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Special Alerts
Risperidone and Ropinirole: Sound-Alike/Look-Alike Alert
June 2011
The U.S. Food and Drug Administration (FDA) issued a statement alerting healthcare practitioners and patients to the potential for medication errors when prescribing and dispensing risperidone (Risperdal®) or ropinirole (Requip®) due to product similarities. Errors have occurred when patients have received the incorrect medication. In some cases the error has lead to patient hospitalization. Confusion between the products includes sound-alike/look-alike characteristics of both the brand and generic names, similarities in container labeling and carton package, illegible handwriting on written prescriptions, and overlapping dosage strengths, forms, and intervals.
The FDA has requested that the manufacturers use “tall man” lettering on container labels and packaging for both brand and generic products. In addition, the FDA has requested that the generic manufacturers change labels and packaging to provide additional visual differentiation between the products.
Healthcare professionals are encouraged to clearly print prescriptions, spell drug name when prescribing over the telephone, provide the medical indication on the prescription, and separate storage of risperidone and ropinirole.
Patients should be counseled on the purpose of their medication and be encouraged to check the name of the medication and appearance of the tablets every time the medication is filled. Patients should talk to their pharmacist or other healthcare professional with any questions.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258905.htm
Pronunciation
(roe PIN i role)
Generic Available (U.S.)
Yes: Excludes combination package, extended-release tablets
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of idiopathic Parkinson's disease; in patients with early Parkinson's disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa; treatment of moderate-to-severe primary Restless Legs Syndrome (RLS)
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects have been observed in animal studies. There are no adequate and well-controlled studies in pregnant women; use only if potential benefit outweighs the risk to the fetus.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Ropinirole inhibits prolactin secretion in humans and may potentially inhibit lactation. It is not known if ropinirole is excreted into breast milk. Due to the potential for serious adverse reactions, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Contraindications
Hypersensitivity to ropinirole or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Hallucinations: May cause hallucinations (dose dependent); risk may be increased in the elderly.
• Impulse control disorders: Dopamine agonists used for Parkinson's 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 should be monitored closely and periodic skin examinations should be performed.
• Orthostatic hypotension: May cause orthostatic hypotension; 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 or antiarrhythmic drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson's 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. Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both early Parkinson's disease (without levodopa) patients and advanced Parkinson's disease (with levodopa) patients.
• Pleural/retroperitoneal fibrosis: Risk of fibrotic complications (eg, pleural effusion/fibrosis, interstitial lung disease) has been reported in patients receiving ropinirole; drug causation has not been established.
• Retinal changes: Pathologic degenerative changes were observed in the retinas of albino rats during studies with this agent, but were not observed in the retinas of albino mice or in other species. The significance of these data for humans remains uncertain.
• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs. Monitor for daytime somnolence or pre-existing sleep disorder; caution with concomitant sedating medication; discontinue if significant daytime sleepiness or episodes of falling asleep occur. 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. Effects with other sedative drugs or ethanol may be potentiated.
Disease-related concerns:
• Dyskinesias: Use with caution in patients with pre-existing dyskinesias; may be exacerbated.
• Hepatic impairment: Use in hepatic impairment has not been studied; use with caution.
• Psychotic disorders: Avoid use in patients with a major psychotic disorder; may exacerbate psychosis.
• Renal impairment: Use in severe renal impairment (Clcr <30 mL/minute) has not been studied; use with caution. Note: The Canadian labeling recommends to avoid use in patients with severe renal impairment and who are not undergoing regular hemodialysis.
• Restless legs syndrome (RLS): Augmentation (earlier onset of symptoms in the evening/afternoon, increase and/or spread of symptoms to other extremities) or rebound (shifting of symptoms to early morning hours) may occur in some RLS patients.
Other warnings/precautions:
• Discontinuation of therapy: Dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal or significant dosage reduction after long-term use.
Adverse Reactions
Data inclusive of trials in early Parkinson's disease (without levodopa) and Restless Legs Syndrome:
>10%:
Cardiovascular: Syncope (1% to 12%)
Central nervous system: Somnolence (11% to 40%), dizziness (6% to 40%), fatigue (8% to 11%)
Gastrointestinal: Nausea (immediate release: 40% to 60%; extended release: 19%), vomiting (11% to 12%)
Miscellaneous: Viral infection (11%)
1% to 10%:
Cardiovascular: Dependent/leg edema (2% to 7%), orthostasis (1% to 6%), hypertension (5%), chest pain (4%), flushing (3%), palpitation (3%), peripheral ischemia (2% to 3%), atrial fibrillation (2%), extrasystoles (2%), hypotension (2%), tachycardia (2%)
Central nervous system: Pain (3% to 8%), headache (extended release: 6%), confusion (5%), hallucinations (up to 5%; dose related), hypoesthesia (4%), amnesia (3%), malaise (3%), yawning (3%), concentration impaired (2%), vertigo (2%)
Dermatologic: Hyperhidrosis (3%)
Gastrointestinal: Dyspepsia (4% to 10%), abdominal pain (3% to 7%), constipation (≥5%), xerostomia (3% to 5%), diarrhea (5%), anorexia (4%), flatulence (3%)
Genitourinary: Urinary tract infection (5%), impotence (3%)
Hepatic: Alkaline phosphatase increased (3%)
Neuromuscular & skeletal: Weakness (6%), arthralgia (4%), muscle cramps (3%), paresthesia (3%), hyperkinesia (2%)
Ocular: Abnormal vision (6%), xerophthalmia (2%)
Respiratory: Pharyngitis (6% to 9%), rhinitis (4%), sinusitis (4%), bronchitis (3%), dyspnea (3%), influenza (3%), cough (3%), nasal congestion (2%)
Miscellaneous: Diaphoresis increased (3% to 6%)
Advanced Parkinson's disease (with levodopa):
>10%:
Central nervous system: Dizziness (immediate release: 26%; extended-release: 8%), somnolence (immediate release: 20%, extended release: 7%), headache (17%)
Gastrointestinal: Nausea (immediate release: 30%; extended-release: 11%)
Neuromuscular & skeletal: Dyskinesias (immediate release: 34%; extended-release: 13%; dose related)
1% to 10%:
Cardiovascular: Hypotension (2% to 5%; including orthostatic), peripheral edema (4%), syncope (3%), hypertension (3%; dose related)
Central nervous system: Hallucinations (7% to 10%; dose related), confusion (9%), anxiety (2% to 6%), amnesia (5%), nervousness (5%), pain (5%), vertigo (4%), abnormal dreaming (3%), paresis (3%), aggravated parkinsonism, insomnia
Gastrointestinal: Abdominal pain (6% to 9%), vomiting (7%), constipation (4% to 6%), diarrhea (3% to 5%), xerostomia (2% to 5%), dysphagia (2%), flatulence (2%), salivation increased (2%), weight loss (2%)
Genitourinary: Urinary tract infection (6%), pyuria (2%), urinary incontinence (2%)
Hematologic: Anemia (2%)
Neuromuscular & skeletal: Falls (2% to 10%; dose related), arthralgia (7%), tremor (6%), hypokinesia (5%), paresthesia (5%), arthritis (3%), back pain (3%)
Ocular: Diplopia (2%)
Respiratory: Upper respiratory tract infection (9%), dyspnea (3%)
Miscellaneous: Injury, diaphoresis increased (7%), viral infection, increased drug level (7%)
Other adverse effects (all phase 2/3 trials for Parkinson's disease and Restless Leg Syndrome):
≥1%: Asthma, BUN increased, depression, gastroenteritis, gastrointestinal reflux, irritability, migraine, muscle spasm, myalgia, neck pain, neuralgia, osteoarthritis, pharyngolaryngeal pain, rash, rigors, sleep disorder, tendonitis
<1% (Limited to important or life-threatening): Abnormal coordination, acidosis, agitation, aneurysm, angina, aphasia, behavioral disorders, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiomegaly, cellulitis, cholecystitis, cholelithiasis, choreoathetosis, colitis, coma, conjunctival hemorrhage, dehydration, diabetes mellitus, diverticulitis, Dupuytren's contracture, dysphonia, electrolyte disturbances, eosinophilia, extrapyramidal symptoms, gangrene, gastrointestinal hemorrhage, gastrointestinal ulceration, glaucoma, goiter, gynecomastia, hematuria, hemiparesis, hemiplegia, hepatitis (ischemic), hyperbilirubinemia, hypercholesterolemia, hyper-/hypothyroidism, hyper-/hypotonia, hypoglycemia, hyponatremia, hyperphosphatemia, hyperuricemia; infections (bacterial, viral, or fungal); intestinal obstruction, leukocytosis, leukopenia, limb embolism, liver enzymes increased, lymphadenopathy, lymphedema, lymphocytosis, lymphopenia, menstrual abnormalities, mitral insufficiency, MI, neoplasms (various), pancreatitis, paralysis, peripheral neuropathy, photosensitivity, pleural effusion, proteinuria, psychiatric disorders, pulmonary edema, pulmonary embolism, renal calculus, renal failure (acute), seizure, sepsis, SIADH, skin disorders, stomatitis, stupor, subarachnoid hemorrhage, suicide attempt, SVT, thrombocytopenia, thrombosis, tinnitus, tongue edema, torticollis, urticaria, vagina/uterine hemorrhage, ventricular tachycardia, visual disturbances
Postmarketing and/or case reports: Cardiac valvulopathy, delusion, delirium, hypersensitivity reactions (angioedema, pruritus), impulsive/compulsive behaviors (eg, pathological gambling, hypersexuality, binge eating), interstitial lung disease, paranoia, pleural fibrosis
Metabolism/Transport Effects
Substrate of CYP1A2 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2D6 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Antipsychotics (Atypical): May diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification
Antipsychotics (Typical): Anti-Parkinson's Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotics (Typical). Antipsychotics (Typical) may enhance the therapeutic effect of Anti-Parkinson's 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's agents. Risk D: Consider therapy modification
Ciprofloxacin: May decrease the metabolism of ROPINIRole. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May decrease the metabolism of ROPINIRole. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Estrogen Derivatives: May increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk C: Monitor therapy
Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Herb/Nutraceutical: Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).
Storage
Store at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from light.
Mechanism of Action
Ropinirole has a high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes; relevance of D3 receptor binding in Parkinson's disease is unknown. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and beta-adrenoreceptors. Although precise mechanism of action of ropinirole is unknown, it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate putamen in the brain. Ropinirole caused decreases in systolic and diastolic blood pressure at doses >0.25 mg. The mechanism of ropinirole-induced postural hypotension is believed to be due to D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance.
Pharmacodynamics/Kinetics
Absorption: Not affected by food
Distribution: Vd: 525 L
Protein binding: 40%
Metabolism: Extensively hepatic via CYP1A2 to inactive metabolites; first-pass effect
Bioavailability: Absolute: 45% to 55%
Half-life elimination: ~6 hours
Time to peak: Immediate release: ~1-2 hours; Extended release: 6-10 hours; Tmax increased by 2.5-3 hours when drug taken with food
Excretion: Urine (<10% as unchanged drug, 60% as metabolites)
Clearance: Reduced by 15% to 30% in patients >65 years of age
Dosage
Oral: Adults:
Parkinson's disease:
Immediate release tablet: The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence and dyskinesia. Recommended starting dose is 0.25 mg 3 times/day; based on individual patient response, the dosage should be titrated with weekly increments as described below:
• Week 1: 0.25 mg 3 times/day; total daily dose: 0.75 mg
• Week 2: 0.5 mg 3 times/day; total daily dose: 1.5 mg
• Week 3: 0.75 mg 3 times/day; total daily dose: 2.25 mg
• Week 4: 1 mg 3 times/day; total daily dose: 3 mg
Note: After week 4, if necessary, daily dosage may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total of 24 mg/day
Parkinson's disease discontinuation taper: Ropinirole should be gradually tapered over 7 days as follows: reduce frequency of administration from 3 times daily to twice daily for 4 days, then reduce to once daily for remaining 3 days.
Extended release tablet: Initial: 2 mg once daily for 1-2 weeks, followed by increases of 2 mg/day at weekly or longer intervals based on therapeutic response and tolerability (maximum: 24 mg/day); Note: When discontinuing gradually taper over 7 days.
Restless legs syndrome: Immediate release tablets: Initial: 0.25 mg once daily 1-3 hours before bedtime. Dose may be increased after 2 days to 0.5 mg daily, and after 7 days to 1 mg daily. Dose may be further titrated upward in 0.5 mg increments every week until reaching a daily dose of 3 mg during week 6. If symptoms persist or reappear, the daily dose may be increased to a maximum of 4 mg beginning week 7.
Note: Doses up to 4 mg per day may be discontinued without tapering.
Converting from ropinirole immediate release tablets to ropinirole extended-release tablets: Choose a once daily extended-release dose that most closely matches current immediate-release daily dose.
Elderly: Clearance is reduced; however, no dosage adjustment necessary. Titrate dose to clinical response. Refer to adult dosing.
Dosage adjustment in renal impairment:
Moderate renal impairment (Clcr 30-50 mL/minute): No adjustment needed
Severe renal impairment (Clcr <30 mL/minute): Use with caution; has not been studied in this patient population. Note: The Canadian labeling recommends to avoid use in patients with severe renal impairment and who are not undergoing regular hemodialysis.
Hemodialysis: Canadian labeling (not in U.S. labeling): Initial: 0.25 mg 3 times daily; may titrate dose upward based on tolerability and efficacy (maximum dose: 18 mg/day); postdialysis supplemental doses are not required
Dosage adjustment in hepatic impairment: Titrate with caution; has not been studied.
Administration: Oral
May be administered without regard to meals; taking with food may reduce nausea. Swallow extended-release tablet whole; do not crush, split, or chew.
Monitoring Parameters
Blood pressure (orthostatic); daytime alertness
Dietary Considerations
May be taken without regard to meals; taking with food may reduce nausea.
Patient Education
Take without regard to food. Avoid alcohol. May cause dizziness; sudden, overwhelming sleepiness; postural hypotension; loss of impulse control (possibly manifested as pathological gambling, libido increases, and/or binge eating); nausea; vomiting; lack of appetite; or mouth sores. Report unusual and persistent sleepiness, chest pain or palpitations, CNS changes (confusion, hallucinations, amnesia, abnormal dreaming, insomnia), suicide ideation, skeletal weakness or increased random tremors or movements, gait changes or difficulty walking, signs of urinary tract or respiratory infection (pain or burning on urination, pus or blood in urine, or unusual cough and chest tightness), changes in the appearance of skin moles, or other unusual skin changes.
Geriatric Considerations
Since the dose is titrated to clinical response, no specific dosage adjustment is necessary in the elderly.
Additional Information
If therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of ropinirole dose may be required. Ropinirole binds to melanin-containing tissues (ie, eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days; not known if ropinirole accumulates in these tissues over time.
Anesthesia and Critical Care Concerns/Other Considerations
If therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of ropinirole dose may be required.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia and increased salivation (normal salivary flow resumes upon discontinuation) and dysphagia.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Nursing: Physical Assessment/Monitoring
Monitor blood pressure periodically. Monitor for CNS depression/somnolence.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg
Requip®: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg
Tablet, extended release, oral:
Requip® XL™: 2 mg, 4 mg, 6 mg, 8 mg, 12 mg
Pricing: U.S. (www.drugstore.com)
Tablet, 24-hour (Requip XL)
4 mg (90): $460.01
8 mg (30): $249.99
12 mg (30): $390.01
Tablets (Requip)
0.25 mg (90): $291.99
0.5 mg (90): $305.98
1 mg (90): $291.99
2 mg (90): $291.99
3 mg (90): $302.00
4 mg (90): $306.98
5 mg (90): $302.00
Tablets (Ropinirole HCl)
0.25 mg (100): $59.99
Tablets (ROPINIRole HCl)
0.5 mg (100): $54.99
1 mg (100): $109.98
2 mg (100): $82.00
Tablets (Ropinirole HCl)
3 mg (100): $79.99
4 mg (100): $79.99
5 mg (100): $65.98
References
Factor SA, “Current Status of Symptomatic Medical Therapy in Parkinson's Disease,” Neurotherapeutics, 2008, 5(2):164-80.
Happe S, Sauter C, Klosch G, et al, “Gabapentin Versus Ropinirole in the Treatment of Idiopathic Restless Legs Syndrome,” Neuropsychobiology, 2003, 48(2):82-6.
Molina JA, Sàinz-Artiga MJ, Fraile A, et al, “Pathologic Gambling in Parkinson's Disease: A Behavioral Manifestation of Pharmacologic Treatment,” Mov Disord, 2000, 15(5):869-72.
Olanow CW, Watts RL, and Koller WC, “An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines,” Neurology, 2001, 56(11 Suppl 5):1-88.
Saletu M, Anderer P, Saletu-Zyhlarz GM, et al, “Comparative Placebo-Controlled Polysomnographic and Psychometric Studies on the Acute Effects of Gabapentin Versus Ropinirole in Restless Legs Syndrome,”J Neural Transm, 2010, 117(4):463-73.
Stern MB, “Contemporary Approaches to the Pharmacotherapeutic Management of Parkinson's Disease: An Overview,” Neurology, 1997, 49(1 Suppl 1):2-9.
Watts RL, “The Role of Dopamine Agonists in Early Parkinson's Disease,” Neurology, 1997, 49(1 Suppl 1):34-48.
Weintraub D, Siderowf AD, Potenza MN, et al, “Association of Dopamine Agonist Use With Impulse Control Disorders in Parkinson Disease,” Arch Neurol, 2006, 63(7):969-73.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2011
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