Neupro (rotigotine)

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

The prescribed dosage of transdermal rotigotine may be achieved using either single or multiple patches of the drug.

Rotigotine is administered percutaneously by topical application of a transdermal system (patch). The transdermal system should be applied once daily at a convenient time for the patient during the day or night, but should be applied at approximately the same time each day.

Because rotigotine is administered transdermally, food is not expected to affect absorption of the drug, and the transdermal system may be applied without regard to meals.

Patients should be carefully instructed in the proper use and disposal of the rotigotine transdermal system.

The rotigotine transdermal system should be applied immediately after removal from its pouch and removal of the protective liner. The transdermal system should be applied 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. The application site should not be oily, irritated, or damaged. In addition, application to areas where the transdermal system could be rubbed by tight clothing or under a waistband and skin folds should be avoided.

If application of the transdermal system to a hairy area is necessary, the area at the application site should be shaved at least 3 days prior to application. Creams, lotions, oils, ointments, or powders should not be applied to the skin where the transdermal system will be placed.

The application site for the rotigotine transdermal system should be moved on a daily basis (i.e., from the right side to the left side, from the upper body to the lower body). The transdermal system should not be applied to the same application site more often than once every 14 days.

Each rotigotine transdermal system should be worn continuously for 24 hours. If a transdermal system should inadvertently come off during the period of use or if a patient forgets to change the patch, a new system should be applied for the remainder of the day; the patient should then change the patch the following day according to their regular time schedule. Patients who experience difficulty with patch adhesion should be advised that they may tape the edges of the system in place with bandage tape.

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

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

No dosing information is available for this tab.

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. In addition, rotigotine is metabolized by multiple sulfotransferases and uridine diphosphate-glucuronosyltransferases (UGT1A9 and UGT2B15); therefore, it is unlikely that inhibition of any one metabolic pathway would substantially alter rotigotine concentrations.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Dopamine Agonists/Selected Antiemetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome (RLS), and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at dopamine-2 (D2) receptors in the central nervous system (CNS). Antiemetic agents which block CNS D2 receptors may counteract this effect.(1-5)

CLINICAL EFFECTS: The efficacy of the dopamine agonist may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(5) Patients with other conditions such as restless legs syndrome may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade.

PATIENT MANAGEMENT: Reassess antiemetic therapy and use an antiemetic without dopamine (D2) blocking effects if possible. If clinically appropriate and available, consider the use of a 5HT3 blocker (e.g. ondansetron) or domperidone (not available in the US).(4) If concomitant treatment is needed, monitor for loss of efficacy for the disease being treated by the dopamine agonist (e.g. Parkinson disease, restless legs syndrome) and adjust medication(s) or dosage if needed.(1-4) Counsel patients to report symptoms of disease exacerbation.

DISCUSSION: Patients with Parkinson or DLB disease are particularly susceptible to adverse effects of dopamine blockade. The European Academy of Neurology guideline for late Parkinson disease states that metoclopramide, cinnarizine and prochlorperazine must be avoided. Ondansetron or domperidone(not available in the US) may be used for nausea and vomiting.(5) Prescribing information for dopamine agonists warn of the risk for disease exacerbation when dopamine blocking agents are co-prescribed.(1-4)

Selected Dopamine Agonists/Selected Antipsychotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)

Selected Dopaminergic Agents/Slt Antipsychotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopaminergic agents are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopaminergic agent. The US manufacturer of ropinirole recommends treatment with dopaminergic agents only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Dopamine Agonists/Select Atypical Antipsychotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated, e.g. Parkinson disease or a psychotic disorder. Dopamine agonists linked to this monograph are: bromocriptine, entacapone, levodopa, pergolide, pramipexole, ropinirole and rotigotine. Atypical antipsychotics linked to this monograph are: aripiprazole, asenapine, iloperidone, lumateperone, lurasidone, paliperidone, quetiapine, risperidone, ziprasidone and zotepine.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing, or stopping the dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic. They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7) Two clozapine trials showed significant improvement in psychosis without worsening of motor symptoms. In contrast, two olanzapine trials were associated with unacceptable worsening of motor symptoms. Risperidone has also been associated with motor worsening in case reports. Quetiapine evaluations have been conflicting with several small studies showing improvement in psychotic symptoms while a more rigorous trial showed no improvement.(6)

*Rotigotine is contraindicated in patients who are hypersensitive to the drug or to any components in the transdermal administration system.

• Magnetic resonance imaging

• Impulse control disorder
• Psychotic disorder

• Chronic heart failure
• Dyskinesia
• Edema
• Hypertension
• Orthostatic hypotension

In patients with early parkinson disease (not receiving concomitant levodopa), the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, insomnia, headache, fatigue, anxiety, peripheral edema, and dyspepsia.

In patients with advanced parkinson disease (receiving concomitant levodopa), the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were application site reactions, nausea, dyskinesia, dizziness, peripheral edema, insomnia, and hallucinations.

In patients with RLS, the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were application site reactions, nausea, somnolence, headache, and insomnia.

More Frequent

• Insomnia

Less Frequent

• Hallucinations
• Hypertension
• Hypotension
• Orthostatic hypotension
• Syncope
• Tachycardia

Rare or Very Rare

• Dropped head syndrome
• Drug-induced psychosis
• Dyskinesia
• Fibrotic drug-induced cardiac valvulopathy
• Heart failure
• Hypertonia
• Pleural effusions
• Purpura
• Rhabdomyolysis
• Skin burn caused by transdermal patch worn during MRI
• Sudden onset of sleep

More Frequent

• Dizziness
• Drowsy
• Erythema
• Headache disorder
• Nausea
• Pruritus of skin
• Skin irritation
• Sleep disorder
• Treatment site sequelae
• Vomiting

Less Frequent

• Anorexia
• Body fluid retention
• Dyspepsia
• Hyperhidrosis
• Myalgia
• Peripheral edema
• Skin inflammation
• Skin rash
• Weight gain
• Weight loss
• Xerostomia

Rare or Very Rare

• Acute cognitive impairment
• Back pain
• Constipation
• Impulse control disorder
• Paresthesia
• Urinary incontinence
• Visual changes

No enhanced messaging available.

Safety and efficacy of rotigotine in pediatric patients have not been established.

There are no adequate data on the developmental risks associated with the use of transdermal rotigotine in pregnant women. In animal studies, adverse developmental effects (e.g., delayed skeletal ossification, decreased fetal body weight, embryofetal death) were observed with subcutaneous administration of rotigotine at dosages similar to or lower than those used clinically.

Because rotigotine decreases prolactin secretion, the drug is expected to inhibit lactation.

Rotigotine and/or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk. The effects of rotigotine on the breast-fed infant or on milk production also are not known. The known benefits of breast-feeding should be considered along with the mother's clinical need for rotigotine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Of the patients with parkinson disease receiving transdermal rotigotine in clinical studies, approximately 50% were 65 years of age or older and approximately 11% were 75 years of age or older. Of the patients with restless legs syndrome receiving transdermal rotigotine in clinical studies, 26% were 65 years of age or older. No overall differences in safety or efficacy were observed between these geriatric patients and younger individuals. Other clinical experience has not revealed age-related differences in response; however, the possibility of greater sensitivity in some geriatric patients cannot be ruled out.

Geriatric patients with parkinson disease are at increased risk for hallucinations compared with younger individuals.

Plasma concentrations of rotigotine in patients 65-80 years of age were similar to those in younger adults (approximately 40-64 years of age). The manufacturer states that rotigotine exposures in older geriatric patients (exceeding 80 years of age) have not been studied, but may be higher because of the skin changes that occur with aging.