Patients with Parkinson's disease and restless legs syndrome are treated with rotigotine (Neupro), which comes as a transdermal patch. Parkinson's disease is a neurodegenerative condition brought on by a dopamine deficit in the substantia nigra. It manifests usually in older individuals with pill-rolling tremors, rigidity, and bradykinesia (slow to move). Restless legs syndrome is a condition in which individuals have an urge to move the legs (usually at night). This is often accompanied by an uncomfortable sensation. It is thought to have a genetic predisposition in most individuals. Other mechanisms include iron depletion in the central nervous system and dopaminergic dysfunction.

Rotigotine Uses:

• Parkinson disease:

  • Used for treating Parkinson's disease.

• Restless legs syndrome:

  • Also used to treat primary restless legs syndrome that ranges from mild to severe.

Rotigotine (Neupro) Dose in Adults

Rotigotine (Neupro) Dose in the treatment of Parkinson disease: Topical: Transdermal:

• Early-stage:

  • Initially, apply a 2 mg/24-hour patch once day; based on clinical response and tolerability, the dose may be increased by 2 mg/24-hours monthly;
  • The manufacturer has advised a maximum dose of 6 mg/24 hours; clinical trials have been conducted on higher doses [e.g., 8 mg/24 hours], however 4 mg/24 hours is the lowest effective amount.

• Advanced-stage:

  • Apply a 4 mg/24-hour patch once a day as a starting dose. Depending on the clinical response and tolerability, the dose may be increased by 2 mg/24-hours every other week.
  • The dosage is 8 milligrammes every 24 hours. Clinical investigations employed a maximal dose of up to 16 mg/24 hours.

• Discontinuation of treatment in Parkinson disease:

  • Reduce by no more than 2 mg/24 hours, ideally every other day, until withdrawal is complete.

Rotigotine (Neupro) Dose in the treatment of Restless legs syndrome (RLS): Topical: Transdermal:

• Initial: Apply 1 mg/24 hours patch once a day;
• The dose may be increased by 1 mg/24 hours weekly, based on clinical response and tolerability;
• 1 mg/24 hours is the lowest effective dose. The maximum dose is 3 mg/24 hours.

• Discontinuation of treatment for RLS:

  • Decrease by 1 mg/24 hours preferably every other day until complete withdrawal

Dose in Children:

Not indicated. 

Pregnancy Risk Category: C

• There is limited information available on the use of rotigotine during pregnancy.
• The use of rotigotine in expecting mothers with Parkinson's disease or restless legs syndrome is not advised by the published recommendations due to a lack of sufficient evidence.

Use while breastfeeding

• It is unknown if breast milk secretes rotigotine.
• It can cause a decrease of prolactin secretion, and possibly inhibit lactation.
• According to the manufacturer the decision to breastfeed during therapy should consider the risks to infants, the benefits to the mother and the benefits to the mother.

Dose in Kidney Disease:

• Mild-to-severe impairment (CrCl ≥15 mL/minute): Adjustment of dose is not required.
• End-stage renal disease (ESRD) requiring hemodialysis: Adjustment of dose is not required.

Dose in Liver disease:

• Mild-to-moderate hepatic impairment (Child-Pugh class A or B): Adjustment of dose is not required.
• Severe hepatic impairment: The manufacturer's labelling does not mention dosage modifications (has not been studied).

Common Side Effects of Rotigotine (Neupro):

• Cardiovascular:

  • Systolic Hypotension
  • Orthostatic Hypotension
  • Peripheral Edema

• Central Nervous System:

  • Drowsiness
  • Dizziness
  • Headache
  • Fatigue
  • Malaise
  • Sleep Disorder
  • Hallucination

• Dermatologic:

  • Hyperhidrosis

• Endocrine & Metabolic:

  • Decreased Serum Glucose

• Gastrointestinal:

  • Nausea
  • Vomiting

• Hematologic & Oncologic:

  • Decreased Hematocrit
  • Decreased Hemoglobin

• Local:

  • Application Site Reaction

• Neuromuscular & Skeletal:

  • Dyskinesia
  • Asthenia
  • Arthralgia

Less Common Side Effects of Rotigotine (Neupro):

• Cardiovascular:

  • Increased Diastolic Blood Pressure
  • Systolic Hypertension
  • Hypertension
  • Atrioventricular Block
  • Hypoesthesia
  • Abnormal T Waves On ECG

• Central Nervous System:

  • Abnormal Dreams
  • Nightmares
  • Paresthesia
  • Vertigo
  • Depression
  • Equilibrium Disturbance
  • Irritability
  • Sudden Onset Of Sleep

• Dermatologic:

  • Pruritus
  • Erythema

• Endocrine & Metabolic:

  • Weight Gain
  • Change In Libido
  • Hot Flash
  • Low Serum Ferritin
  • Menstrual Disease

• Gastrointestinal:

  • Constipation
  • Anorexia
  • Xerostomia
  • Diarrhea
  • Dyspepsia
  • Viral Gastroenteritis

• Hematologic & Oncologic:

  • Basal Cell Carcinoma
  • Leukocyturia

• Infection:

  • Herpes Simplex Infection
  • Influenza

• Neuromuscular & Skeletal:

  • Tremor
  • Muscle Spasm

• Ophthalmic:

  • Visual Disturbance

• Otic:

  • Tinnitus

• Renal:

  • Increased Blood Urea Nitrogen

• Respiratory:

  • Nasopharyngitis
  • Cough
  • Nasal Congestion
  • Paranasal Sinus Congestion
  • Sinusitis

Contraindications to Rotigotine (Neupro):

• Hypersensitivity to rotigotine and any other component of the formulation

Warnings and precautions

• Reactions at the application site:

  • Potentially severe dose-dependent reactions have been observed at the application site.
  • It has been demonstrated that daily application site rotation reduces the frequency of reactions.
  • Treatment should be halted if there is a significant, non-application site reaction.

• Fibrosis

  • Rare reports of patients taking ergot-derived dopamine antagonists developing pleural effusion, thickening, retroperitoneal fibrisis, pericarditis, and/or cardiac valveopathy have been made.
  • It is not known if rotigotine (a non-ergot-derived dopamine antagonist) could cause similar fibrotic complications.
  • Sometimes, complications can be treated with therapy discontinuation. However, this is not always possible.

• Fluid retention

  • There have been reports of fluid retention and weight gain that is primarily related to the development in Parkinson's patients.

• Hallucinations, psychotic-like behavior and hallucinations:

  • Use may cause hallucinations and other psychotic-like behavior 
  • Patients with major psychotic disorders should avoid its use.

• Disorders of impulse control:

  • A loss of impulse control and/or obsessive behaviour may be brought on by dopamine agonists. Pathological gambling, increased libido (hypersexuality), and/or binge eating are some possible symptoms.
  • It is not clear if the cause of this phenomenon is causation.
  • These behaviors can be reversed by reducing or stopping therapy, according to reports. However, not all cases are affected.

• Melanoma

  • Those who have Parkinson's disease are more likely to get melanoma.
  • However, it is not known if there is a drug causality or other factors that contribute to the risk.
  • Monitor patients receiving any type of therapy closely and conduct periodic skin checks.

• Orthostatic hypotension

  • Parkinson's patients are less able to respond to postural difficulties, and dopamine agonists can result in orthostatic hypotension or syncope.
  • Patients at high risk for hypotension (such patients who are taking antihypertensive medications) and those with low tolerance to transient hypotensive episodes (cardiovascular disease, cerebrovascular disease) should be used with caution.
  • Parkinson's and RLS patients who are being treated with dopaminergic antagonists should be monitored for signs and symptoms such as postural hypotension. This is especially true if the dose is increased.

• Somnolence

  • It is common to experience somnolence when you use it..
  • However, without any prior notice, people have been known to nod off while engaging in routine activities like driving.
  • Daytime somnolence and pre-existing sleep disorders should be monitored.
  • Patients should be aware that driving or operating machinery requires mental alertness.
  • This medication should not be used by patients who are also taking other CNS depressants or psychotropic medications. Stop using if you suffer severe daytime tiredness or instances of falling asleep.
  • Sedative medications and ethanol may intensify the symptoms.

• Cardiovascular disease

  • Patients with pre-existing heart disease should exercise caution because the therapy can result in significant blood pressure increases (as well as orthostatic hypotension; an increase of >40 mm Hg or >=20 mm Hg in diastolic or systolic measurements, respectively), an increase in heart rate, syncope, and weight gain or fluid retention.

• Dyskinesia

  • Patients with dyskinesia should be cautious as the therapy could cause or exacerbate dyskinesia.

Rotigotine: Drug Interaction

Monitoring parameters:

• Blood pressure (including orthostatic)
• Daytime alertness;
• Skin evaluations, periodically (melanoma development)

How to administer Rotigotine?

Transdermal patch

• Use the patch every day to parts of the abdomen, hips, flank, shoulder, and upper arms with dry, hairless, intact, healthy skin. Remove the patch from its pouch before applying it to the skin, and press it there for around 30 seconds.
• Every day, switch up the application sites.
• Applying to the same website more than once in a 14-day period is not advised.
• Avoid exposing the patch to heat sources including hot tubs, electric blankets, heating pads, heat lamps, and direct sunlight.
• At least three days should pass after shaving the region before placing the patch.
• If the patch is not well attached, any part that comes off should be patched over right away.

Mechanism of action of Rotigotine:

• It acts as a non-ergot D1, D2 and D3 dopamine agonist. 
• It is unknown what causes rotigotine to act.
• However, stimulation of D2 autoreceptors in the brain's substantianigra results in enhanced dopaminergic transmission in motor areas of basal ganglia.

Protein binding: Almost 90%

Metabolism: Extensively metabolised via N-dealkylation and conjugation; metabolism is carried out by two UDP-glucuronosyltransferases and a number of CYP isoenzymes.

Half-life elimination: ~5 to 7 hours after removal of the patch

Time to peak, plasma: 15 to 18 hours; can occur 4 to 27 hours post application

Excretion:

• Urine (almost 71% as inactive conjugates and metabolites, <1% as unchanged drug)
• Feces (almost 23%)

International Brand Names of Rotigotine:

• Neupro
• Leganto
• Nubrenza

Rotigotine Brand Names in Pakistan:

No Brands Available in Pakistan.