Rotigotine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Patch 24 Hour, Transdermal:

Neupro: 1 mg/24 hr (30 ea); 2 mg/24 hr (30 ea); 3 mg/24 hr (30 ea); 4 mg/24 hr (30 ea); 6 mg/24 hr (30 ea); 8 mg/24 hr (30 ea) [contains sodium metabisulfite]

Pharmacology

Mechanism of Action

Rotigotine is a nonergot dopamine agonist with specificity for D₃-, D₂-, and D₁-dopamine receptors. Although the precise mechanism of action of rotigotine is unknown, it is believed to be due to stimulation of postsynaptic dopamine D₂-type auto receptors within the substantia nigra in the brain, leading to improved dopaminergic transmission in the motor areas of the basal ganglia, notably the caudate nucleus/putamen regions.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~84 L/kg

Metabolism

Extensive via conjugation and N-dealkylation; multiple CYP isoenzymes, sulfotransferases, and two UDP-glucuronosyltransferases involved in catalyzing the metabolism

Excretion

Urine (~71% as inactive conjugates and metabolites, <1% as unchanged drug); feces (~23%)

Time to Peak

15 to 18 hours; can occur 4 to 27 hours post application

Half-Life Elimination

After removal of patch: ~5 to 7 hours

Protein Binding

~90%

Use in Specific Populations

Special Populations: Renal Function Impairment

In subjects with severe renal impairment not on dialysis (eg, CrCl 15 to <30 mL/minute), exposure to conjugated rotigotine metabolites was doubled.

Special Populations: Elderly

Although not studied, exposures in older subjects (older than 80 years of age) may be higher because of skin changes with aging.

Use: Labeled Indications

Parkinson disease: For the treatment of Parkinson disease.

Restless legs syndrome: For the treatment of moderate to severe primary restless legs syndrome.

Contraindications

Hypersensitivity to rotigotine or any component of the formulation

Dosage and Administration

Dosing: Adult

Parkinson disease: Topical: Transdermal:

Early-stage: Initial: Apply 2 mg/24 hours patch once daily; may increase by 2 mg/24 hours weekly, based on clinical response and tolerability; lowest effective dose: 4 mg/24 hours (manufacturer recommends a maximum dose of 6 mg/24 hours; higher doses [eg, 8 mg/24 hours] have been studied in clinical trials [Giladi 2007]).

Advanced-stage: Initial: Apply 4 mg/24 hours patch once daily; may increase by 2 mg/24 hours weekly, based on clinical response and tolerability. Recommended dose: 8 mg/24 hours; in clinical trials maximum doses up to 16 mg/24 hours were used.

Discontinuation of treatment in Parkinson disease: Decrease by ≤2 mg/24 hours preferably every other day until withdrawal complete

Restless legs syndrome (RLS): Topical: Transdermal: Initial: Apply 1 mg/24 hours patch once daily; may increase by 1 mg/24 hours weekly, based on clinical response and tolerability; lowest effective dose: 1 mg/24 hours (maximum dose: 3 mg/24 hours)

Discontinuation of treatment for RLS: Decrease by 1 mg/24 hours preferably every other day until withdrawal complete

Dosing: Geriatric

Refer to adult dosing.

Administration

Transdermal patch: Apply patch to clean, dry, hairless area of intact healthy skin on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at approximately the same time daily. Remove from pouch immediately before use and press patch firmly in place on skin for 30 seconds. Application sites should be rotated on a daily basis. Do not apply to same application site more than once every 14 days or apply patch to oily, irritated or damaged skin. Avoid exposing patch to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub, direct sunlight). If applied to hairy area, shave ≥3 days prior to applying patch. If patch falls off, immediately apply a new one to a new site.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF). Store in original pouch until application.

Drug Interactions

Alcohol (Ethyl): May enhance the sedative effect of Rotigotine. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alizapride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Avoid combination

Antipsychotic Agents (First Generation [Typical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromopride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Monitor therapy

CNS Depressants: May enhance the sedative effect of Rotigotine. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Solriamfetol: Anti-Parkinson Agents (Dopamine Agonist) may enhance the hypertensive effect of Solriamfetol. Monitor therapy

Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Systolic hypotension (13% to 32%), orthostatic hypotension (8% to 29%), peripheral edema (3% to 14%)

Central nervous system: Drowsiness (5% to 32%), dizziness (5% to 23%), headache (10% to 21%), fatigue (6% to 18%), malaise (≤14%), sleep disorder (disturbance in initiating/maintaining sleep; 2% to 14%), hallucination (3% to 13%)

Dermatologic: Hyperhidrosis (1% to 11%)

Endocrine & metabolic: Decreased serum glucose (1% to 15%)

Gastrointestinal: Nausea (15% to 48%), vomiting (2% to 20%)

Hematologic & oncologic: Decreased hematocrit (8% to 17%), decreased hemoglobin (8% to 15%)

Local: Application site reaction (21% to 46%)

Neuromuscular & skeletal: Dyskinesia (14% to 17%), asthenia (≤14%), arthralgia (8% to 11%)

1% to 10%:

Cardiovascular: Increased diastolic blood pressure (4% to 8%), systolic hypertension (5%), hypertension (1% to 5%), atrioventricular block (3%), hypoesthesia (3%), abnormal T waves on ECG (2% to 3%)

Central nervous system: Abnormal dreams (1% to 7%), nightmares (3% to 5%), paresthesia (3% to 4%), vertigo (3% to 4%), depression (2% to 3%), equilibrium disturbance (2% to 3%), irritability (1% to 3%), sudden onset of sleep (1% to 2%)

Dermatologic: Pruritus (4% to 9%), erythema (2% to 6%)

Endocrine & metabolic: Weight gain (2% to 9%), change in libido (4% to 6%), hot flash (3% to 4%), low serum ferritin (2%), menstrual disease (1% to 2%)

Gastrointestinal: Constipation (5% to 9%), anorexia (2% to 9%), xerostomia (7%), diarrhea (5% to 7%), dyspepsia (2% to 3%), viral gastroenteritis (1% to 2%)

Hematologic & oncologic: Basal cell carcinoma (3%), leukocyturia (3%)

Infection: Herpes simplex infection (3%), influenza (1% to 3%)

Neuromuscular & skeletal: Tremor (4%), muscle spasm (3% to 4%)

Ophthalmic: Visual disturbance (3% to 5%)

Otic: Tinnitus (2% to 3%)

Renal: Increased blood urea nitrogen (3% to 11%)

Respiratory: Nasopharyngitis (8% to 10%), cough (3%), nasal congestion (3%), paranasal sinus congestion (2% to 3%), sinusitis (2% to 3%)

<1%, postmarketing, and/or case reports: Aggressive behavior, agitation, confusion, delirium, delusions, disorientation, heavy headedness (dropped head syndrome), impulse control disorder, increased creatine phosphokinase, increased pulse, neuroleptic malignant syndrome (resembling), paranoia, psychotic symptoms, skin rash

Warnings/Precautions

Concerns related to adverse effects:

• Application site reactions: Dose-dependent application site reactions, potentially severe, have been observed; daily rotation of application sites has been shown to decrease incidence of reactions. If a generalized (nonapplication site) skin reaction occurs; discontinue therapy.
• Fibrosis: Rare cases of pleural effusion, pleural thickening, pulmonary infiltrates, retroperitoneal fibrosis, pericarditis and/or cardiac valvulopathy have been reported in patients treated with ergot-derived dopamine agonists. The potential of rotigotine, a nonergot derived dopamine agonist, to cause similar fibrotic complications is unknown. Discontinuation of therapy may resolve complications, but not in all cases.
• Fluid retention: Weight gain and fluid retention have been reported, primarily associated with development of peripheral edema in Parkinson disease patients; use caution and monitor for weight gain in patients with concomitant illnesses (eg, heart failure or renal insufficiency).
• Hallucinations/psychotic-like behavior: May cause hallucinations (dose-related) and other psychotic-like behaviors (eg, agitation, delirium, delusions, aggression). In general, avoid use in patients with preexisting major psychotic disorders.
• Impulse control disorders: Dopamine agonists used for Parkinson disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), and/or binge eating. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.
• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients receiving therapy for any indication should be monitored closely and periodic skin examinations should be performed.
• Orthostatic hypotension: Dopamine agonists may cause orthostatic hypotension and syncope; Parkinson disease patients appear to have an impaired capacity to respond to a postural challenge. Use with caution in patients at risk of hypotension (such as those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and should be informed of this risk.
• Somnolence: Use is commonly associated with somnolence. In addition, falling asleep during activities of daily living, including while driving, has also been reported and may occur without significant warning signs. Monitor for daytime somnolence or pre-existing sleep disorder. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents; discontinue if significant daytime sleepiness or episodes of falling asleep occur. Effects with other sedative drugs or ethanol may be potentiated.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease; therapy has been associated with increases in blood pressure (as well as orthostatic hypotension), which may be significant (>40 mm Hg or ≥20 mm Hg increase in systolic or diastolic measurements, respectively), increased heart rate, syncope, and weight gain/fluid retention.
• Dyskinesia: Use with caution in patients with preexisting dyskinesia; therapy may cause or exacerbate dyskinesia.

Special populations:

• Restless legs syndrome: Augmentation (earlier onset of symptoms each day and/or an overall increase in symptom severity) may occur in some restless leg syndrome (RLS) patients. Risk factors for dopaminergic-induced augmentation include higher doses of dopaminergic agents, use of shorter-acting dopamine agonists (ie, pramipexole, ropinirole) or levodopa, low iron stores, and increased severity of symptoms prior to treatment initiation. To minimize risk of augmentation, use the lowest effective dose and avoid exceeding recommended doses. Patients may also be switched to alternative therapy if augmentation occurs (Garcia-Borreguero 2016). End-of-dose rebound (reappearance of symptoms in the early morning hours) may also occur. Consider dosage adjustment or discontinuation of treatment if rebound symptoms occur.

Dosage form specific issues:

• Aluminum: Patch contains aluminum; remove patch prior to magnetic resonance imaging or cardioversion to avoid skin burns.
• Heat application: Avoid exposure of application site to any direct external heat sources (eg, hair dryers, heating pads, electric blankets, saunas, hot tubs, direct sunlight); heat exposure has not been studied with the rotigotine patch, but an increase in the rate and extent of absorption has been observed with other transdermal products.
• Sulfites: Patch contains sodium metabisulfite which may cause allergic reaction in susceptible individuals.

Other warnings/precautions:

• Discontinuation of therapy: Taper treatment when discontinuing therapy; do not stop abruptly. Other dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on withdrawal and/or significant dosage reduction.

Monitoring Parameters

Blood pressure (including orthostatic); daytime alertness; periodic skin evaluations (melanoma development)

Pregnancy

Pregnancy Considerations

Information related to the use of rotigotine in pregnancy is limited (Dostal 2013).

Available guidelines note there is insufficient evidence to recommend rotigotine for use in pregnant females with restless leg syndrome (Picchietti 2015) or Parkinson disease (Seier 2017)

Patient Education

What is this drug used for?

• It is used to treat Parkinson disease.
• It is used to treat restless leg syndrome.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Constipation
• Lack of appetite
• Nightmares
• Diarrhea
• Dry mouth
• Sweating a lot
• Loss of strength and energy
• Trouble sleeping
• Application site irritation
• Joint pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Uncontrollable urges
• Severe dizziness
• Passing out
• Confusion
• Skin growths
• Mole changes
• Severe headache
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Mood changes
• Sensing things that seem real but are not
• Behavioral changes
• Muscle pain
• Stiff muscles
• Abnormal movements
• Shortness of breath
• Sex drive changes
• Severe skin irritation
• Excessive weight gain
• Swelling of arms or legs
• Vision changes
• Severe fatigue
• Narcolepsy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.