Ropinirole hydrochloride
DRUG DESCRIPTION
REQUIP (ropinirole hydrochloride) is an orally administered non-ergoline dopamine agonist. It is the hydrochloride salt of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochloride and has an empirical formula of C16H24N2O•HCl. The molecular weight is 296.84 (260.38 as the free base).
Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.
Each pentagonal film-coated TILTAB® tablet with beveled edges contains ropinirole hydrochloride equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of: croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.
INDICATIONS
Parkinson's Disease
REQUIP is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.
The effectiveness of REQUIP was demonstrated in randomized, controlled trials in patients with early Parkinson's disease who were not receiving concomitant L-dopa therapy as well as in patients with advanced disease on concomitant L-dopa (see CLINICAL PHARMACOLOGY: Clinical Trials).
Restless Legs Syndrome
REQUIP is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).
Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with moderate-to-severe RLS.
DOSAGE AND ADMINISTRATION
General Dosing Considerations for Parkinson's Disease and RLS
REQUIP can be taken with or without food. Patients may be advised that taking REQUIP with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials.
If a significant interruption in therapy with REQUIP has occurred, retitration of therapy may be warranted.
Geriatric Use: Pharmacokinetic studies demonstrated a reduced clearance of ropinirole in the elderly (see CLINICAL PHARMACOLOGY). Dose adjustment is not necessary since the dose is individually titrated to clinical response.
Renal Impairment: The pharmacokinetics of ropinirole were not altered in patients with moderate renal impairment (see CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is necessary in patients with moderate renal impairment. The use of REQUIP in patients with severe renal impairment has not been studied.
Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Since patients with hepatic impairment may have higher plasma levels and lower clearance, REQUIP should be titrated with caution in these patients.
Dosing for Parkinson's Disease
In all clinical studies, dosage was initiated at a subtherapeutic level and gradually titrated to therapeutic response. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence, and dyskinesia.
The recommended starting dose for Parkinson's disease is 0.25 mg 3 times daily. Based on individual patient response, dosage should then be titrated with weekly increments as described in Table 5. 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 dose of 24 mg/day. Doses greater than 24 mg/day have not been tested in clinical trials.
Table 5. Ascending-Dose Schedule of REQUIP for Parkinson's DiseaseWeek Dosage Total Daily Dose
1 0.25 mg 3 times daily 0.75 mg
2 0.5 mg 3 times daily 1.5 mg
3 0.75 mg 3 times daily 2.25 mg
4 1 mg 3 times daily 3 mg
When REQUIP is administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. L-dopa dosage reduction was allowed during the advanced Parkinson's disease (with L-dopa) study if dyskinesias or other dopaminergic effects occurred. Overall, reduction of L-dopa dose was sustained in 87% of patients treated with REQUIP and in 57% of patients on placebo. On average the L-dopa dose was reduced by 31% in patients treated with REQUIP.
REQUIP for Parkinson's disease patients should be discontinued gradually over a 7-day period. The frequency of administration should be reduced from 3 times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of REQUIP.
Dosing for Restless Legs Syndrome
In all clinical trials, the dose for REQUIP was initiated at 0.25 mg once daily, 1 to 3 hours before bedtime. Patients were titrated based on clinical response and tolerability.
The recommended adult starting dosage for RLS is 0.25 mg once daily, 1 to 3 hours before bedtime. After 2 days, the dosage can be increased to 0.5 mg once daily and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 6 as needed to achieve efficacy. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.
Table 6. Dose Titration Schedule for RLSDay/Week Dosage to be taken once daily, 1 to 3 hours before bedtime
Days 1 and 2 0.25 mg
Days 3-7 0.5 mg
Week 2 1 mg
Week 3 1.5 mg
Week 4 2 mg
Week 5 2.5 mg
Week 6 3 mg
Week 7 4 mg
In clinical trials of patients being treated for RLS with doses up to 4 mg once daily, REQUIP was discontinued without a taper.
SIDE EFFECTS
Parkinson's Disease
During the premarketing development of REQUIP, patients received REQUIP either without L-dopa (early Parkinson's disease studies) or as concomitant therapy with L-dopa (advanced Parkinson's disease studies). Because these 2 populations may have differential risks for various adverse events, this section will, in general, present adverse event data for these 2 populations separately.
Early Parkinson's Disease (Without L-dopa): The most commonly observed adverse events ( > 5%) in the double-blind, placebo-controlled early Parkinson's disease trials associated with the use of REQUIP (n = 157) not seen at an equivalent frequency among the placebo-treated patients (n = 147) were, in order of decreasing incidence: nausea, dizziness, somnolence, headache, vomiting, syncope, fatigue, dyspepsia, viral infection, constipation, pain, increased sweating, asthenia, dependent/leg edema, orthostatic symptoms, abdominal pain, pharyngitis, confusion, hallucinations, urinary tract infections, and abnormal vision.
Approximately 24% of 157 patients treated with REQUIP who participated in the double-blind, placebo-controlled early Parkinson's disease (without L-dopa) trials discontinued treatment due to adverse events compared to 13% of 147 patients who received placebo. The adverse events most commonly causing discontinuation of treatment by patients treated with REQUIP were: nausea (6.4%), dizziness (3.8%), aggravated Parkinson's disease (1.3%), hallucinations (1.3%), somnolence (1.3%), vomiting (1.3%), and headache (1.3%). Of these, hallucinations appear to be dose-related. While other adverse events leading to discontinuation may be dose-related, the titration design utilized in these trials precluded an adequate assessment of the dose response. For example, in the larger of the 2 trials described in CLINICAL PHARMACOLOGY: Clinical Trials, the difference in the rate of discontinuations emerged only after 10 weeks of treatment, suggesting, although not proving, that the effect could be related to dose.
Adverse Event Incidence in Controlled Clinical Studies: Table 2 lists treatment-emergent adverse events that occurred in ? 2% of patients with early Parkinson's disease (without L-dopa) treated with REQUIP participating in the double-blind, placebo-controlled studies and were numerically more common in the group treated with REQUIP. In these studies, either REQUIP or placebo was used as early therapy (i.e., without L-dopa).
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse-events incidence rate in the population studied.
Table 2. Treatment-Emergent Adverse Event* Incidence in Double-Blind, Placebo-Controlled Early Parkinson's Disease (Without L-dopa) Trials (Events ? 2% of Patients Treated With REQUIP and Numerically More Frequent Than the Placebo Group)Adverse Experience REQUIP
(n = 157)
(%) Placebo
(n = 147)
(%)
Autonomic nervous system
Flushing 3 1
Dry mouth 5 3
Increased sweating 6 4
Body as a whole
Asthenia 6 1
Chest pain 4 2
Dependent edema 6 3
Leg edema 7 1
Fatigue 11 4
Malaise 3 1
Pain 8 4
Cardiovascular general
Hypertension 5 3
Hypotension 2 0
Orthostatic symptoms 6 5
Syncope 12 1
Central/peripheral nervous system
Dizziness 40 22
Hyperkinesia 2 1
Hypesthesia 4 2
Vertigo 2 0
Gastrointestinal system
Abdominal pain 6 3
Anorexia 4 1
Dyspepsia 10 5
Flatulence 3 1
Nausea 60 22
Vomiting 12 7
Heart rate/rhythm
Extrasystoles 2 1
Atrial fibrillation 2 0
Palpitation 3 2
Tachycardia 2 0
Metabolic/nutritional
Increased alkaline phosphatase 3 1
Psychiatric
Amnesia 3 1
Impaired concentration 2 0
Confusion 5 1
Hallucination 5 1
Somnolence 40 6
Yawning 3 0
Reproductive male
Impotence 3 1
Resistance mechanism
Viral infection 11 3
Respiratory system
Bronchitis 3 1
Dyspnea 3 0
Pharyngitis 6 4
Rhinitis 4 3
Sinusitis 4 3
Urinary system
Urinary tract infection 5 4
Vascular extracardiac
Peripheral ischemia 3 0
Vision
Eye abnormality 3 1
Abnormal vision 6 3
Xerophthalmia 2 0
* Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
Other events reported by 1% or more of early Parkinson's disease (without L-dopa) patients treated with REQUIP, but that were equally or more frequent in the placebo group, were: headache, upper respiratory infection, insomnia, arthralgia, tremor, back pain, anxiety, dyskinesias, aggravated Parkinsonism, depression, falls, myalgia, leg cramps, paresthesias, nervousness, diarrhea, arthritis, hot flushes, weight loss, rash, cough, hyperglycemia, muscle spasm, arthrosis, abnormal dreams, dystonia, increased salivation, bradycardia, gout, basal cell carcinoma, gingivitis, hematuria, and rigors.
Among the treatment-emergent adverse events in patients treated with REQUIP, hallucinations appear to be dose-related.
The incidence of adverse events was not materially different between women and men.
Advanced Parkinson's Disease (With L-dopa): The most commonly observed adverse events ( > 5%), in the double-blind, placebo-controlled advanced Parkinson's disease (with L-dopa) trials associated with the use of REQUIP (n = 208) as an adjunct to L-dopa not seen at an equivalent frequency among the placebo-treated patients (n = 120) were, in order of decreasing incidence: dyskinesias, nausea, dizziness, aggravated Parkinsonism, somnolence, headache, insomnia, injury, hallucinations, falls, abdominal pain, upper respiratory infection, confusion, increased sweating, vomiting, viral infection, increased drug level, arthralgia, tremor, anxiety, urinary tract infection, constipation, dry mouth, pain, hypokinesia, and paresthesia.
Approximately 24% of 208 patients who received REQUIP in the double-blind, placebo-controlled advanced Parkinson's disease (with L-dopa) trials discontinued treatment due to adverse events compared to 18% of 120 patients who received placebo. The events most commonly ( ? 1%) causing discontinuation of treatment by patients treated with REQUIP were: dizziness (2.9%), dyskinesias (2.4%), vomiting (2.4%), confusion (2.4%), nausea (1.9%), hallucinations (1.9%), anxiety (1.9%), and increased sweating (1.4%). Of these, hallucinations and dyskinesias appear to be dose-related.
Adverse Event Incidence in Controlled Clinical Studies: Table 3 lists treatment-emergent adverse events that occurred in ? 2% of patients with advanced Parkinson's disease (with L-dopa) treated with REQUIP who participated in the double-blind, placebo-controlled studies and were numerically more common in the group treated with REQUIP. In these studies, either REQUIP or placebo was used as an adjunct to L-dopa. Adverse events were usually mild or moderate in intensity.
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse events incidence rate in the population studied.
Table 3. Treatment-Emergent Adverse Event* Incidence in Double-Blind, Placebo-Controlled Advanced Parkinson's Disease (With L-dopa) Trials (Events ? 2% of Patients Treated With REQUIP and Numerically More Frequent Than the Placebo Group)Adverse Experience REQUIP
(n = 208)
(%) Placebo
(n = 120)
(%)
Autonomic nervous system
Dry mouth 5 1
Increased sweating 7 2
Body as a whole
Increased drug level 7 3
Pain 5 3
Cardiovascular general
Hypotension 2 1
Syncope 3 2
Central/peripheral nervous system
Dizziness 26 16
Dyskinesia 34 13
Falls 10 7
Headache 17 12
Hypokinesia 5 4
Paresis 3 0
Paresthesia 5 3
Tremor 6 3
Gastrointestinal system
Abdominal pain 9 8
Constipation 6 3
Diarrhea 5 3
Dysphagia 2 1
Flatulence 2 1
Nausea 30 18
Increased saliva 2 1
Vomiting 7 4
Metabolic/nutritional
Weight decrease 2 1
Musculoskeletal system
Arthralgia 7 5
Arthritis 3 1
Psychiatric
Amnesia 5 1
Anxiety 6 3
Confusion 9 2
Abnormal dreaming 3 2
Hallucinations 10 4
Nervousness 5 3
Somnolence 20 8
Red blood cell
Anemia 2 0
Resistance mechanism
Upper respiratory tract infection 9 8
Respiratory system
Dyspnea 3 2
Urinary system
Pyuria 2 1
Urinary incontinence 2 1
Urinary tract infection 6 3
Vision
Diplopia 2 1
* Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
Other events reported by 1% or more of patients treated with both REQUIP and L-dopa, but equally or more frequent in the placebo/L-dopa group, were: myocardial infarction, orthostatic symptoms, virus infections, asthenia, dyspepsia, myalgia, back pain, depression, leg cramps, fatigue, rhinitis, chest pain, hematuria, vertigo, tinnitus, leg edema, hot flushes, abnormal gait, hyperkinesia, and pharyngitis.
Among the treatment-emergent adverse events in patients treated with REQUIP, hallucinations and dyskinesias appear to be dose-related.
Restless Legs Syndrome
The most commonly observed adverse events ( > 5%) in the 12-week double-blind, placebo-controlled trials in the treatment of Restless Legs Syndrome with REQUIP (n = 496) and at least twice the rate for placebo-treated patients (n = 500) were, in order of decreasing incidence: nausea, somnolence, vomiting, dizziness, and fatigue (see Table 4). Occurrences of nausea in clinical trials were generally mild to moderate in intensity (see also DOSAGE AND ADMINISTRATION: General Dosing Considerations).
Approximately 5% of 496 patients treated with REQUIP who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse events compared to 4% of 500 patients who received placebo. The adverse events most commonly causing discontinuation of treatment by patients treated with REQUIP were: nausea (1.6%), dizziness (0.8 %), and headache (0.8%).
Adverse Event Incidence in Controlled Clinical Studies: Table 4 lists treatment-emergent adverse events that occurred in ? 2% of patients with RLS treated with REQUIP participating in the 12-week double-blind, placebo-controlled studies and were numerically more common in the group treated with REQUIP.
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse-events incidence rate in the population studied.
Table 4. Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled RLS Trials (Events ? 2% of Patients Treated With REQUIP and Numerically More Frequent Than the Placebo Group)Adverse Experience REQUIP
(n = 496)
(%) Placebo
(n =500)
(%)
Ear and labyrinth disorders
Vertigo 2 1
Gastrointestinal disorders
Nausea 40 8
Vomiting 11 2
Diarrhea 5 3
Dyspepsia 4 3
Dry mouth 3 2
Abdominal pain upper 3 1
General disorders and administration site conditions
Fatigue 8 4
Edema peripheral 2 1
Infections and infestations
Nasopharyngitis 9 8
Influenza 3 2
Musculoskeletal and connective tissue disorders
Arthralgia 4 3
Muscle cramps 3 2
Pain in extremity 3 2
Nervous system disorders
Somnolence 12 6
Dizziness 11 5
Paresthesia 3 1
Respiratory, thoracic, and mediastinal disorders
Cough 3 2
Nasal congestion 2 1
Skin and subcutaneous tissue disorders
Hyperhidrosis 3 1
Other events reported by 2% or more of patients treated with REQUIP, but equally or more frequent in the placebo group, were headache, insomnia, restless legs syndrome, upper respiratory tract infection, back pain, and sinusitis.
Other Adverse Events Observed During All Phase 2/3 Clinical Trials for Parkinson's Disease
REQUIP has been administered to 1,599 individuals in clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 1,599 individuals exposed to REQUIP who experienced events of the type cited on at least 1 occasion while receiving REQUIP. All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, and terms too vague to be meaningful, are included without regard to determination of a causal relationship to REQUIP, except that events very unlikely to be drug-related have been deleted.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients and infrequent adverse events are those occurring in 1/100 to 1/1,000 patients and rare events are those occurring in fewer than 1/1,000 patients.
Body as a Whole: Infrequent: Cellulitis, peripheral edema, fever, influenza-like symptoms, enlarged abdomen, precordial chest pain, and generalized edema. Rare: Ascites.
Cardiovascular: Infrequent: Cardiac failure, bradycardia, tachycardia, supraventricular tachycardia, angina pectoris, bundle branch block, cardiac arrest, cardiomegaly, aneurysm, mitral insufficiency. Rare: Ventricular tachycardia.
Central/Peripheral Nervous System: Frequent: Neuralgia. Infrequent: Involuntary muscle contractions, hypertonia, dysphonia, abnormal coordination, extrapyramidal disorder, migraine, choreoathetosis, coma, stupor, aphasia, convulsions, hypotonia, peripheral neuropathy, paralysis. Rare: Grand mal convulsions, hemiparesis, hemiplegia.
Endocrine: Infrequent: Hypothyroidism, gynecomastia, hyperthyroidism. Rare: Goiter, SIADH.
Gastrointestinal: Infrequent: Increased hepatic enzymes, bilirubinemia, cholecystitis, cholelithiasis colitis, dysphagia, periodontitis, fecal incontinence, gastroesophageal reflux, hemorrhoids, toothache, eructation, gastritis, esophagitis, hiccups, diverticulitis, duodenal ulcer, gastric ulcer, melena, duodenitis, gastrointestinal hemorrhage, glossitis, rectal hemorrhage, pancreatitis, stomatitis and ulcerative stomatitis, tongue edema. Rare: Biliary pain, hemorrhagic gastritis, hematemesis, salivary duct obstruction.
Hematologic: Infrequent: Purpura, thrombocytopenia, hematoma, Vitamin B12 deficiency, hypochromic anemia, eosinophilia, leukocytosis, leukopenia, lymphocytosis, lymphopenia, lymphedema.
Metabolic/Nutritional: Frequent: Increased BUN. Infrequent: Hypoglycemia, increased alkaline phosphatase, increased LDH, weight increase, hyperphosphatemia, hyperuricemia, diabetes mellitus, glycosuria, hypokalemia, hypercholesterolemia, hyperkalemia, acidosis, hyponatremia, thirst, increased CPK, dehydration. Rare: Hypochloremia.
Musculoskeletal: Infrequent: Aggravated arthritis, tendonitis, osteoporosis, bursitis, polymyalgia rheumatica, muscle weakness, skeletal pain, torticollis. Rare: Dupuytren's contracture requiring surgery.
Neoplasm: Infrequent: Malignant breast neoplasm. Rare: Bladder carcinoma, benign brain neoplasm, esophageal carcinoma, malignant laryngeal neoplasm, lipoma, rectal carcinoma, uterine neoplasm.
Psychiatric: Infrequent: Increased libido, agitation, apathy, impaired concentration, depersonalization, paranoid reaction, personality disorder, euphoria, delirium, dementia, delusion, emotional lability, decreased libido, manic reaction, somnambulism, aggressive reaction, neurosis. Rare: Suicide attempt.
Genitourinary: Infrequent: Amenorrhea, vaginal hemorrhage, penile disorder, prostatic disorder, balanoposthitis, epididymitis, perineal pain, dysuria, micturition frequency, albuminuria, nocturia, polyuria, renal calculus. Rare: Breast enlargement, mastitis, uterine hemorrhage, ejaculation disorder, Peyronie's disease, pyelonephritis, acute renal failure, uremia.
Resistance Mechanism: Infrequent: Herpes zoster, otitis media, sepsis, abscess, herpes simplex, fungal infection, genital moniliasis.
Respiratory: Infrequent: Asthma, epistaxis, laryngitis, pleurisy, pulmonary edema.
Skin/Appendage: Infrequent: Pruritus, dermatitis, eczema, skin ulceration, alopecia, skin hypertrophy, skin discoloration, urticaria, fungal dermatitis, furunculosis, hyperkeratosis, photosensitivity reaction, psoriasis, maculopapular rash, psoriaform rash, seborrhea.
Special Senses: Infrequent: Tinnitus, earache, decreased hearing, abnormal lacrimation, conjunctivitis, blepharitis, glaucoma, abnormal accommodation, blepharospasm, eye pain, photophobia. Rare: Scotoma.
Vascular Extracardiac: Infrequent: Varicose veins, phlebitis, peripheral gangrene. Rare: Limb embolism, pulmonary embolism, gangrene, subarachnoid hemorrhage, deep thrombophlebitis, leg thrombophlebitis, thrombosis.
Falling Asleep During Activities of Daily Living: Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded WARNING).
Other Adverse Events Observed During Phase 2/3 Clinical Trials for RLS
REQUIP has been administered to 911 individuals in clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 911 individuals exposed to REQUIP who experienced events of the type cited on at least one occasion while receiving REQUIP. All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed, trivial events, and terms too vague to be meaningful, are included without regard to determination of a causal relationship to REQUIP, except that events very unlikely to be drug-related have been deleted.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients and infrequent adverse events are those occurring in 1/100 to 1/1,000 patients.
Blood and Lymphatic System Disorders: Infrequent: Anemia, lymphadenopathy.
Cardiac Disorders: Frequent: Palpitations. Infrequent: Acute coronary syndrome, angina pectoris, angina unstable, bradycardia, cardiac failure, cardiovascular disorder, coronary artery disease, myocardial infarction, sick sinus syndrome, tachycardia.
Congenital, Familial, and Genetic Disorders: Infrequent: Pigmented nevus.
Ear and Labyrinth Disorders: Infrequent: Ear pain, middle ear effusion, tinnitus.
Endocrine Disorders: Infrequent: Goiter, hypothyroidism.
Eye Disorders: Infrequent: Blepharitis, conjunctival hemorrhage, conjunctivitis, eye irritation, eye pain, keratoconjunctivitis sicca, vision blurred, visual acuity reduced, visual disturbance.
Gastrointestinal Disorders: Frequent: Abdominal pain, constipation, gastroesophageal reflux disease, stomach discomfort, toothache. Infrequent: Abdominal adhesions, abdominal discomfort, abdominal distension, abdominal pain lower, duodenal ulcer, dysphagia, eructation, flatulence, gastric disorder, gastric hemorrhage, gastric polyps, gastric ulcer, gastritis, gastrointestinal pain, hematemesis, hemorrhoids, hiatus hernia, intestinal obstruction, irritable bowel syndrome, loose stools, mouth ulceration, pancreatitis acute, peptic ulcer, rectal hemorrhage, reflux esophagitis.
General Disorders and Administration Site Conditions: Frequent: Asthenia, chest pain, influenza-like illness, rigors. Infrequent: Chest discomfort, feeling cold, feeling hot, hunger, lethargy, malaise, edema, pain, pyrexia.
Hepatobiliary Disorders: Infrequent: Cholecystitis, cholelithiasis, ischemic hepatitis.
Immune System Disorders: Infrequent: Hypersensitivity.
Infections and Infestations: Frequent: Bronchitis, gastroenteritis, gastroenteritis viral, lower respiratory tract infection, rhinitis, tooth abscess, urinary tract infection. Infrequent: Appendicitis, bacterial infection, bladder infection, bronchitis acute, candidiasis, cellulitis, cystitis, diarrhea infectious, diverticulitis, ear infection, folliculitis, fungal infection, gastrointestinal infection, herpes simplex, infected cyst, laryngitis, localized infection, mastitis, otitis externa, otitis media, pharyngitis, pneumonia, postoperative infection, respiratory tract infection, tonsillitis, tooth infection, vaginal candidiasis, vaginal infection, vaginal mycosis, viral infection, viral upper respiratory tract infection, wound infection.
Injury, Poisoning, and Procedural Complications: Infrequent: Concussion, lower limb fracture, post procedural hemorrhage, road traffic accident.
Investigations: Infrequent: Blood cholesterol increased, blood iron decreased, blood pressure increased, blood urine present, hemoglobin decreased, heart rate increased, protein urine present, weight decreased, weight increased.
Metabolism and Nutrition Disorders: Infrequent: Anorexia, decreased appetite, diabetes mellitus non-insulin-dependent, fluid retention, gout, hypercholesterolemia.
Musculoskeletal and Connective Tissue Disorders: Frequent: Muscle spasms, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, tendonitis. Infrequent: Arthritis, aseptic necrosis bone, bone pain, bone spur, bursitis, groin pain, intervertebral disc degeneration, intervertebral disc protrusion, joint stiffness, joint swelling, localized osteoarthritis, monoarthritis, muscle contracture, muscle tightness, muscle twitching, osteoporosis, rotator cuff syndrome, sacroiliitis, synovitis.
Neoplasms Benign, Malignant, and Unspecified: Infrequent: Anaplastic thyroid cancer, angiomyolipoma, basal cell carcinoma, breast cancer, gastric cancer, gastrointestinal stromal tumor, malignant melanoma, prostate cancer, skin papilloma, squamous cell carcinoma, uterine leiomyoma.
Nervous System Disorders: Frequent: Hypoesthesia, migraine. Infrequent: Amnesia, aphasia, ataxia, balance disorder, benign intracranial hypertension, burning sensation, carpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, dyskinesia, head discomfort, hyperesthesia, hypersomnia, lethargy, loss of consciousness, memory impairment, migraine with aura, migraine without aura, neuralgia, sciatica, sedation, sinus headache, sleep apnea syndrome, syncope vasovagal, tension headache, transient ischemic attack, tremor.
Psychiatric Disorders: Frequent: Anxiety, depression, irritability, sleep disorder. Infrequent: Abnormal dreams, agitation, bruxism, confusional state, depressed mood, disorientation, early morning awakening, libido decreased, loss of libido, mood swings, nervousness, nightmare, panic attack, stress symptoms, tension.
Renal and Urinary Disorders: Infrequent: Dysuria, hematuria, hypertonic bladder, micturition disorder, nephrolithiasis, nocturia, pollakiuria, proteinuria, urinary retention.
Reproductive System and Breast Disorders: Frequent: Erectile dysfunction. Infrequent: Breast cyst, dysmenorrhea, menorrhagia, pelvic peritoneal adhesions, postmenopausal hemorrhage, premenstrual syndrome, prostatitis.
Respiratory, Thoracic and Mediastinal Disorders: Frequent: Asthma, pharyngolaryngeal pain. Infrequent: Dry throat, dyspnea, epistaxis, hemoptysis, hoarseness, interstitial lung disease, nasal mucosal disorder, nasal polyps, respiratory tract congestion, rhinorrhea, sinus congestion, sneezing, wheezing, yawning.
Skin and Subcutaneous Tissue Disorders: Frequent: Night sweats, rash. Infrequent: Acne, actinic keratosis, alopecia, cold sweat, dermatitis, dermatitis allergic, dermatitis contact, eczema, exanthem, face edema, photosensitivity reaction, pruritus, psoriasis, rash pruritic, skin lesion, urticaria.
Vascular Disorders: Frequent: Hot flush, hypertension, hypotension. Infrequent: Atherosclerosis, circulatory collapse, flushing, hematoma, thrombosis, varicose vein.
Postmarketing Reports
Psychiatric Disorders: Impulse control symptoms, pathological gambling, increased libido including hypersexuality.
Drug Abuse And Dependence
Controlled Substance Class: REQUIP is not a controlled substance
Physical and Psychological Dependence: Animal studies and human clinical trials with REQUIP did not reveal any potential for drug-seeking behavior or physical dependence.
DRUG INTERACTIONS
P450 Interaction: In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for substrates or inhibitors of this enzyme when coadministered with ropinirole to alter its clearance. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with REQUIP, adjustment of the dose of REQUIP may be required.
L-dopa: Co-administration of carbidopa + L-dopa (SINEMET® 10/100 mg twice daily) with ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of REQUIP 2 mg 3 times daily increased mean steady state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).
Digoxin: Co-administration of REQUIP (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.
Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg 3 times daily) in 12 patients with Parkinson's disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson's disease.
Ciprofloxacin: Co-administration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).
Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients. Dosage adjustment may not be needed for REQUIP in patients on estrogen therapy because patients must be carefully titrated with ropinirole to tolerance or adequate effect. However, if estrogen therapy is stopped or started during treatment with REQUIP, then adjustment of the dose of REQUIP may be required.
Dopamine Antagonists: Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may diminish the effectiveness of REQUIP. Patients with major psychotic disorders treated with neuroleptics should only be treated with dopamine agonists if the potential benefits outweigh the risks.
Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the oral clearance of ropinirole.
WARNINGS
Falling Asleep During Activities of Daily Living: Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on REQUIP, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as 1 year after initiation of treatment.
In controlled clinical trials, somnolence was a common occurrence in patients receiving REQUIP and is more frequent in Parkinson's disease (up to 40% REQUIP, 6% placebo) than in Restless Legs Syndrome (12% REQUIP, 6% placebo). Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with REQUIP, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP such as concomitant sedating medications, the presence of sleep disorders (other than Restless Legs Syndrome), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin-see PRECAUTIONS: DRUG INTERACTIONS). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), REQUIP should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing REQUIP.) If a decision is made to continue REQUIP, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Syncope
Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both Parkinson's disease patients and RLS patients. In the 2 double-blind, placebo-controlled studies of REQUIP in patients with Parkinson's disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on REQUIP had syncope compared to 1.4% (2 of 147) of patients on placebo. Most of these cases occurred more than 4 weeks after initiation of therapy with REQUIP, and were usually associated with a recent increase in dose.
Of 208 patients being treated with both L-dopa and REQUIP in placebo-controlled advanced Parkinson's disease trials, there were reports of syncope in 6 (2.9%) compared to 2 of 120 (1.7%) of placebo/L-dopa patients.
In patients with RLS, of 496 patients treated with REQUIP in 12-week placebo-controlled trials, there were reports of syncope in 5 (1.0%) compared with 1 of 500 (0.2%) patients treated with placebo.
Because the studies of REQUIP excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figures apply to either Parkinson's disease or RLS patients in clinical practice. Therefore, patients with severe cardiovascular disease should be treated with caution.
Two of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies had syncope following a 1-mg dose. In 2 studies in RLS patients that used a forced titration regimen and orthostatic challenge with intensive blood pressure monitoring, 1 of 55 RLS patients treated with REQUIP compared with 0 of 27 patients receiving placebo reported syncope. In phase 1 studies including 110 healthy volunteers, 1 patient developed hypotension, bradycardia, and sinus arrest of 26 seconds accompanied by syncope; the patient recovered spontaneously without intervention. One other healthy volunteer reported syncope.
Symptomatic Hypotension
Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting postural hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, Parkinson's patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk (see PRECAUTIONS: Information for Patients).
Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of postural hypotension in early Parkinson's disease (without L-dopa) in patients treated with REQUIP. Most of these cases occurred more than 4 weeks after initiation of therapy with REQUIP and were usually associated with a recent increase in dose.
In 12-week placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with REQUIP compared with 2 of 500 patients (0.4%) receiving placebo.
In two phase 2 studies in patients with RLS that used a forced-titration regimen and orthostatic challenges with intensive blood pressure monitoring, 14 of 55 patients (25%) receiving REQUIP experienced an adverse event of hypotension or postural hypotension. As described above, one additional patient was noted to have an episode of vasovagal syncope (although no blood pressure recording was documented). None of the 27 patients receiving placebo had a similar adverse event. In these studies, 11 of the 55 patients (20%) receiving REQUIP and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic; not all of these changes were associated with clinical symptoms. Except for its forced nature these studies used a similar titration schedule as those in the phase 3 efficacy trials.
In phase 1 studies of REQUIP that included 110 healthy volunteers, 9 subjects had documented symptomatic postural hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for either Parkinson's disease patients or RLS patients. In 8 of these 9 individuals, the hypotension was accompanied by bradycardia, but did not develop into syncope (see Syncope subsection). None of these events resulted in death or hospitalization.
One of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies had documented hypotension following a 2-mg dose on 2 occasions.
Hallucinations
In double-blind, placebo-controlled, early-therapy studies in patients with Parkinson's disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with REQUIP reported hallucinations, compared to 1.4% of patients on placebo (2 of 147). Among those patients receiving both REQUIP and L-dopa in advanced Parkinson's disease (with L-dopa) studies, 10.1% (21 of 208) were reported to experience hallucinations, compared to 4.2% (5 of 120) of patients treated with placebo and L-dopa.
Hallucinations were of sufficient severity to cause discontinuation of treatment in 1.3% of the early Parkinson's disease (without L-dopa) patients and 1.9% of the advanced Parkinson's disease (with L-dopa) patients, compared to 0% and 1.7% of placebo patients, respectively.
In patients with RLS, hallucinations were reported by 0% of patients treated with REQUIP (0 of 496) compared with 0.2% of patients who received placebo (1 of 500) in the 12-week placebo-controlled trials; in premarketing long-term open-label studies, 0.5% of patients reported hallucinations during therapy with REQUIP (2 of 390) but did not discontinue treatment and symptoms resolved.