Requip Side Effects, and Drug Interactions - Ropinirole

Requip Side Effects, and Drug Interactions - Ropinirole

SIDE EFFECTS

During the pre-marketing 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 Requip -treated patients 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 Requip -treated patients 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 1 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 Requip group. In these studies, either Requip (ropinirole hydrochloride) 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.

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 (ropinirole hydrochloride) 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 Requip -treated patients 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 2 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 Requip group. 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.

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.

Other Adverse Events Observed During All Phase 2/3 Clinical Trials:    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 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 above, trivial events, and terms too vague to be meaningful are included, without regard to determination of a causal relationship to Requip (ropinirole hydrochloride), 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 1/1000 patients and rare events are those occurring in fewer than 1/1000 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, tendinitis, 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.

Genito-urinary:    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 pruritis, 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 ).

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 (ropinirole hydrochloride) did not reveal any potential for drug-seeking behavior or physical dependence.

P ₄₅₀ 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 Requip dose may be required.

L-dopa:   Co-administration of carbidopa + L-dopa (Sinemet® 10/100 mg b.i.d.) with ropinirole (2.0 mg t.i.d.) had no effect on the steady-state pharmacokinetics of ropinirole (n=28 patients). Oral administration of Requip 2.0 mg t.i.d. increased mean steady state C _max of L-dopa by 20% but its AUC was unaffected (n=23 patients).

Digoxin:   Co-administration of Requip (2.0 mg t.i.d.) with digoxin (0.125-0.25 mg q.d.) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Theophylline:    Administration of theophylline (300 mg b.i.d., a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg t.i.d.) in 12 patients with Parkinson's disease. Ropinirole (2 mg t.i.d.) did not alter the pharmacokinetics of theophylline (5 mg/kg i.v.) in 12 patients with Parkinson's disease.

Ciprofloxacin:   Co-administration of ciprofloxacin (500 mg b.i.d.), an inhibitor of CYP1A2, with ropinirole (2 mg t.i.d.) increased ropinirole AUC by 84% on average, and C _max by 60% (n=12 patients).

Estrogens:   Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6-3 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 Requip (ropinirole hydrochloride) dose 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.