PRAMIPEXOLE

1 INDICATIONS & USAGE PRAMIPEXOLE DIHYDROCHLORIDE tablets is a non-ergot dopamine agonist indicated for the treatment of • the signs and symptoms of idiopathic Parkinson's disease (PD) ( 1.1 ) 1.1 Parkinson's Disease Pramipexole dihydrochloride tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

2 DOSAGE AND ADMINISTRATION Parkinson's Disease-Normal Renal Function* ( 2.2 ) Week Dosage (mg) Total Daily Dose (mg) 1 0.125 TID 0.375 2 0.25 TID 0.75 3 0.5 TID 1.5 4 0.75 TID 2.25 5 1 TID 3 6 1.25 TID 3.75 7 1.5 TID 4.5 * Doses should not be increased more frequently than every 5-7 days. Titrate to effective dose. If used with levodopa, may need to reduce levodopa dose. Parkinson's Disease-Impaired Renal Function ( 2.2 ) Creatinine Clearance Starting Dose (mg) Maximum Dose (mg) > 50 mL/min 0.125 TID 1.5 TID 30 to 50 mL/min 0.125 BID 0.75 TID 15 to 30 mL/min 0.125 QD 1.5 QD 50 mL/min) 0.125 TID 1.5 TID Moderate impairment (creatinine Cl =30 to 50 mL/min) 0.125 BID 0.75 TID Severe impairment (creatinine Cl =15 to <30 mL/min) 0.125 QD 1.5 QD Very severe impairment (creatinine Cl <15 mL/min and hemodialysis patients) The use of pramipexole dihydrochloride tablets has not been adequately studied in this group of patients Discontinuation of Treatment Pramipexole dihydrochloride tablets should 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 should be reduced by 0.375 mg per day. [see Warnings and Precautions(5.9)].

3 DOSAGE FORMS & STRENGTHS 0.125 mg: white to off-white, round, flat, beveled edge uncoated tablets, debossed with 'SG' on one side '126' on other side. 0.25 mg: white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G'on the right side of bisect and other side '1' on the left side and '27' on the right side of the bisect. 0.5 mg: white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with'S' on the left side of bisect and'G'on the right side of bisect and other side'1'on the left side and '28' on the right side of the bisect. 0.75 mg: white to off white, oval, flat, beveled edge uncoated tablets, debossed with 'SG' on one side '129'on other side. 1.0 mg: white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '30' on the right side of the bisect. 1.5 mg: white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '31' on the right side of the bisect. Tablets: 0.125 mg, 0.25 mg (functional scored tablets), 0.5 mg (functional scored tablets), 0.75 mg, 1 mg (functional scored tablets), and 1.5 mg (functional scored tablets) ( 3 ).

4 CONTRAINDICATIONS None. None (4)

6 ADVERSE 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's Disease During the premarketing development of pramipexole, patients with either early or advanced Parkinson'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'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 …

7 DRUG INTERACTIONS See also Dosage and Administration (2.2) and Clinical Pharmacology ( 12.3 ) 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 tablets. 7.2 Drug/Laboratory Test Interactions There are no known interactions between pramipexole and laboratory tests.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ). Pediatric use: Safety and effectiveness in pediatric patients have not been established ( 8.4 ) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, and 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD 8.2 Lactation Risk Summary There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole and any potential adverse effects on the breastfed infant from pramipexole or from the underlying maternal condition. Data In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma. 8.4 Pediatric Use Safety and effectiveness of pramipexole dihydrochloride tablets in pediatric patients has not been established. 8.5 Geriatric Use Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly. 8.6 Patients with Renal I …

12.1 Mechanism of Action Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Parkinson's Disease The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson's disease is unknown.

11 DESCRIPTION Pramipexole dihydrochloride tablets contain pramipexole dihydrochloride a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride 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•H2O, and its molecular weight is 302.27. The structural formula is: Pramipexole dihydrochloride is a white to almost white crystalline powder. Melting occurs in the range of 296 ̊C to 301 ̊C, with decomposition. Pramipexole Dihydrochloride is freely soluble in water, soluble in methanol, sparingly soluble to slightly soluble in ethanol (96%) and practically insoluble in methylene chloride. Pramipexole dihydrochloride tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride, USP. Inactive ingredients consist of mannitol, corn starch, colloidal silicon dioxide, povidone, and magnesium stearate. pramipexolestructure

10 OVERDOSAGE There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse events were reported related to the increased dose. There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Pramipexole dihydrochloride tablets are available as follows: 0.125 mg, white to off-white, round, flat, beveled edge uncoated tablets, debossed with 'SG' on one side '126' on other side. NDC 31722-906-90: Bottles of 90 tablets NDC 31722-906-05: Bottles of 500 tablets NDC 31722-906-10: Bottles of 1000 tablets 0.25 mg, white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '27' on the right side of the bisect. NDC 31722-907-90: Bottles of 90 tablets NDC 31722-907-05: Bottles of 500 tablets NDC 31722-907-10: Bottles of 1000 tablets 0.5 mg, white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '28' on the right side of the bisect. NDC 31722-908-90: Bottles of 90 tablets NDC 31722-908-05: Bottles of 500 tablets NDC 31722-908-10: Bottles of 1000 tablets 0.75 mg, white to off white, oval, flat, beveled edge uncoated tablets, debossed with 'SG' on one side '129' on other side. NDC 31722-909-90: Bottles of 90 tablets NDC 31722-909-05: Bottles of 500 tablets NDC 31722-909-10: Bottles of 1000 tablets 1.0 mg, white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '30' on the right side of the bisect. NDC 31722-910-90: Bottles of 90 tablets NDC 31722-910-05: Bottles of 500 tablets NDC 31722-910-10: Bottles of 1000 tablets 1.5 mg, white to off white, oval, flat, beveled edge uncoated functional scored tablets debossed on one side with 'S' on the left side of bisect and 'G' on the right side of bisect and other side '1' on the left side and '31' on the right side of the bisect. NDC 31722-911-90: Bottles of 90 tablets NDC 31722-911-05: Bottles of 500 tablets NDC 31722-11-10: Bottles of 1000 tablets 16.2 Storage and Handling Store at 20 oC to 25oC (68 oF to 77oF); (see USP controlled Room Temperature). Protect from light. Store in a safe place out of the reach of children.