Pramipexole dihydrochloride 0.5 MG Oral Tablet
WARNINGS
Falling Asleep During Activities of Daily Living Patients treated with pramipexole dihydrochloride tablets 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 dihydrochloride tablets, some perceived that they had no warning signs 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 dihydrochloride tablets at doses above 1.5 mg/day (0.5 mg TID) for Parkinson’s disease.
Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.
For this reason, prescribers should continually 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, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with pramipexole dihydrochloride tablets such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine – see PRECAUTIONS, Drug Interactions ).
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, patients should be advised to not drive and to avoid other potentially dangerous activities.
While dose reduction clearly 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.
Symptomatic 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, both Parkinson’s disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk (see PRECAUTIONS, Information for Patients (also see Patient Package Insert) ).
In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole dihydrochloride tablets than among those assigned to placebo.
This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.
While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials.
Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded.
Hallucinations In the three double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo.
In the four double-blind, placebo-controlled trials in advanced Parkinson’s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo.
Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson’s disease patients and 2.7% of the advanced Parkinson’s disease patients compared with about 0.4% of placebo patients in both populations.
Age appears to increase the risk of hallucinations attributable to pramipexole.
In the early Parkinson’s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years.
In the advanced Parkinson’s disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.
DRUG INTERACTIONS
Drug Interactions Carbidopa/levodopa Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10).
Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa C max by about 40% and a decrease in T max from 2.5 to 0.5 hours.
Selegiline In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.
Amantadine Population pharmacokinetic analysis suggest that amantadine may slightly decrease the oral clearance of pramipexole.
Cimetidine Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).
Probenecid Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).
OVERDOSAGE
There is no clinical experience with massive overdosage.
One patient, with a 10 year history of schizophrenia, took 11 mg/day of pramipexole for 2 days in a clinical trial to evaluate the effect of pramipexole in schizophrenic patients.
No adverse events were reported related to the increased dose.
Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute.
The patient withdrew from the study at the end of week 2 due to lack of efficacy.
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.
DESCRIPTION
Pramipexole dihydrochloride tablets contain pramipexole, a nonergot dopamine agonist.
The chemical name of pramipexole dihydrochloride is ( S )-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride monohydrate.
The structural formula is: C 10 H 17 N3 S · 2HCl · H2O Molecular Weight: 302.27 Pramipexole dihydrochloride is a white to off-white powder substance.
Melting occurs in the range of 296°C to 301°C, with decomposition.
Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.
Pramipexole dihydrochloride tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate.
Inactive ingredients consist of corn starch, hydrogenated vegetable oil, mannitol, povidone and pregelatinized corn starch.
Chemical Structure 1
CLINICAL STUDIES
Parkinson’s Disease The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials.
Three were conducted in patients with early Parkinson’s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson’s disease who were receiving concomitant levodopa.
Among these seven studies, three studies provide the most persuasive evidence of pramipexole’s effectiveness in the management of patients with Parkinson’s disease who were and were not receiving concomitant levodopa.
Two of these three trials enrolled patients with early Parkinson’s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson’s disease who were receiving maximally tolerated doses of levodopa.
In all studies, the Unified Parkinson’s Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure.
The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).
Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52.
Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II.
It is designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
Studies in Patients with Early Parkinson’s Disease Patients (N=599) in the two studies of early Parkinson’s disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the “on-off” phenomenon and dyskinesia characteristic of later stages of the disease.
One of the two early Parkinson’s disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose escalation period and a 6 month maintenance period.
Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine.
Patients were randomized to pramipexole dihydrochloride tablets or placebo.
Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses.
At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant.
The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant.
A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).
The second early Parkinson’s disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6 week dose-escalation period and a 4 week maintenance period.
Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products.
Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo.
At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients.
The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo treated patients.
No dose-response relationship was demonstrated.
The between treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses.
No differences in effectiveness based on age or gender were detected.
There were too few non- caucasian patients to evaluate the effect of race.
Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.
Studies in Patients with Advanced Parkinson’s Disease In the advanced Parkinson’s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of “on” and “off” time.
Patients in the advanced Parkinson’s disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had “on-off” periods.
The advanced Parkinson’s disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period.
Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination.
Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses.
At selected times during the 6 month maintenance period, patients were asked to record the amount of “off,” “on,” or “on with dyskinesia” time per day for several sequential days.
At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant.
The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant.
A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day).
Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients.
On average, the levodopa dose was reduced 27%.
The mean number of “off” hours per day during baseline was 6 hours for both treatment groups.
Throughout the trial, patients treated with pramipexole dihydrochloride had a mean of 4 “off” hours per day, while placebo-treated patients continued to experience 6 “off” hours per day.
No differences in effectiveness based on age or gender were detected.
There were too few non-caucasian patients to evaluate the effect of race.
HOW SUPPLIED
Pramipexole Dihydrochloride tablets are available as follows: 0.125 mg: White, round unscored tablet.
Debossed with stylized b on one side and C2 on the other side.
Available in bottles of: 63 Tablets NDC 0555-0617-62 0.25 mg: White, oval tablet scored on both sides.
Debossed with stylized b on one side and C|3 on the other side.
Available in bottles of: 90 Tablets NDC 0555-0612-14 0.5 mg: White, oval tablet scored on both sides.
Debossed with stylized b on one side and C|4 on the other side.
Available in bottles of: 90 Tablets NDC 0555-0613-14 1 mg: White, round tablet scored on both sides.
Debossed with stylized b on one side and C|5 on the other side.
Available in bottles of: 90 Tablets NDC 0555-0614-14 1.5 mg: White, round tablet scored on both sides.
Debossed with stylized b on one side and C|6 on the other side.
Available in bottles of: 90 Tablets NDC 0555-0615-14 KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
Protect from light.
PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET
GERIATRIC USE
Geriatric Use Pramipexole total oral clearance was 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.
MECHANISM OF ACTION
Mechanism of Action Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors, binding with higher affinity to D 3 than to D 2 or D 4 receptor subtypes.
Parkinson’s Disease: The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.
This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.
The relevance of D 3 receptor binding in Parkinson’s disease is unknown.
INDICATIONS AND USAGE
Parkinson’s Disease Pramipexole dihydrochloride tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.
The effectiveness of pramipexole dihydrochloride tablets 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 ).
PEDIATRIC USE
Pediatric Use The safety and efficacy of pramipexole dihydrochloride tablets in pediatric patients has not been established.
PREGNANCY
Pregnancy Teratogenic Effects Pregnancy Category C When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose (MRHD) on a mg/m 2 basis).
Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos.
The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD.
These findings are thought to be due to the prolactin lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans).
Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated.
There was no evidence of adverse effects on embryo fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 71 times that in humans at the MRHD).
Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m 2 basis) or greater during the latter part of pregnancy and throughout lactation.
There are no studies of pramipexole in human pregnancy.
Because animal reproduction studies are not always predictive of human response, pramipexole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
NUSRING MOTHERS
Nursing Mothers A single-dose, radio-labeled study showed that drug-related materials were excreted into the breast milk of lactating rats.
Concentrations of radioactivity in milk were three to six times higher than concentrations in plasma at equivalent time points.
Other studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
INFORMATION FOR PATIENTS
Information for Patients (also see Patient Package Insert) Patients should be instructed to take pramipexole dihydrochloride tablets only as prescribed.
Patients should be alerted to the potential sedating effects associated with pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living.
Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely.
Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.
Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).
Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson’s disease.
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including pramipexole dihydrochloride.
Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped.
Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with pramipexole dihydrochloride.
Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking pramipexole dihydrochloride.
Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride.
Patients may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating.
Hypotension may occur more frequently during initial therapy.
Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride tablets.
Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy ).
Because of the possibility that pramipexole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.
If patients develop nausea, they should be advised that taking pramipexole with food may reduce the occurrence of nausea.
DOSAGE AND ADMINISTRATION
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 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: Table 3: Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for Parkinson’s Disease Week Dosage (mg) Total Daily Dose (mg) 1 0.125 tid 0.375 2 0.25 tid 0.75 3 0.5 tid 1.50 4 0.75 tid 2.25 5 1 tid 3 6 1.25 tid 3.75 7 1.5 tid 4.50 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 Impairment Table 4: Pramipexole Dosage in Parkinson’s Disease Patients With Renal Impairment Renal Status Starting Dose (mg) Maximum Dose (mg) Normal to mild impairment (creatinine Cl > 60 mL/min) 0.125 tid 1.5 tid Moderate impairment (creatinine Cl = 35 to 59 mL/min) 0.125 bid 1.5 bid Severe impairment (creatinine Cl = 15 to 34 mL/min) 0.125 qd 1.5 qd 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 Treatment It is recommended that pramipexole dihydrochloride tablets be discontinued over a period of 1 week; in some studies, however, abrupt discontinuation was uneventful.