Pramipexole Dihydrochloride

PRAMIPEXOLE DIHYDROCHLORIDE — pramipexole dihydrochloride tablet, extended release
NorthStar RxLLC

1 INDICATIONS AND USAGE

Pramipexole dihydrochloride extended-release tablets are indicated for the treatment of Parkinson’s disease.

2 DOSAGE AND ADMINISTRATION

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 Dosing for Parkinson’s Disease

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)]
Dosing 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’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.

3 DOSAGE FORMS AND STRENGTHS

• 0.375 mg: White colored, circular, flat, beveled edged, uncoated tablet debossed ‘ER 1’ on one side of the tablet and ‘0.375’ on other side. Each extended-release tablet contains 0.375 mg pramipexole dihydrochloride monohydrate equivalent to 0.352 mg pramipexole dihydrochloride USP.
• 0.75 mg: White colored, circular, flat, beveled edged, uncoated tablet debossed ‘ER 2’ on one side of the tablet and ‘0.75’ on other side. Each extended-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent to 0.705 mg pramipexole dihydrochloride USP.
• 1.5 mg: White colored, oval shaped, biconvex, uncoated tablet debossed ‘ER 3’ on one side of the tablet and ‘1.5’ on other side. Each extended-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent to 1.41 mg pramipexole dihydrochloride USP.
• 2.25 mg: White colored, oval shaped, biconvex, uncoated tablet debossed ‘ER 4’ on one side of the tablet and ‘2.25’ on other side. Each extended-release tablet contains 2.25 mg pramipexole dihydrochloride monohydrate equivalent to 2.12 mg pramipexole dihydrochloride USP.
• 3 mg: White colored, oval shaped, biconvex, uncoated tablet debossed ‘ER 5’ on one side of the tablet and ‘3.0’ on other side. Each extended-release tablet contains 3 mg pramipexole dihydrochloride monohydrate equivalent to 2.82 mg pramipexole dihydrochloride USP.
• 3.75 mg: White colored, oval shaped, biconvex, uncoated tablet debossed ‘ER 6’ on one side of the tablet and ‘3.75’ on other side. Each extended-release tablet contains 3.75 mg pramipexole dihydrochloride monohydrate equivalent to 3.53 mg pramipexole dihydrochloride USP.
• 4.5 mg: White colored, oval shaped, biconvex, uncoated tablet debossed ‘ER 7’ on one side of the tablet and ‘4.5’ on other side. Each extended-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent to 4.23 mg pramipexole dihydrochloride USP.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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’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’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’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’s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson’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’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.

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