Pramipexole Dihydrochloride (Page 5 of 10)

6.2 Postmarketing 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.

Cardiac Disorders: cardiac failure

Gastrointestinal Disorders: vomiting

General Disorders and Administration Site Conditions: withdrawal symptoms [ see Warnings and Precautions ( 5.11) ]

Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase

Musculoskeletal and Connective Tissue Disorders: postural deformity [ see Warnings and Precautions ( 5.6) ]

Nervous System Disorders: syncope

Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

7 DRUG INTERACTIONS

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.

8 USE IN SPECIFIC POPULATIONS

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% to 4% and 15% to 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 in 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, or 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.

DataIn 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.

In clinical studies with RLS patients, 22% of patients were at least 65 years old. There were no apparent differences in efficacy or safety between older and younger patients.

8.6 Renal Impairment

The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering pramipexole dihydrochloride tablets to patients with renal disease [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.7) , and Clinical Pharmacology ( 12.3) ].

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 reactions 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.

11 DESCRIPTION

Pramipexole dihydrochloride tablets contain pramipexole dihydrochloride (as a monohydrate). Pramipexole is a nonergot 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 302.27. The structural formula is:

Structural formula
(click image for full-size original)

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 0.125 mg:
Each tablet contains 0.125 mg pramipexole dihydrochloride monohydrate equivalent to 0.118 mg pramipexole dihydrochloride.

Pramipexole dihydrochloride tablets 0.25 mg:
Each tablet contains 0.25 mg pramipexole dihydrochloride monohydrate equivalent to 0.235 mg pramipexole dihydrochloride.

Pramipexole dihydrochloride tablets 0.5 mg:
Each tablet contains 0.5 mg pramipexole dihydrochloride monohydrate equivalent to 0.47 mg pramipexole dihydrochloride.

Pramipexole dihydrochloride tablets 0.75 mg:
Each tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent to 0.705 mg pramipexole dihydrochloride.

Pramipexole dihydrochloride tablets 1 mg:
Each tablet contains 1 mg pramipexole dihydrochloride monohydrate equivalent to 0.94 mg pramipexole dihydrochloride.

Pramipexole dihydrochloride tablets 1.5 mg:
Each tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent to 1.41 mg pramipexole dihydrochloride.

Inactive ingredients for all strengths of pramipexole dihydrochloride tablets consist of mannitol, corn starch, colloidal silicon dioxide, povidone, and magnesium stearate.

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