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Rotigotine

Pronunciation

(roe TIG oh teen)

Index Terms

  • N-0923

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]

Brand Names: U.S.

  • Neupro

Pharmacologic Category

  • Anti-Parkinson's Agent, Dopamine Agonist

Pharmacology

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.

Distribution

Vd: ~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%

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

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 (maximum dose: 6 mg/24 hours [U.S. labeling] or 8 mg/24 hours [Canadian labeling])

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’s 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.

Dosing: Renal Impairment

Mild-to-severe impairment (CrCl ≥15 mL/minute): No dosage adjustment necessary.

End-stage renal disease (ESRD) requiring hemodialysis: No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild-to-moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment: There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

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

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

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). 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

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: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. 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

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

Adverse Reactions

>10%:

Cardiovascular: Systolic hypotension (13% to 32%), peripheral edema (dose related; 3% to 14%)

Central nervous system: Drowsiness (dose related; 5% to 32%), orthostatic hypotension (8% to 29%), dizziness (5% to 23%), headache (10% to 21%), fatigue (6% to 18%), sleep disorder (disturbance in initiating/maintaining sleep; dose related; 2% to 14%), malaise (≤14%), hallucination (dose related; 3% to 13%), insomnia (7% to 11%)

Dermatologic: Hyperhidrosis (dose related; 1% to 11%)

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

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

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

Local: Application site reaction (dose related; 21% to 46%)

Neuromuscular & skeletal: Dyskinesia (dose related; 14% to 17%), weakness (≤14%), arthralgia (8% to 11%)

1% to 10%:

Cardiovascular: Increased diastolic blood pressure (4% to 8%), systolic hypertension (5%), hypertension (dose related; 1% to 5%), atrioventricular block (3%), abnormal T waves on ECG (≤3%), syncope

Central nervous system: Abnormal dreams (dose related; 1% to 7%), nightmares (dose related; 3% to 5%), depression (2% to 5%), paresthesia (dose related; 4%), vertigo (3% to 4%), equilibrium disturbance (2% to 3%), irritability (1% to 3%), sleep attacks (dose related; 1% to 2%)

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

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

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

Genitourinary: Change in WBC count (urine, ≤3%)

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

Infection: Herpes simplex infection (3%)

Neuromuscular & skeletal: Tremor (4%), muscle spasm (dose related; 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%), sinus congestion (2% to 3%), sinusitis (dose related; 2% to 3%)

Miscellaneous: Hiccups (dose related; 2% to 3%)

<1% (Limited to important or life-threatening): Confusion, delirium, delusions, impulse control disorder, increased creatine phosphokinase, neuroleptic malignant syndrome, paranoia, psychotic symptoms

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’s 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’s 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’s 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 (RLS): Augmentation (earlier onset of symptoms each day and/or an overall increase in symptom severity) or rebound (considered to be an end of dose effect) may occur in some patients with RLS.

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 Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. The Canadian labeling does not recommend use in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, constipation, lack of appetite, diarrhea, fatigue, sweating a lot, loss of strength and energy, insomnia, application site irritation, or joint pain. Have patient report immediately to prescriber uncontrollable urges, severe dizziness, passing out, confusion, skin growths, mole changes, severe headache, nightmares, burning or numbness feeling, angina, tachycardia, arrhythmia, mood changes, hallucinations, behavioral changes, abnormal movements, severe skin irritation, weight gain, swelling of arms or legs, tinnitus, vision changes, or narcolepsy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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