PRAMIPEXOLE: 6,044 Adverse Event Reports & Safety Profile

Pramipexole dihydrochloride extended-release tablets contain pramipexole dihydrochloride (as a monohydrate). Pramipexole is, a non-ergot dopamine agonist. The chemical name of pramipexole dihydrochloride monohydrate is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C 10 H 17 N 3 S ·2HCl·H 2 O, and its molecular weight is 302.26. The structural formula is: Pramipexole dihydrochloride monohydrate USP is a white to almost white crystalline powder. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride monohydrate USP is freely soluble in water, soluble in methanol, slightly soluble in alcohol, practically insoluble in methylene chloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 0.375 mg: Each extended-release tablet contains 0.375 mg pramipexole dihydrochloride monohydrate equivalent to 0.352 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 0.75 mg: Each extended-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent to 0.705 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 1.5 mg: Each extended-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent to 1.41 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 2.25 mg: Each extended-release tablet contains 2.25 mg pramipexole dihydrochloride monohydrate equivalent to 2.12 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 3 mg: Each extended-release tablet contains 3 mg pramipexole dihydrochloride monohydrate equivalent to 2.82 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 3.75 mg: Each extended-release tablet contains 3.75 mg pramipexole dihydrochloride monohydrate equivalent to 3.53 mg pramipexole dihydrochloride.

Pramipexole Dihydrochloride

Extended-Release Tablets 4.5 mg: Each extended-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent to 4.23 mg pramipexole dihydrochloride. Pramipexole dihydrochloride extended-release tablets, for oral administration, contain 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg or 4.5 mg of pramipexole dihydrochloride monohydrate USP. Inactive ingredients are betadex, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methyl cellulose, magnesium stearate and microcrystalline cellulose. Structure

AND USAGE Pramipexole dihydrochloride tablets are a non-ergot dopamine agonist indicated for the treatment of:

• Parkinson’s disease (PD) ( 1.1 )
• Moderate-to-severe primary Restless Legs Syndrome (RLS) ( 1.2 )

1.1 Parkinson's Disease Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson's disease.

1.2 Restless Legs Syndrome Pramipexole dihydrochloride tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

AND ADMINISTRATION Pramipexole dihydrochloride extended-release tablets are taken once daily, with or without food ( 2.1 ) Tablets must be swallowed whole and must not be chewed, crushed, or divided ( 2.1 ) Starting dose is 0.375 mg given once daily ( 2.2 ) Dose may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. Assess therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment ( 2.2 ) Patients may be switched overnight from immediate-release pramipexole tablets to pramipexole dihydrochloride extended-release tablets at the same daily dose. Dose adjustment may be needed in some patients ( 2.3 ) Pramipexole dihydrochloride extended-release tablets should be discontinued gradually ( 2.2 )

2.1 General Dosing Considerations Pramipexole dihydrochloride extended-release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended-release tablets has occurred, re-titration of therapy may be warranted.

2.2 Recommended Dosage The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [ see Clinical Studies ( 14 ) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [ see Clinical Studies ( 14 ) ]. Pramipexole dihydrochloride extended-release tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [ see Warnings and Precautions ( 5.10 , 5.11 ) ].

Recommended

Dosage in Patients with Renal Impairment In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended-release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients.

2.3 Switching from Immediate-Release Pramipexole Tablets to Pramipexole Dihydrochloride Extended-Release Tablets Patients with Parkinson&apos;s disease may be switched overnight from immediate-release pramipexole tablets to pramipexole dihydrochloride extended-release tablets at the same daily dose. When switching between immediate-release pramipexole tablets and pramipexole dihydrochloride extended-release tablets, patients should be monitored to determine if dosage adjustment is necessary.

2.1 General Dosing Considerations Pramipexole dihydrochloride extended-release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended-release tablets has occurred, re-titration of therapy may be warranted.

2.2 Recommended Dosage The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [ see Clinical Studies ( 14 ) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [ see Clinical Studies ( 14 ) ]. Pramipexole dihydrochloride extended-release tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [ see Warnings and Precautions ( 5.10 , 5.11 ) ].

Recommended

Dosage in Patients with Renal Impairment In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended-release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients.

2.3 Switching from Immediate-Release Pramipexole Tablets to Pramipexole Dihydrochloride Extended-Release Tablets Patients with Parkinson&apos;s disease may be switched overnight from immediate-release pramipexole tablets to pramipexole dihydrochloride extended-release tablets at the same daily dose. When switching between immediate-release pramipexole tablets and pramipexole dihydrochloride extended-release tablets, patients should be monitored to determine if dosage adjustment is necessary.

None. None ( 4 )

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Falling Asleep During Activities of Daily Living [see Warnings and Precautions (5.1)].
• Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2)].
• Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.3)].
• Hallucinations [see Warnings and Precautions ( 5.4 )].
• Dyskinesia [see Warnings and Precautions ( 5.5)].
• Renal Impairment [see Warnings and Precautions (5.6)].
• Rhabdomyolysis [see Warnings and Precautions (5.7)].
• Retinal Pathology [see Warnings and Precautions ( 5.8)].
• Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.9)]. Most common adverse events (incidence >5% and greater than placebo):
• Early PD without levodopa: nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations ( 6.1 ).
• Advanced PD with levodopa: postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Parkinson&apos;s Disease During the premarketing development of pramipexole, patients with either early or advanced Parkinson&apos;s disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson&apos;s disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse events, this section will, in general, present adverse-event data for these two populations separately. Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.

Early

Parkinson's Disease In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately

12% of 388 patients with early Parkinson's disease and treated with pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 11% of 235 patients who received placebo. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs 0% on placebo]; extrapyramidal syndrome [1.6% on pramipexole dihydrochloride tablets vs 6.4% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets vs 0% on placebo]); and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]). Adverse-event Incidence in Controlled Clinical Studies in Early Parkinson's Disease: Table 4 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa. 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 nondrug factors to the adverse-event incidence rate in the population studied.

Table

4 Treatment-Emergent Adverse-Event* Incidence in Double-Blind, Placebo-Controlled Trials in Early Parkinson's Disease (Events ≥1% of Patients Treated with pramipexole dihydrochloride tablets and Numerically More Frequent than in the Placebo Group)

Body

System/ Adverse Event Pramipexole dihydrochloride tablets (N=388) % Placebo (N=235) % Body as a Whole Asthenia 14 12 General edema 5 3 Malaise 2 1 Reaction unevaluable 2 1 Fever 1 0 Digestive System Nausea 28 18 Constipation 14 6 Anorexia 4 2 Dysphagia 2 0 Metabolic & Nutritional System Peripheral edema 5 4 Decreased weight 2 0 Nervous System Dizziness 25 24 Somnolence 22 9 Insomnia 17 12 Hallucinations 9 3 Confusion 4 1 Amnesia 4 2 Hypesthesia 3 1 Dystonia 2 1 Akathisia 2 0 Thinking abnormalities 2 0 Decreased libido 1 0 Myoclonus 1 0 Special Senses Vision abnormalities 3 0 Urogenital System Impotence 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 with early Parkinson's disease and treated with pramipexole dihydrochloride tablets but reported equally or more frequently in the placebo group were infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritus, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and taste perversions. In a fixed-dose study in early Parkinson's disease, occurrence of the following events increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.

Advanced

Parkinson's Disease In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most commonly adverse events (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.

Approximately

12% of 260 patients with advanced Parkinson's disease who received pramipexole dihydrochloride tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 16% of 264 patients who received placebo and concomitant levodopa. The events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [2.7% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dyskinesia [1.9% on pramipexole dihydrochloride tablets vs 0.8% on placebo]; extrapyramidal syndrome [1.5% on pramipexole dihydrochloride tablets vs 4.9% on placebo]; dizziness [1.2% on pramipexole dihydrochloride tablets vs 1.5% on placebo]; confusion [1.2% on pramipexole dihydrochloride tablets vs 2.3% on placebo]); and cardiovascular system (postural [orthostatic] hypotension [2.3% on pramipexole dihydrochloride tablets vs 1.1% on placebo]). Adverse-event Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease: Table 5 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by ≥1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, pramipexole dihydrochloride tablets or placebo was administered to patients who were also receiving concomitant levodopa. 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 nondrug factors to the adverse-events incidence rate in the population studied.

Table

5 Treatment-Emergent Adverse-Event* Incidence in Double-Blind, Placebo-Controlled Trials in Advanced Parkinson's Disease (Events ≥1% of Patients Treated with pramipexole dihydrochloride tablets and Numerically More Frequent than in the Placebo Group)

Body

System/ Adverse Event Pramipexole dihydrochloride tablets † (N=260) % Placebo† (N=264) % Body as a Whole Accidental injury 17 15 Asthenia 10 8 General edema 4 3 Chest pain 3 2 Malaise 3 2 Cardiovascular System Postural hypotension 53 48 Digestive System Constipation 10 9 Dry mouth 7 3 Metabolic & Nutritional System Peripheral edema 2 1 Increased creatine PK 1 0 Musculoskeletal System Arthritis 3 1 Twitching 2 0 Bursitis 2 0 Myasthenia 1 0 Nervous System Dyskinesia 47 31 Extrapyramidal syndrome 28 26 Insomnia 27 22 Dizziness 26 25 Hallucinations 17 4 Dream abnormalities 11 10 Confusion 10 7 Somnolence 9 6 Dystonia 8 7 Gait abnormalities 7 5 Hypertonia 7 6 Amnesia 6 4 Akathisia 3 2 Thinking abnormalities 3 2 Paranoid reaction 2 0 Delusions 1 0 Sleep disorders 1 0 Respiratory System Dyspnea 4 3 Rhinitis 3 1 Pneumonia 2 0 Skin & Appendages Skin disorders 2 1 Special Senses Accommodation abnormalities 4 2 Vision abnormalities 3 1 Diplopia 1 0 Urogenital System Urinary frequency 6 3 Urinary tract infection 4 3 Urinary incontinence 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. †Patients received concomitant levodopa Other events reported by 1% or more of patients with advanced Parkinson's disease and treated with pramipexole dihydrochloride tablets but reported equally or more frequently in the placebo group were nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety, rash, paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hypesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis, and lacrimation disorders.

General Adverse

Events: Relationship to Age, Gender, and Race Among the treatment-emergent adverse events in patients treated with pramipexole dihydrochloride tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson’s disease. No gender-related differences were observed in Parkinson’s disease patients. Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse events related to race is not possible.

Laboratory Tests

During the development of pramipexole dihydrochloride tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.

Other Adverse Events Observed During

Phase 2 and 3 Clinical Trials Pramipexole dihydrochloride tablets have been administered to 1620 Parkinson’s disease patients in Phase 2 and 3 clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing; 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. Adverse events which are not listed above but occurred on at least two occasions (one occasion if the event was serious) in the 2509 individuals exposed to pramipexole dihydrochloride tablets are listed below. The reported events below are included without regard to determination of a causal relationship to pramipexole dihydrochloride tablets. Blood and lymphatic system disorders : anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia Cardiac disorders: angina pectoris, arrhythmia supraventricular, atrial fibrillation, atrioventricular block first degree, atrioventricular block second degree, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac failure congestive, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy Congenital, familial and genetic disorders: atrial 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 withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, pitting edema, thirst Hepatobiliary disorders: biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis Immune system disorders : drug hypersensitivity Infections and infestations: abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection Injury, poisoning and procedural complications: accidental falls, drug toxicity epicondylitis, road traffic accident, sunburn, tendon rupture Metabolism and nutrition disorders: cachexia, decreased appetite, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased appetite, metabolic alkalosis Musculoskeletal and connective tissue disorders: bone pain, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, muscle spasms, musculoskeletal stiffness, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis Neoplasms benign, malignant and unspecified: abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma Nervous system disorders: ageusia, akinesia, anticholinergic syndrome, aphasia, balance disorder, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, syncope vasovagal, tension headache Psychiatric disorders: affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, hallucination auditory, hallucination visual, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation Renal and urinary disorders: chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary retention Reproductive system and breast disorders: amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage Respiratory, thoracic and mediastinal disorders: apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, dyspnea exertional, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, pneumonia aspiration, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, rhinitis allergic, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing Skin and subcutaneous tissue disorders: acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria Vascular disorders: aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein

6.2 Post-Marketing Experience In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride tablets, primarily in Parkinson’s disease patients.Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, , compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), inappropriate antidiuretic hormone secretion (SIADH), skin reactions (including erythema, rash, pruritus, urticaria), syncope, vomiting, and weight increase.

AND PRECAUTIONS Falling Asleep During Activities of Daily Living: Sudden onset of sleep may occur without warning; advise patients to report symptoms ( 5.1 )

Symptomatic Orthostatic

Hypotension: Monitor closely especially during dose escalation ( 5.2 )

Impulse Control/Compulsive

Behaviors: Patients may experience compulsive behaviors and other intense urges ( 5.3 ) Hallucinations and Psychotic-like Behavior: May occur; risk increases with age ( 5.4 ) Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride extended-release tablets ( 5.5 )

Postural

Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets if postural deformity occurs ( 5.6 )

5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole 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 pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson&apos;s disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo. In early Parkinson&apos;s disease, somnolence was reported in 36% of 223 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson&apos;s disease, somnolence was reported in 15% of 164 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should 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 pramipexole dihydrochloride extended-release tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [ see Clinical Pharmacology ( 12.3 ) ]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride extended-release tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride extended-release tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson&apos;s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson&apos;s disease patients being treated with dopaminergic agonists, including pramipexole dihydrochloride extended-release tablets, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In placebo-controlled clinical trials in Parkinson&apos;s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on pramipexole dihydrochloride extended-release tablets discontinued treatment due to hypotension.

5.3 Impulse Control/Compulsive Behaviors Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride extended-release tablets, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride extended-release tablets for Parkinson&apos;s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride extended-release tablets. A total of 1056 patients with Parkinson&apos;s disease who participated in two pramipexole dihydrochloride extended-release tablets placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with pramipexole dihydrochloride extended-release tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

5.4 Hallucinations and Psychotic-like Behavior In placebo-controlled clinical trials in Parkinson&apos;s disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on pramipexole dihydrochloride extended-release tablets. Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson&apos;s disease, hallucinations were reported in 15 of 162 (9%) patients ≥65 years of age taking pramipexole dihydrochloride extended-release tablets compared to 10 of 225 (4%) patients &lt;65 years of age taking pramipexole dihydrochloride extended-release tablets. Postmarketing reports with dopamine agonists, including pramipexole dihydrochloride extended-release tablets, indicate that patients with Parkinson&apos;s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride extended-release tablets or after starting or increasing the dose of pramipexole dihydrochloride extended-release tablets. Other drugs prescribed to improve the symptoms of Parkinson&apos;s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride extended-release tablets, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson&apos;s disease and may decrease the effectiveness of pramipexole dihydrochloride extended-release tablets [ see Drug Interactions ( 7.1 ) ].

5.5 Dyskinesia Pramipexole dihydrochloride extended-release tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of pramipexole dihydrochloride extended-release tablets. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment The elimination of pramipexole is dependent on renal function [ see Clinical Pharmacology ( 12.3 ) ]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance &lt;50 mL/min) or on hemodialysis [ see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 ) ].

5.8 Rhabdomyolysis In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson&apos;s disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication. Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology Human Data A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson&apos;s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments.

Of

234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [ see Nonclinical Toxicology ( 13.2 ) ].

5.10 Events Reported with Dopaminergic Therapy Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date. Hyperpyrexia and Confusion Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride extended-release tablets. If the decision is made to discontinue pramipexole dihydrochloride extended-release tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [ see Dosage and Administration ( 2.2 ) ].

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown. Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

5.11 Withdrawal Symptoms Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including pramipexole dihydrochloride extended-release tablets. These symptoms generally do not respond to levodopa. Prior to discontinuation of pramipexole dihydrochloride extended-release tablets, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole 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 pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson&apos;s disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo. In early Parkinson&apos;s disease, somnolence was reported in 36% of 223 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson&apos;s disease, somnolence was reported in 15% of 164 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should 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 pramipexole dihydrochloride extended-release tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [ see Clinical Pharmacology ( 12.3 ) ]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride extended-release tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride extended-release tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson&apos;s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson&apos;s disease patients being treated with dopaminergic agonists, including pramipexole dihydrochloride extended-release tablets, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In placebo-controlled clinical trials in Parkinson&apos;s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on pramipexole dihydrochloride extended-release tablets discontinued treatment due to hypotension.

5.3 Impulse Control/Compulsive Behaviors Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride extended-release tablets, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride extended-release tablets for Parkinson&apos;s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride extended-release tablets. A total of 1056 patients with Parkinson&apos;s disease who participated in two pramipexole dihydrochloride extended-release tablets placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with pramipexole dihydrochloride extended-release tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

5.4 Hallucinations and Psychotic-like Behavior In placebo-controlled clinical trials in Parkinson&apos;s disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on pramipexole dihydrochloride extended-release tablets. Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson&apos;s disease, hallucinations were reported in 15 of 162 (9%) patients ≥65 years of age taking pramipexole dihydrochloride extended-release tablets compared to 10 of 225 (4%) patients &lt;65 years of age taking pramipexole dihydrochloride extended-release tablets. Postmarketing reports with dopamine agonists, including pramipexole dihydrochloride extended-release tablets, indicate that patients with Parkinson&apos;s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride extended-release tablets or after starting or increasing the dose of pramipexole dihydrochloride extended-release tablets. Other drugs prescribed to improve the symptoms of Parkinson&apos;s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride extended-release tablets, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson&apos;s disease and may decrease the effectiveness of pramipexole dihydrochloride extended-release tablets [ see Drug Interactions ( 7.1 ) ].

5.5 Dyskinesia Pramipexole dihydrochloride extended-release tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of pramipexole dihydrochloride extended-release tablets. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment The elimination of pramipexole is dependent on renal function [ see Clinical Pharmacology ( 12.3 ) ]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance &lt;50 mL/min) or on hemodialysis [ see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 ) ].

5.8 Rhabdomyolysis In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson&apos;s disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication. Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology Human Data A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson&apos;s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments.

Of

234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [ see Nonclinical Toxicology ( 13.2 ) ].

5.10 Events Reported with Dopaminergic Therapy Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date. Hyperpyrexia and Confusion Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride extended-release tablets. If the decision is made to discontinue pramipexole dihydrochloride extended-release tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [ see Dosage and Administration ( 2.2 ) ].

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown. Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

5.11 Withdrawal Symptoms Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including pramipexole dihydrochloride extended-release tablets. These symptoms generally do not respond to levodopa. Prior to discontinuation of pramipexole dihydrochloride extended-release tablets, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

INTERACTIONS Dopamine antagonists: May diminish the effectiveness of pramipexole ( 7.1 )

7.1 Dopamine Antagonists Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride extended-release tablets.

7.1 Dopamine Antagonists Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride extended-release tablets.