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pramipexole 0.5 mg tablet generic mirapex

Out of Stock Manufacturer MACLEODS PHARMA 33342003310
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Uses

Parkinsonian Syndrome

Pramipexole dihydrochloride is used for the symptomatic management of idiopathic parkinsonian syndrome.

Dopamine receptor agonists (bromocriptine mesylate, pramipexole dihydrochloride, pergolide mesylate, ropinirole hydrochloride) are used as adjuncts to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease. Dopamine receptor agonists also are used as monotherapy for the initial symptomatic management of parkinsonian syndrome. Levodopa currently is the most effective drug for relieving the symptoms of parkinsonian syndrome and traditionally has been considered the drug of choice for the initial symptomatic management of idiopathic parkinsonian syndrome. However, long-term administration of levodopa is associated with motor complications. One strategy to reduce the risk of motor complications and to improve long-term outcome is to initiate symptomatic therapy with a dopamine receptor agonist and to add levodopa as supplemental therapy when dopamine receptor agonist monotherapy no longer provides adequate symptom control. However, clinical studies evaluating this strategy are limited both in number and duration, and it remains to be determined whether initiating therapy with a dopamine receptor agonist rather than levodopa results in a more favorable long-term outcome. Factors to consider when choosing an agent for the initial symptomatic management of idiopathic parkinsonian syndrome include patient age, cognitive status, disease severity, and cost. Most clinicians would use levodopa for initial therapy in individuals older than 70 years of age (since these individuals are less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease. A dopamine receptor agonist may be preferred for initial therapy in patients 70 years of age or younger.

Efficacy of pramipexole for the management of idiopathic parkinsonian syndrome has been established in several placebo-controlled studies of up to 6 months' duration in patients with early parkinsonian syndrome receiving no concomitant levodopa therapy, and in patients with advanced parkinsonian syndrome who were receiving levodopa therapy concomitantly. In these studies, improvement in manifestations of parkinsonian syndrome was assessed principally using the Unified Parkinson's Disease Rating Scale (UPDRS), a 4-part rating scale intended to evaluate mentation, activities of daily living, motor performance, and complications of therapy.

Pramipexole appears to improve activities of daily living as well as motor manifestations of parkinsonian syndrome, such as tremor, rigidity, bradykinesia, and postural stability. In a limited number of clinical studies in patients with early parkinsonian syndrome, pramipexole was more effective than placebo in reducing the severity of symptoms associated with this disorder. In a study in patients with early (less than 7 years' duration) parkinsonian syndrome, 10 weeks of therapy with pramipexole resulted in an average 20% improvement in total UPDRS scores compared with placebo (score of 5.9-7 versus 0.9 units, respectively). In this study, concomitant therapy with amantadine, selegiline, or anticholinergic drugs, but not levodopa or other dopamine receptor agonists, was allowed.

In placebo-controlled clinical studies in patients with advanced parkinsonian syndrome who were receiving concomitant levodopa therapy, pramipexole reduced the severity of symptoms associated with this disorder and allowed a reduction in levodopa dosage. In patients with advanced parkinsonian syndrome who were experiencing ''on-off'' phenomena (i.e., a deteriorating response to levodopa therapy), pramipexole was more effective than placebo in reducing ''off'' time (as measured by the activities of daily living portion of the UPDRS). In one study, the duration of ''off'' time with pramipexole or placebo was reduced by an average of 31 or 7%, respectively, while the severity of ''off'' time was reduced by 17 or 5%, respectively. Further study is required to establish safety and efficacy of pramipexole during long-term administration and to determine the long-term effect of the drug on disability in parkinsonian syndrome.

In 2 controlled studies of up to 33 weeks' duration in patients with early or advanced parkinsonian syndrome, pramipexole dihydrochloride extended-release tablets (given once daily) were more effective than placebo and as effective as conventional tablets of the drug (given 3 times daily) in improving activities of daily living and motor manifestations of the disease (as assessed by the UPDRS); tolerability of the 2 pramipexole formulations was similar. In another study in patients with early parkinsonian syndrome, about 81% of patients who were switched overnight from conventional tablets of pramipexole given 3 times daily to extended-release tablets of the drug given once daily at the same total daily dosage required no dosage adjustment following the change in therapy; about 84% of patients were successfully switched to the extended-release formulation with or without a change in dosage.

Sudden, irresistible attacks of sleep that resemble narcolepsy have been reported in patients treated with pramipexole. Patients receiving a dopamine receptor agonist (e.g., pramipexole, ropinirole) have reported falling asleep while engaged in activities of daily living, including business meetings, telephone calls, and operating a motor vehicle, which occasionally resulted in accidents. Although many of these patients reported somnolence while receiving pramipexole or ropinirole, some perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event. Some of these events have been reported as late as 1 year after initiation of therapy with the drug. Spontaneous postmarketing reports indicate that patients with a previous history of sleep disorders (e.g., somnolence) or who were taking multiple drugs known to cause sedation may be at an increased risk of experiencing sudden sleep onset. Although such sleep attacks may occur more frequently at higher dosages of pramipexole, they may occur at any dosage. Although the incidence of somnolence with pramipexole dihydrochloride at a dosage of 1.5 mg daily was comparable to that reported with placebo, somnolence is a common adverse effect in patients receiving the drug at dosages exceeding 1.5 mg daily.

Many 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. Therefore, it is recommended that clinicians continually reassess patients for drowsiness or sleepiness especially since some incidents of sudden sleep onset occurred well after the start of pramipexole therapy. Clinicians also should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities. In addition, patients should be asked about any factors that may increase the risk of somnolence during pramipexole therapy (e.g., concomitant sedating drugs, the presence of sleep disorders, concomitant drugs that increase pramipexole plasma concentrations [e.g., cimetidine]). If a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), pramipexole generally should be discontinued. If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities. While dose reduction clearly reduces the degree of somnolence, the manufacturer states that there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Patients should be informed that hallucinations can occur with pramipexole therapy; geriatric patients are at increased risk for this adverse effect. Patients also should be advised that pramipexole may cause somnolence and that they should not drive a car or operate other complex machinery until they have gained sufficient experience with the drug to determine whether it has adverse effects on their mental and/or motor performance. In addition, the possibility of additive sedative effects should be considered in patients receiving other CNS depressants concomitantly with pramipexole.

Restless Legs Syndrome

Pramipexole dihydrochloride is used for the symptomatic management of moderate-to-severe primary restless legs syndrome (Ekbom syndrome). Restless legs syndrome is a sensorimotor disorder characterized by a distressing urge to move the legs accompanied by sensations deep in the limbs that have been described as twitching, pulling, and sometimes painful. These symptoms are present at rest, especially in the evening and at night, and are relieved by movement. Some clinicians consider a dopamine receptor agonist (e.g., pramipexole) the drug of choice for patients with symptoms that occur nightly.

Efficacy of pramipexole for this indication has been established in 4 randomized, double-blind, placebo-controlled studies in patients with primary moderate-to-severe restless legs syndrome (defined in most of the studies as a score exceeding 15 on the International Restless Legs Syndrome [IRLS] scale and a history of symptoms of restless legs syndrome at least 2 or 3 days per week for at least the past 3 months). Patients were excluded from these studies if they had restless legs syndrome associated with other conditions, such as renal failure, anemia, or pregnancy. Pramipexole dihydrochloride was administered in dosages ranging from 0.125-0.75 mg daily (administered 2-3 hours before bedtime), and response was assessed using the IRLS scale and the Clinical Global Impression-Improvement (CGI-I) scale. Two studies evaluated fixed dosages of the drug, one study evaluated flexible dosages, and one study evaluated time to treatment failure following discontinuance of the drug. The 4 studies together included about 1000 patients.

The 3-week, placebo-controlled, fixed-dosage study evaluated 4 dosages of pramipexole dihydrochloride (0.125, 0.25, 0.5, and 0.75 mg once daily); each treatment group in this dose-finding study included about 20 patients. The results indicated that a dosage of 0.5 mg daily generally was superior to 0.25 mg daily, but there were no significant differences in response between the 0.125-mg dosage and placebo or between the 0.5- and 0.75-mg dosages. Three of these dosage levels (0.25, 0.5, and 0.75 mg once daily) were evaluated in a larger 12-week, placebo-controlled, fixed-dosage study in 344 patients. At 12 weeks, the mean improvement in IRLS score was greater in patients receiving pramipexole than in those receiving placebo, but improvement was similar across all 3 pramipexole dosages. In addition, 74.7, 67.9, or 72.9% of patients receiving pramipexole dihydrochloride 0.25, 0.5, or 0.75 mg once daily, respectively, were described as responders (defined as being much improved or very much improved) on the CGI-I scale, compared with 51.2% of those receiving placebo. Although all 3 dosage levels were superior to placebo in this study, there was no clear evidence of a dose-response relationship across the 3 dosage groups.

In the flexible-dosage study, 345 patients were randomized in a 2:1 ratio to receive pramipexole dihydrochloride (median dosage of 0.35 mg daily; range: 0.125-0.75 mg daily) or placebo for 6 weeks. At 6 weeks, the mean improvement in IRLS score was greater in patients receiving pramipexole than in those receiving placebo; in addition, 62.9% of patients receiving pramipexole compared with 32.5% of those receiving placebo were described as responders (defined as being much improved or very much improved) on the CGI-I scale.

In the randomized drug withdrawal study, 147 patients who had achieved a sustained response after 6 months of open-label pramipexole therapy were randomized to receive continued pramipexole therapy or placebo. Following 12 weeks of follow-up, approximately 85% of patients switched to placebo experienced treatment failure, compared with approximately 21% of those who continued receiving pramipexole. Most of the treatment failures occurred within 10 days of randomization.

Augmentation of the symptoms of restless legs syndrome may occur in patients receiving therapy for this disorder; augmentation can take the form of onset of symptoms earlier in the day, increase in symptoms, or extension of symptoms to other extremities. In a 26-week clinical trial in patients with restless legs syndrome, augmentation was reported more frequently in patients receiving pramipexole dihydrochloride (up to 0.75 mg once daily) compared with those receiving placebo (12% versus 9%), and the incidence of augmentation increased with increasing duration of treatment. Patients receiving pramipexole also were more likely than placebo recipients to report a rebound in symptoms of the disorder when treatment was discontinued abruptly (10% versus 2%); the worsening of symptoms generally was considered mild. The incidence, severity, and appropriate management of augmentation and/or rebound in patients receiving long-term therapy with pramipexole have not been adequately evaluated in controlled clinical trials to date.

In clinical trials evaluating pramipexole for the symptomatic management of restless legs syndrome, somnolence was reported in 6% of patients receiving the drug at dosages of 0.25-0.75 mg daily and in 3% of placebo recipients.

Dosage and Administration

Administration

Pramipexole dihydrochloride is administered orally. For the management of parkinsonian syndrome, pramipexole dihydrochloride is administered as conventional tablets in 3 equally divided doses daily or as extended-release tablets given once daily. When used for the management of restless legs syndrome, the drug is administered as conventional tablets given once daily 2-3 hours before bedtime.

Pramipexole dihydrochloride extended-release tablets should be swallowed whole and should not be chewed, crushed, or divided.

Administration of pramipexole dihydrochloride conventional tablets with food decreases the rate, but not the extent, of absorption; time to peak concentration is delayed by about 1 hour. Administration of the extended-release tablets with food increases peak plasma concentrations by approximately 20% and delays time to peak concentration by approximately 2 hours, but does not affect the extent of exposure. Therefore, pramipexole dihydrochloride conventional or extended-release tablets may be administered without regard to meals. Patients in whom pramipexole causes nausea should be advised that taking the drug with food may reduce the occurrence of this adverse effect.

Dosage

The manufacturer states that safety and efficacy of pramipexole in children have not been established.

Dosage of pramipexole dihydrochloride is calculated in terms of the monohydrated form of this salt.

Pramipexole therapy is initiated at a low dosage and then titrated slowly based on response and tolerability. Increases in blood pressure and heart rate have been observed in healthy individuals when dosage was titrated up to 4.5 mg daily more quickly (i.e., every 3 days) than is recommended.

Use of dopamine agonists in patients with parkinsonian syndrome or restless legs syndrome ordinarily requires careful monitoring for manifestations of orthostatic hypotension, especially during dosage escalation, since these drugs appear to impair systemic regulation of blood pressure. In addition, patients with parkinsonian syndrome generally have a reduced capacity to respond to an orthostatic challenge. In clinical trials in patients with parkinsonian syndrome, symptomatic orthostatic hypotension occurred in 3% of patients receiving extended-release pramipexole and 1% of those receiving placebo. However, unexpectedly, the reported incidence of clinically important orthostatic hypotension with pramipexole as conventional tablets did not differ from that with placebo in clinical trials in patients with parkinsonian syndrome, although the incidence of postural hypotension increased in a dose-dependent manner over the dosage range of 1.5-6 mg daily. The manufacturer states that patients with either parkinsonian syndrome or restless legs syndrome should be cautioned about rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning pramipexole therapy.

Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including operating a motor vehicle, which sometimes resulted in accidents.(See Uses: Parkinsonian Syndrome for associated precautions.)

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and inability to control these urges have been reported in some patients receiving agents that increase central dopaminergic tone (including pramipexole). Although a causal relationship has not been established, these urges stopped in some cases when dosage was reduced or the drug was discontinued. Clinicians should ask patients whether they have developed new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while receiving pramipexole and should advise them of the importance of reporting such urges. If a patient develops such urges while receiving pramipexole, consideration should be given to reducing the dosage or discontinuing the drug.

Parkinsonian Syndrome

For the management of idiopathic parkinsonian syndrome, therapy with pramipexole dihydrochloride (as conventional tablets) is initiated at a low dosage and increased slowly (at intervals of not less than 5-7 days) until the maximum therapeutic response is achieved. The usual initial dosage of pramipexole dihydrochloride is 0.125 mg 3 times daily (total of 0.375 mg daily) the first week, then 0.25 mg 3 times daily (total of 0.75 mg daily) the second week, 0.5 mg 3 times daily (total of 1.5 mg daily) the third week, 0.75 mg 3 times daily (total of 2.25 mg daily) the fourth week, 1 mg 3 times daily (total of 3 mg daily) the fifth week, 1.25 mg 3 times daily (total of 3.75 mg daily) the sixth week, and 1.5 mg 3 times daily (total of 4.5 mg daily) the seventh week.

When pramipexole dihydrochloride extended-release tablets are used for the management of idiopathic parkinsonian syndrome, therapy is initiated at a dosage of 0.375 mg once daily and increased slowly (at intervals of not less than 5-7 days). Based on response and tolerability (assessed after the patient has received each dosage for 5 or more days), dosage may be increased to 0.75 mg once daily and then in increments of 0.75 mg, up to a maximum recommended dosage of 4.5 mg once daily. Dosages exceeding 4.5 mg daily have not been evaluated in clinical trials. If therapy is interrupted for a substantial period of time, retitration of dosage may be warranted.

Because equivalent daily dosages of pramipexole dihydrochloride conventional tablets (administered 3 times daily) and extended-release tablets (administered once daily) result in comparable peak and trough plasma concentrations and systemic exposure over 24 hours, patients may be switched overnight from the conventional tablets to the extended-release tablets at the same total daily dosage. However, because some patients may require dosage adjustment, patients being switched between the 2 formulations should be monitored to determine if dosage adjustment is necessary.

The dosage of pramipexole dihydrochloride must be continually reevaluated and changed according to the needs of the patient in a constant effort to find a dosage schedule that provides maximum relief of symptoms with minimum adverse effects. In a fixed-dose study in patients with early parkinsonian syndrome, pramipexole dihydrochloride dosages exceeding 1.5 mg daily (i.e., 3, 4.5, or 6 mg daily as conventional tablets) were not associated with additional therapeutic benefit. However, as the dosage increased over the range from 1.5 mg to 6 mg daily, the incidence of postural hypotension, nausea, constipation, somnolence, and amnesia also increased. For pramipexole dosages exceeding 3 mg daily, the frequency of these events generally was twofold greater than with placebo. Specific relationships between dose and either therapeutic response or frequency of adverse effects have not been established for the extended-release formulation.

In clinical studies, pramipexole dihydrochloride 1.5-4.5 mg daily in 3 equally divided doses has been effective and well tolerated when administered with or without concomitant levodopa therapy (approximately 800 mg daily). Since concomitant therapy with pramipexole and levodopa may result in additive therapeutic and/or adverse (e.g., dyskinesia) effects, a reduction in levodopa dosage should be considered when pramipexole is added to levodopa therapy. In a controlled study in patients with advanced parkinsonian syndrome, the dosage of levodopa was reduced by an average of 27% from baseline with concomitant pramipexole therapy.

Although not reported in clinical trials with pramipexole, a symptom complex resembling neuroleptic malignant syndrome (e.g., elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with rapid dosage reduction, withdrawal of, or changes in antiparkinsonian therapy. The manufacturer recommends that discontinuance of pramipexole therapy in patients with parkinsonian syndrome take place over a period of 1 week. However, in some studies, abrupt discontinuance of the drug (as conventional tablets) has been uneventful.

Restless Legs Syndrome

The usual initial dosage of pramipexole dihydrochloride (as conventional tablets) for the management of restless legs syndrome in adults is 0.125 mg given once daily 2-3 hours before bedtime. If symptomatic relief with the initial dosage is inadequate, dosage may be increased at intervals of 4-7 days to 0.25 mg daily and then to 0.5 mg daily. Although some patients received a dosage of 0.75 mg daily during long-term open-label treatment with the drug, there is no evidence in patients with restless legs syndrome that a dosage of 0.75 mg daily provides additional benefit compared with a dosage of 0.5 mg daily.

Pramipexole dihydrochloride (administered at dosages of up to 0.75 mg once daily) was discontinued without a taper in clinical trials in patients with restless legs syndrome. However, in a 26-week clinical trial, patients receiving the drug at dosages of up to 0.75 mg daily were more likely than placebo recipients to report a rebound in symptoms of restless legs syndrome when treatment was discontinued abruptly.(See Uses: Restless Legs Syndrome.)

Dosage in Renal and Hepatic Impairment

When pramipexole dihydrochloride is used for the management of idiopathic parkinsonian syndrome in patients with impaired renal function, dosage and/or frequency of administration must be modified in response to the degree of impairment.

When conventional tablets of pramipexole dihydrochloride are used for the management of idiopathic parkinsonian syndrome in patients with creatinine clearances of 60 mL/minute or greater, the usual dosage of pramipexole dihydrochloride (0.125 mg 3 times daily in an ascending dosage schedule up to a maximum dosage of 1.5 mg 3 times daily) is recommended.(See Parkinsonian Syndrome under Dosage and Administration: Dosage.) Patients with creatinine clearances of 35-59 mL/minute should receive an initial pramipexole dihydrochloride dosage (as conventional tablets) of 0.125 mg twice daily (up to a maximum dosage of 1.5 mg twice daily), and those with creatinine clearances of 15-34 mL/minute should receive 0.125 mg once daily (up to a maximum dosage of 1.5 mg once daily). Safety and efficacy of pramipexole dihydrochloride (as conventional tablets) have not been evaluated systematically in patients with creatinine clearances of less than 15 mL/minute or in those undergoing hemodialysis, and the manufacturer currently makes no specific recommendation for dosage adjustment in such patients.

When extended-release tablets of pramipexole dihydrochloride are used for the management of idiopathic parkinsonian syndrome in patients with creatinine clearances exceeding 50 mL/minute, the usual dosage of pramipexole dihydrochloride is recommended.(See Parkinsonian Syndrome under Dosage and Administration: Dosage.) In patients with creatinine clearances of 30-50 mL/minute, treatment with the extended-release tablets should be initiated with an every-other-day dosing schedule; response and tolerability should be carefully assessed before increasing to daily dosing after one week and before any further dosage titration. Dosage may be titrated no more frequently than once weekly in increments of 0.375 mg, up to a maximum dosage of 2.25 mg once daily. Extended-release tablets of the drug have not been studied in patients with creatinine clearances of less than 30 mL/minute or in those undergoing hemodialysis, and are not recommended for use in these patients.

When conventional tablets of pramipexole dihydrochloride are used for the management of restless legs syndrome in patients with creatinine clearances of 20-60 mL/minute, the interval between dosage adjustments should be increased to 14 days.

The effect of hepatic impairment on the pharmacokinetics of pramipexole has not been evaluated to date, and the manufacturer currently makes no specific recommendation for dosage adjustment in patients with hepatic impairment. Because pramipexole is eliminated mainly (90%) as unchanged drug in the urine, hepatic impairment would not be expected to substantially affect pramipexole elimination.

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