Pramipexole Dihydrochloride

Pronunciation: (PRAM-i-PEX-ole dye-HYE-droe-KLOR-ide)
Class: Nonergot dopamine receptor agonist

Trade Names

Mirapex
- Tablets 0.125 mg
- Tablets 0.25 mg
- Tablets 0.5 mg
- Tablets 1 mg
- Tablets 1.5 mg

Mirapex ER
- Tablets, ER 0.375 mg
- Tablets, ER 0.75 mg
- Tablets, ER 1.5 mg
- Tablets, ER 3 mg
- Tablets, ER 4.5 mg

Apo-Pramipexole (Canada)
PMS-Pramipexole (Canada)

Pharmacology

Stimulates dopamine receptors in the corpus striatum.

Pharmacokinetics

Absorption

Rapid absorption. T _max is approximately 2 h (6 h for ER); increased 1 h (2 h for ER) if taken with food. Bioavailability is more than 90%. Steady state is 2 days (5 days for ER).

Distribution

Extensively distributed. Distributes into red blood cells, as indicated by an erythrocyte to plasma ratio of approximately 2. Vd is 500 L. Protein binding is 15%.

Metabolism

Pramipexole is metabolized only to a negligible extent (less than 10%).

Elimination

Renal (90% mostly as unchanged in urine). Renal Cl is 400 mL/min. The terminal half-life is approximately 8 h in healthy adults and approximately 12 h in elderly patients.

Special Populations

Renal Function Impairment

Cl is 75% lower with severe impairment (CrCl less than 20 mL/min) and approximately 60% lower with moderate impairment (CrCl less than 40 mL/min). Recommend lower starting and maintenance dose.

Elderly

The half-life increases approximately 40% and Cl decreases approximately 30% in patients 65 yr of age and older mostly because of reduced renal function with age.

Children

The pharmacokinetics of pramipexole in children have not been evaluated.

Gender

Cl is approximately 30% lower in women.

Race

No racial differences in metabolism and elimination have been identified.

Parkinson disease

Cl is reduced approximately 30%; appears to be related to reduced renal function in these patients.

Indications and Usage

Treatment of the signs and symptoms of idiopathic Parkinson disease (immediate-release may be used in conjunction with levodopa in advanced disease). Treatment of moderate to severe primary restless legs syndrome (immediate-release only).

Contraindications

Standard considerations.

Dosage and Administration

Parkinson disease
Adults Immediate release

PO Start with 0.125 mg 3 times daily. After 5 to 7 days, the dosage may be increased to 0.25 mg 3 times daily. Further increases in dosage may be made in increments of 0.25 mg 3 times daily, at intervals of 5 to 7 days, to a dosage of 1.5 mg 3 times daily.

ER

Start with 0.375 mg once daily. If needed, dosage may be gradually titrated every 5 to 7 days, first to 0.75 mg once daily; further dose increases should be made in 0.75 mg increments (max, 4.5 mg/day).

Restless legs syndrome (immediate release only)
Adults

PO Start with 0.125 mg once daily 2 to 3 h before bedtime. If additional symptomatic relief is needed, the dosage may be increased to 0.25 mg once daily in 4 to 7 days. If needed, an additional increase in dosage to 0.5 mg once daily may be made in 4 to 7 days.

Renal function impairment
Adults Parkinson disease Immediate-release Moderate impairment (CrCl 35 to 59 mL/min)

Start with 0.125 mg 2 times daily (max, 1.5 mg 2 times daily).

Severe impairment (CrCl 15 to 34 mL/min)

Start with 0.125 daily (max, 1.5 daily).

Very severe impairment (CrCl less than 15 mL/min and hemodialysis patients)

Use has not been adequately studied.

ER Moderate impairment (CrCl 30 to 50 mL/min)

Initially, the dosage should be taken every other day. May increase to daily dosing after 1 week based on therapeutic response and tolerability. Further titrations may be made in 0.375 mg increments (max, 2.25 mg/day), not more frequently than once weekly.

Restless legs syndrome

In moderate and severe impairment (CrCl 20 to 60 mL/min), increase the duration between titration steps to 14 days.

General Advice

Administer without regard to meals. Administer with food if GI upset occurs.
ER tablets should not be chewed, crushed, or divided.
If significant interruption in therapy has occurred, retitration of therapy must be warranted.

Storage/Stability

Store at 59° to 86°F. Protect from light and high humidity.

Drug Interactions

Alcohol

Because the chances of falling asleep may be increased, alcohol ingestion should be avoided.

Amantadine

The oral Cl or pramipexole may be slightly decreased.

Carbidopa/Levodopa

Levodopa plasma concentrations may be increased and T _max may be decreased. However, the extent of carbidopa/levodopa absorption (AUC) or elimination was not affected.

Cimetidine

Pramipexole AUC and a 40% increase in half-life may be increased. Monitor the patient. If an interaction is suspected, be prepared to adjust the pramipexole dose as needed.

Dopamine antagonists (eg, butyrophenones, metoclopramide, phenothiazines, thioxanthenes)

May reduce pramipexole efficacy. Monitor the patient. If an interaction is suspected, adjust the pramipexole dose as needed.

Drugs eliminated via cationic renal secretion (eg, cimetidine, diltiazem, quinidine, quinine, ranitidine, triamterene, verapamil)

May reduce oral Cl of pramipexole. Pramipexole dosage adjustment may be needed if therapy with any of these agents is started or stopped during treatment with pramipexole

Food

Food does not affect the extent of pramipexole absorption, although the T _max is increased about 1 h when pramipexole tablets are taken with a meal. Administration of pramipexole ER tablets with a high-fat meal did not affect AUC but increased C _max approximately 20% and delayed the T _max approximately 2 h, compared with fasting. These differences are not considered to be clinically important.

Adverse Reactions

Cardiovascular

Orthostatic hypotension (3%).

CNS

Somnolence (36%); dizziness (25%); insomnia (17%); headache (16%); asthenia (14%); fatigue, hallucinations (9%); sleep attacks or sudden onset of sleep (6%); amnesia, confusion, vertigo (4%); asthenia, hypesthesia, sleep disorder, tremor (3%); akathisia, balance disorder, depression, dystonia, malaise, thinking abnormalities (2%); decreased libido, myoclonus (1%); abnormal behavior, libido disorders, including increased and decreased libido and hypersexuality, pathological gambling, syncope (postmarketing).

EENT

Vision abnormalities (3%).

GI

Nausea (28%); constipation (14%); dry mouth (5%); anorexia, upper abdominal pain, vomiting (4%); diarrhea, dyspepsia (3%); abdominal discomfort, dysphagia (2%).

Genitourinary

Impotence (2%).

Metabolic-Nutritional

Peripheral edema (8%); general edema (5%); increased appetite (3%); decreased weight (2%); increased eating, including binge eating, compulsive eating, and hyperphagia (postmarketing).

Musculoskeletal

Muscle spasms (5%).

Respiratory

Cough (3%).

Miscellaneous

Fall (4%); influenza (3%); fever (1%); compulsive shopping (postmarketing).

Precautions

Monitor

Signs and symptoms of orthostatic hypotension, especially during dose escalation. Continually assess for drowsiness or sleepiness. Patients should undergo periodic dermatologic screening.

Pregnancy

Category C .

Lactation

Inhibits prolactin secretion. Do not give to breast-feeding mothers.

Children

Safety and efficacy not established.

Renal Function

Use with caution and adjust dose in presence of moderate to severe renal function impairment. Use lower initial and maintenance doses.

Abrupt withdrawal

Rapid withdrawal or dose reduction of antiparkinsonism drugs may produce symptoms resembling NMS. It is recommended that pramipexole be discontinued over a period of 1 week.

CNS effect

Use concomitant CNS depressants with caution because of additive sedative effects.

Concurrent levodopa use

When pramipexole is used in combination with levodopa, the dose of levodopa may be reduced as tolerated.

Dyskinesia

Pramipexole may potentiate dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

Fibrosis

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients taking ergot-derived dopaminergic agents.

Hallucinations

Can occur during pramipexole therapy. Frequency is greater when used in conjunction with levodopa. Incidence appears to increase with age.

Hypotension

Orthostatic hypotension may occur, especially during dose escalation.

Impulse control

Pathological gambling, hypersexuality, compulsive shopping, and compulsive eating have been reported.

Melanoma

Can occur at a higher frequency in patients with Parkinson disease.

Rebound restless legs syndrome

During treatment, shifting of symptoms to early morning hours or earlier in the afternoon has been reported.

Retinal pathology

Pathological changes were observed in the retinas of albino rats receiving dopaminergic receptor agonists. The potential significance of this effect in humans has not been established but cannot be disregarded.

Rhabdomyolysis

Can occur along with elevated CPK levels.

Sleepiness

Patients have reported falling asleep while engaging in activities of daily living (eg, operating a motor vehicle).

Overdosage

Symptoms

None known.

Patient Information

Instruct patient to take exactly as prescribed. Advise patient that dose may be taken without regard to meals but to take with food if nausea occurs.
Advise patients to swallow pramipexole ER tablets whole, and to not chew, crush, or divide.
Inform patient that drug may cause drowsiness, including falling asleep while engaged in activities of daily living, and to use caution while driving or performing other tasks requiring mental alertness.
Instruct patient to avoid sudden position changes to prevent orthostatic hypotension.
Instruct patient to report the following symptoms to health care provider: dizziness, headache, mood or mental changes, severe or persistent nausea, uncontrollable movements.
Inform patient that hallucinations can occur and that elderly patients are more susceptible.
Advise patient to use caution when taking other drugs with CNS depressant effects (eg, alcohol, sedatives).
Inform patient that impulse control disorders, such as pathological gambling, compulsive eating, compulsive shopping, or hypersexuality, can occur.
Advise patients to contact health care provider if they experience unexplained muscle pain, tenderness, or weakness.