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postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, gait disturbance, impaired healing, influenza-like illness,
extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu irritability, localized edema, edema, pitting edema, thirst. Hepatobiliary disorders: biliary colic, cholecystitis, cholecystitis chronic,
syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic cholelithiasis. Immune system disorders: drug hypersensitivity. Infections and infestations: abscess, acute tonsillitis, appendicitis,
reaction, hypertension, pruritus, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal
paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, intervertebral discitis,
taste perversions. laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media,
In a fixed-dose study in early Parkinson’s disease, occurrence of the following events increased in frequency as the dose increased over paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection,
the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection. Injury, poisoning and procedural complications:
events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with accidental falls, drug toxicity epicondylitis, road traffic accident, sunburn, tendon rupture. Metabolism and nutrition disorders:
pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo. cachexia, decreased appetite, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia,
Advanced Parkinson’s Disease: In the four double-blind, placebo-controlled trials of patients with advanced Parkinson’s hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased appetite,
disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with metabolic alkalosis. Musculoskeletal and connective tissue disorders: bone pain, fasciitis, flank pain, intervertebral disc disorder,
MIRAPEX tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, muscle spasms, musculoskeletal
insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, stiffness, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid arthritis, shoulder
dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency. pain, spinal osteoarthritis, tendonitis, tenosynovitis. Neoplasms benign, malignant and unspecified: abdominal neoplasm,
Approximately 12% of 260 patients with advanced Parkinson’s disease who received Mirapex
®
(pramipexole dihydrochloride) tablets and adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic
concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 16% of leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm,
264 patients who received placebo and concomitant levodopa. The events most commonly causing discontinuation of treatment were hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer
related to the nervous system (hallucinations [2.7% on MIRAPEX tablets vs 0.4% on placebo]; dyskinesia [1.9% on MIRAPEX tablets vs metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign,
0.8% on placebo]; extrapyramidal syndrome [1.5% on MIRAPEX tablets vs 4.9% on placebo]; dizziness [1.2% on MIRAPEX tablets vs neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma,
1.5% on placebo]; confusion [1.2% on MIRAPEX tablets vs 2.3% on placebo]); and cardiovascular system (postural [orthostatic] pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma.
hypotension [2.3% on MIRAPEX tablets vs 1.1% on placebo]). Nervous system disorders: ageusia, akinesia, anticholinergic syndrome, aphasia, balance disorder, brain edema, carotid artery
Adverse-event Incidence in Controlled Clinical Studies in Advanced Parkinson’s Disease: This section lists treatment- occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea,
emergent adverse events that occurred in the double-blind, placebo-controlled studies in advanced Parkinson’s disease that were cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention,
reported by 1% or more of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. dizziness postural, dysarthria, dysgraphia, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia,
In these studies, MIRAPEX tablets or placebo was administered to patients who were also receiving concomitant levodopa. hyporeflexia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, narcolepsy,
Adverse events were usually mild or moderate in intensity. neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual disturbance, sleep talking, stupor, syncope vasovagal, tension headache. Psychiatric disorders: affect lability, aggression, agitation,
medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, bradyphrenia, bruxism, suicide, delirium, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric
the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, mood, hallucination auditory, hallucination visual, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare,
uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative obsessive thoughts, obsessive-compulsive disorder, panic reaction, parasomnia, personality disorder, psychotic disorder, restlessness,
contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied. sleep walking, suicidal ideation. Renal and urinary disorders: chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis,
Treatment-emergent adverse events are listed by body system in order of decreasing incidence for MIRAPEX tablets (N=260) vs neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal
placebo (N=264), respectively. Body as a whole: accidental injury (17% vs 15%), asthenia (10% vs 8%), general edema (4% vs 3%), impairment, urinary retention. Reproductive system and breast disorders: amenorrhea, breast pain, dysmenorrhea, epididymitis,
chest pain (3% vs 2%), malaise (3% vs 2%). Cardiovascular system: postural hypotension (53% vs 48%). Digestive system: gynaecomastia, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine
constipation (10% vs 9%), dry mouth (7% vs 3%). Metabolic and nutritional system: peripheral edema (2% vs 1%), increased hemorrhage, vaginal discharge, vaginal hemorrhage. Respiratory, thoracic and mediastinal disorders: apnea, aspiration, asthma,
creatine PK (1% vs 0%). Musculoskeletal system: arthritis (3% vs 1%), twitching (2% vs 0%), bursitis (2% vs 0%), myasthenia (1% vs choking, chronic obstructive pulmonary disease, dry throat, dysphonia, dyspnea exertional, epistaxis, haemoptysis, hiccups,
0%). Nervous system: dyskinesia (47% vs 31%), extrapyramidal syndrome (28% vs 26%), insomnia (27% vs 22%), dizziness (26% vs hyperventilation, increased bronchial secretion, laryngospasm, nasal dryness, nasal polyps, obstructive airways disorder,
25%), hallucinations (17% vs 4%), dream abnormalities (11% vs 10%), confusion (10% vs 7%), somnolence (9% vs 6%), dystonia (8% pharyngolaryngeal pain, pleurisy, pneumonia aspiration, pneumothorax, postnasal drip, productive cough, pulmonary embolism,
vs 7%), gait abnormalities (7% vs 5%), hypertonia (7% vs 6%), amnesia (6% vs 4%), akathisia (3% vs 2%), thinking abnormalities (3% pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, rhinitis allergic,
vs 2%), paranoid reaction (2% vs 0%), delusions (1% vs 0%), sleep disorders (1% vs 0%). Respiratory system: dyspnea (4% vs 3%), rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing. Skin and subcutaneous tissue
rhinitis (3% vs 1%), pneumonia (2% vs 0%). Skin and appendages: skin disorders (2% vs 1%). Special senses: accommodation disorders: acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema,
abnormalities (4% vs 2%), vision abnormalities (3% vs 1%), diplopia (1% vs 0%). Urogenital system: urinary frequency (6% vs 3%), erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis,
urinary tract infection (4% vs 3%), urinary incontinence (2% vs 1%). Patients may have reported multiple adverse experiences during purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation,
the study or at discontinuation; thus, patients may be included in more than one category. skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer,
Other events reported by 1% or more of patients with advanced Parkinson’s disease and treated with MIRAPEX tablets but urticaria. Vascular disorders: aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma,
reported equally or more frequently in the placebo group were nausea, pain, infection, headache, depression, tremor, hypokinesia, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose
anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety, rash, vein.
paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, Falling Asleep During Activities of Daily Living: Patients treated with MIRAPEX tablets have reported falling asleep while
nervousness, pruritus, hypesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded
conjunctivitis, and lacrimation disorders. WARNING).
Restless Legs Syndrome: MIRAPEX tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 Post-Marketing Experience: In addition to the adverse events reported during clinical trials, the following adverse reactions
treated for over six months and 75 for over one year. have been identified during post-approval use of MIRAPEX tablets, primarily in Parkinson’s disease patients. Because these
The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency
RLS were treated with MIRAPEX tablets for up to 12 weeks. The most commonly observed adverse events with MIRAPEX tablets in or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or
the treatment of RLS (observed in >5% of pramipexole-treated patients and at a rate at least twice that observed in placebo- more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to
treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and pramipexole tablets. Similar types of events were grouped into a smaller number of standardized categories using the MedDRA
transient. dictionary: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, fatigue, hallucinations (all kinds),
Approximately 7% of 575 patients treated with MIRAPEX tablets during the double-blind periods of three placebo-controlled trials headache, hypotension (including postural hypotension), increased eating (including binge eating, compulsive eating, and
discontinued treatment due to adverse events compared to 5% of 223 patients who received placebo. The adverse event most hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus,
commonly causing discontinuation of treatment was nausea (1%). syncope, and weight increase.
This section lists treatment-emergent events that occurred in three double-blind, placebo-controlled studies in RLS patients that DRUG ABUSE AND DEPENDENCE
were reported by 2% or more of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo Pramipexole is not a controlled substance. Pramipexole has not been systematically studied in animals or humans for its potential
group. for abuse, tolerance, or physical dependence. However, in a rat model on cocaine self-administration, pramipexole had little or no
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual effect.
medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, OVERDOSAGE
the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, There is no clinical experience with massive overdosage. One patient, with a 10-year history of schizophrenia, took
uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative 11 mg/day of pramipexole for 2 days in a clinical trial to evaluate the effect of pramipexole in schizophrenic patients. No adverse
contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied. events were reported related to the increased dose. Blood pressure remained stable although pulse rate increased to between 100
Treatment-emergent adverse events are listed by body system in order of decreasing incidence for MIRAPEX tablets (N=575) vs and 120 beats/minute. The patient withdrew from the study at the end of week 2 due to lack of efficacy.
placebo (N=223), respectively. Gastrointestinal disorders: nausea (16% vs 5%), constipation (4% vs 1%), diarrhea (3% vs 1%), There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a
dry mouth (3% vs 1%). General disorders and administration site conditions: fatigue (9% vs 7%). Infections and phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of
infestations: influenza (3% vs 1%). Nervous system disorders: headache (16% vs 15%), somnolence (6% vs 3%). Patients overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage,
may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more intravenous fluids, and electrocardiogram monitoring.
than one category. ANIMAL TOXICOLOGY
This section summarizes data for adverse events that appeared to be dose related in the 12-week fixed dose study. Dose related Retinal Pathology in Albino Rats: Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina
adverse events in a 12-week, double-blind, placebo-controlled, fixed dose study in Restless Legs Syndrome (occurring in 5% or of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were
more of all patients in the treatment phase) are listed by body system in order of decreasing incidence for MIRAPEX (0.25 mg dose dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times the AUC in humans that
[N=88]; 0.5 mg [N=80]; 0.75 mg [N=90]) vs placebo (n=86), respectively. Gastrointestinal disorders: nausea (11%; 19%; received 1.5 mg TID). In a similar study of pigmented rats with 2 years’ exposure to pramipexole at 2 or 8 mg/kg/day, retinal
27% vs 5%), diarrhea (3%; 1%; 7% vs 0%), dyspepsia (3%; 1%; 4% vs 7%). Infections and infestations: influenza (1%; 4%; degeneration was not diagnosed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly
7% vs 1%). General disorders and administration site conditions: fatigue (3%; 5%; 7% vs 5%). Psychiatric disorders: greater than that seen in control rats utilizing morphometry.
insomnia (9%; 9%; 13% vs 9%), abnormal dreams (2%; 1%; 8% vs 2%). Respiratory, thoracic and mediastinal disorders: Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the
nasal congestion (0%; 3%; 6% vs 1%). Musculoskeletal and connective tissue disorders: pain in extremity (3%; 3%; 7% vs retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study,
1%). degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of
Other events reported by 2% or more of RLS patients treated with MIRAPEX tablets but equally or more frequently in the placebo group, pramipexole (54 times the highest clinical dose on a mg/m
2
basis) and constant light (100 lux) but not in pigmented rats exposed
were: vomiting, nasopharyngitis, back pain, pain in extremity, dizziness, and insomnia. to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the
General damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino
Adverse Events; Relationship to Age, Gender, and Race: Among the treatment-emergent adverse events in patients treated with mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the highest clinical dose on a mg/m
2
basis). Evaluation of the
MIRAPEX tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson’s disease. Although no retinas of monkeys given 0.1, 0.5, or 2.0 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the highest clinical dose on a mg/m
2
gender-related differences were observed in Parkinson’s disease patients, nausea and fatigue, both generally transient, were more basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.
frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian, therefore, an evaluation The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a
of adverse events related to race is not possible. mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
Other Adverse Events Observed During Phase 2 and 3 Clinical Trials: MIRAPEX tablets have been administered to 1620 Fibro-osseous Proliferative Lesions in Mice: An increased incidence of fibro-osseous proliferative lesions occurred in the
Parkinson’s disease patients and to 889 RLS patients in Phase 2 and 3 clinical trials. During these trials, all adverse events were
femurs of female mice treated for 2 years with 0.3, 2.0, or 10 mg/kg/day (0.3, 2.2, and 11 times the highest clinical dose on a
recorded by the clinical investigators using terminology of their own choosing; similar types of events were grouped into a smaller
mg/m
2
basis). Lesions occurred at a lower rate in control animals. Similar lesions were not observed in male mice or rats and
number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. Adverse
monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.
events which are not listed above but occurred on at least two occasions (one occasion if the event was serious) in the 2509 Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
individuals exposed to MIRAPEX tablets are listed below. The reported events below are included without regard to determination Licensed from: Boehringer Ingelheim International GmbH
of a causal relationship to MIRAPEX tablets.
Trademark under license from: Boehringer Ingelheim International GmbH
Blood and lymphatic system disorders: anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy,
U.S. Patent Nos. 4,886,812; 6,001,861; and 6,194,445.
thrombocythaemia, thrombocytopenia. Cardiac disorders: angina pectoris, arrhythmia supraventricular, atrial fibrillation, atrioventricular
Rx only
block first degree, atrioventricular block second degree, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac
©2007, Boehringer Ingelheim International GmbH OT1317GH1507
failure congestive, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal
ALL RIGHTS RESERVED Revised November 2007 10003128/US/4
2001/02
arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia,
tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy. Congenital, familial and genetic disorders: atrial
MRLS51717
septal defect, congenital foot malformation, spine malformation. Ear and labyrinth disorders: deafness, ear pain, hearing impaired,
hypoacusis, motion sickness, vestibular ataxia. Endocrine disorders: goiter, hyperthyroidism, hypothyroidism. Eye disorders: amaurosis
fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema,
eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma,
vision blurred, visual acuity reduced, vitreous floaters. Gastrointestinal disorders: abdominal discomfort, abdominal distension,
aphthous stomatitis, ascites, cheilitis, colitis, colitis ulcerative, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal
incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage, gastroesophageal reflux disease,
gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus, inguinal hernia, intestinal obstruction,
irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux
esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia. General disorders: chest discomfort, chills, death, drug
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