Mirapex (Pramipexole Dihydrochloride) - Indications and Dosage

INDICATIONS AND USAGE

MIRAPEX (pramipexole dihydrochloride) Tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

The effectiveness of MIRAPEX (pramipexole dihydrochloride) was demonstrated in randomized, controlled trials in patients with early Parkinson's disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa (see CLINICAL STUDIES).

DOSAGE AND ADMINISTRATION

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. MIRAPEX (pramipexole dihydrochloride) should be titrated gradually in all patients. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth.

DOSING IN PATIENTS WITH NORMAL RENAL FUNCTION

Initial Treatment: Dosages should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in the following table:

Maintenance Treatment: MIRAPEX (pramipexole dihydrochloride) Tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of MIRAPEX (pramipexole dihydrochloride) were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: 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 reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.

When MIRAPEX (pramipexole dihydrochloride) is used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline.

Discontinuation of Treatment: It is recommended that MIRAPEX (pramipexole dihydrochloride) be discontinued over a period of 1 week; in some studies, however, abrupt discontinuation was uneventful.

HOW SUPPLIED

MIRAPEX (pramipexole dihydrochloride) Tablets are available as follows:

0.125 mg: white, round tablet with "U" on one side and "2" on the reverse side.

Bottles of 63 NDC 0597-0083-53

0.25 mg: white, oval, scored tablet with "U" twice on one side and "4" twice on the reverse side.

Bottles of 90 NDC 0597-0084-90

Unit dose packages of 100 NDC 0597-0084-61

0.5 mg: white, oval, scored tablet with "U" twice on one side and "8" twice on the reverse side.

Bottles of 90 NDC 0597-0085-90

Unit dose packages of 100 NDC 0597-0085-61

1 mg: white, round, scored tablet with "U" twice on one side and "6" twice on the reverse side.

Bottles of 90 NDC 0597-0090-90

Unit dose packages of 100 NDC 0597-0090-61

1.5 mg: white, round, scored tablet with "U" twice on one side and "37" twice on the reverse side.

Bottles of 90 NDC 0597-0091-90

Unit dose packages of 100 NDC 0597-0091-61

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light.

Rx only

ANIMAL TOXICOLOGY

RETINAL PATHOLOGY IN ALBINO RATS

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were 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 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 degeneration was not diagnosed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater than that seen in control rats utilizing morphometry.

Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the highest clinical dose on a mg/m² basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino 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/m² basis). Evaluation of the 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/m² basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.

The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (ie, disk shedding) may be involved.

FIBRO-OSSEOUS PROLIFERATIVE LESIONS IN MICE

An increased incidence of fibro-osseous proliferative lesions occurred in the 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 mg/m² basis). Lesions occurred at a lower rate in control animals. Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

Distributed by:	Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Co-marketed by:	Boehringer Ingelheim Pharmaceuticals, Inc. and Pfizer Inc, New York, NY 10017
Licensed from:	Boehringer Ingelheim International GmbH

Trademark under license from:

Boehringer Ingelheim International GmbH

U.S. Patent Nos. 4,886,812 and 4,843,086

© 2003, Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

Revised October 2003 819898001/US/1