns.

• Importance of advising patients about the potential for heat application to increase rotigotine absorption from the patch. Instruct patients to avoid applying external heat sources to the transdermal system and to avoid direct sun exposure of the transdermal system.

• Importance of informing patients that transdermal rotigotine may cause nausea, vomiting, and general GI distress (i.e., dyspepsia, abdominal discomfort).

• Importance of following recommended procedure for administration, removal, and disposal of rotigotine transdermal systems and of reviewing the instruction sheet provided by the manufacturer.

• Importance of patient (or individual assisting the patient) thoroughly washing hands with soap and water after handling the rotigotine transdermal system (e.g., initial application, removal) and to wash the application site thoroughly after removing the system.

• Importance of proper transdermal system disposal, including keeping it out of the reach of children or pets.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., CNS depressants including sedatives, antidepressants, and antipsychotics) and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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