Pramipexole Dihydrochloride

PRAMIPEXOLE DIHYDROCHLORIDE — pramipexole dihydrochloride tablet
Citron Pharma LLC

1 INDICATIONS AND USAGE

1.1 Parkinson’s Disease

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

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

Pramipexole dihydrochloride tablets are taken orally, with or without food.If a significant interruption in therapy with pramipexole dihydrochloride tablets has occurred, re-titration of therapy may be warranted.

2.2 Dosing for Parkinson’s Disease

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Pramipexole dihydrochloride tablets should be titrated gradually in all patients. The dose 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 Doses 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 Table 1:

Table 1 Ascending Dosage Schedule of Pramipexole Dihydrochloride tablets for Parkinson’s Disease
Week Dosage (mg) Total Daily Dose (mg)
1 0.125 three times a day 0.375
2 0.25 three times a day 0.75
3 0.5 three times a day 1.5
4 0.75 three times a day 2.25
5 1 three times a day 3
6 1.25 three times a day 3.75
7 1.5 three times a day 4.5

Maintenance Treatment
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 pramipexole dihydrochloride tablets 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 pramipexole dihydrochloride tablets are 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.
Dosing in Patients with Renal ImpairmentThe recommended dosing of pramipexole dihydrochloride tablets in Parkinson’s disease patients with renal impairment is provided in Table 2.

Table 2 Dosing of Pramipexole Dihydrochloride tablets in Parkinson’s Disease Patients with Renal Impairment
Renal Status Starting Dose (mg) Maximum Dose (mg)
Normal to mild impairment (creatinine Cl > 50 mL/min) 0.125 three times a day 1.5 three times a day
Moderate impairment (creatinine Cl = 30 to 50 mL/min) 0.125 twice a day 0.75 three times a day
Severe impairment (creatinine Cl = 15 to <30 mL/min) 0.125 once a day 1.5 once a day
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 TreatmentPramipexole dihydrochloride 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.

3 DOSAGE FORMS AND STRENGTHS

  • 0.125 mg: white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ on one side ‘41’ on other side.
  • 0.25 mg: white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ and ‘42’ separated by score line on one side and plain with score line on other side.
  • 0.5 mg: white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ and ‘43’ separated by score line on one side and plain with score line on other side.
  • 0.75 mg: white to off-white, oval, biconcave, beveled edge uncoated tablets, debossed with ‘Y’ on one side and ‘44’ on other side.
  • 1 mg: white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ and ‘45’ separated by score line on one side and plain with score line on other side.
  • 1.5 mg: white to off-white, round, flat, beveled edge uncoated tablets, debossed with ‘Y’ and ‘46’ separated by score line on one side and plain with score line on other side.

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.
Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg three times a day) for Parkinson’s disease. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing 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 tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with pramipexole dihydrochloride tablets 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 tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride 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.

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