PRAMIPEXOLE DIHYDROCHLORIDE — pramipexole dihydrochloride tablet
Unichem Pharmaceuticals (USA), Inc.
If a significant interruption in therapy with pramipexole dihydrochloride tablets has occurred, re-titration of therapy may be warranted.
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
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:
|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||1.50|
|4||0.75 three times a day||2.25|
|5||1 three times a day||3.0|
|6||1.25 three times a day||3.75|
|7||1.5 three times a day||4.50|
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 Impairment
The recommended dosing of pramipexole dihydrochloride tablets in Parkinson’s disease patients with renal impairment is provided in Table 2.
|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.|
Pramipexole 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 [see 5.10, 5.11].
The recommended starting dose of Pramipexole dihydrochloride tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (Table 3). Although the dose of Pramipexole dihydrochloride tablets was increased to 0.75 mg in some patients during long-term open-label treatment, there is no evidence that the 0.75 mg dose provides additional benefit beyond the 0.5 mg dose.
|Titration Step||Duration||Dose (mg) to be taken once daily, 2-3 hours before bedtime|
|* if needed|
The duration between titration steps should be increased to 14 days in RLS patients with moderate and severe renal impairment (creatinine clearance 20-60 ml/min) [see Clinical Pharmacology (12.3)].
Discontinuation of Treatment
In clinical trials of patients being treated for RLS with doses up to 0.75 mg once daily, Pramipexole dihydrochloride tablets were discontinued without a taper. In a 26 week placebo-controlled clinical trial, patients reported a worsening of RLS symptom severity as compared to their untreated baseline when Pramipexole dihydrochloride tablets treatment was suddenly withdrawn [see Warnings and Precautions (5.10)].
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