Clinical medicine profile
Pramipexole
Therapeutic agent (verify pharmacological class)
- Route
- See product SmPC
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
Contraindications
- Hypersensitivity to the active substance or excipients.
- Additional absolute contraindications are indication- and product-specific — consult SmPC.
Precautions
- 5 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living: Sudden onset of sleep may occur without warning
- advise patients to report symptoms.
- (5.1) Symptomatic Orthostatic Hypotension: Monitor closely especially during dose escalation.
- (5.2) Impulse Control/Compulsive Behaviors: Patients may experience compulsive behaviors and other intense urges.
- (5.3) Hallucinations and Psychotic-like Behavior: May occur
- risk increases with age.
- (5.4) Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride extended-release.
- (5.5) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets if postural deformity occurs.
- ( 5.6 ) 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.
- In placebo-controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
daily, with or without food (2.1) Tablets must be swallowed whole and must not be chewed, crushed, or divided (2.1) Starting dose is 0.375 mg given once daily (2.2) Dose may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. Assess therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment. (2.2) Patients may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. Dose adjustment may be needed in some patients (2.3) Pramipexole dihydrochloride extended-release tablets should be discontinued gradually. (2.2) 2.1 General Dosing Considerations Pramipexole dihydrochloride extended-release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended-release tablets has occurred, re-titration of therapy may be warranted. 2.2 Recommended Dosage The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Clinical Studies ( 14) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [see Clinical Studies ( 14 ) ]. Pramipexole dihydrochloride extended-release 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 Warnings and Precautions ( 5.10 , 5.11 )]. Recommended Dosage in Patients with Renal Impairment: In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended-release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients. 2.3 Switching from Immediate-Release Pramipexole Tablets to Extended-Release Pramipexole Tablets Patients with Parkinson’s disease may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. When switching between immediate-release pramipexole tablets and extended-release pramipexole tablets, patients should be monitored to determine if dosage adjustment is necessary.
8.4 Pediatric Use Safety and effectiveness of pramipexole dihydrochloride extended-release tablets in pediatric patients have not been evaluated.
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Use, effects & interactions
Indications
- Parkinson's disease.
- Pramipexole dihydrochloride extended-release tablet is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease (PD) (1) Clinical selection for Pramipexole should follow culture results where relevant, Kenya STG/EML recommendations, and the current product SmPC.
- Class context: Therapeutic agent (verify pharmacological class).
- Confirm site-specific dose, duration and monitoring before prescribing.
Adverse effects
- labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ] Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2) ] Impulse Control / Compulsive Behaviors [see Warnings and Precautions (5.3) ] Hallucinations and Psychotic-like Behavior [see Warnings and Precautions (5.4) ] Dyskinesia [see Warnings and Precautions (5.5) ] Postural Deformity [see Warnings and Precautions ( 5.6 ) ] Rhabdomyolysis [see Warnings and Precautions (5.8) ] Retinal Pathology [see Warnings and Precautions (5.9) ] Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.10) ] Withdrawal Symptoms [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (incidence ≥5% and greater than placebo) : Early PD without levodopa: somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema (6.1) Advanced PD with levodopa: dyskinesia, nausea, constipation, hallucinations, headache, and anorexia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr.
- Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.
- During the premarketing development of pramipexole dihydrochloride extended-release tablets, patients with early Parkinson's disease were treated with pramipexole dihydrochloride extended-release tablets, placebo, or immediate-release pramipexole tablets.
- In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to extended-release pramipexole tablets.
- In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed.
- In a third trial, advanced Parkinson’s disease patients received pramipexole extended-release tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa.
- Early Parkinson's Disease The most common adverse reactions (≥5% and more frequent than placebo) after 33 weeks of treatment with pramipexole dihydrochloride extended-release tablets in the trial of early Parkinson’s disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.
- Twenty four of 223 (11%) patients treated with pramipexole dihydrochloride extended-release tablets for 33 weeks discontinued treatment due to adverse reactions compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets.
- The adverse reaction most commonly causing discontinuation of treatment with pramipexole dihydrochloride extended-release tablets was nausea (2%).
- Table 1 lists adverse reactions that occurred with a frequency of at least 2% with pramipexole dihydrochloride extended-release and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease.
- In this study, patients did not receive concomitant levodopa
- however, levodopa was permitted as rescue medication.
- Table 1 Adverse-Reactions in a 33-Week Double-Blind, Placebo-Controlled Trial with Pramipexole Dihydrochloride Extended-Release in Early Parkinson’s Disease Body System / Adverse Reaction Placebo Extended-Release Pramipexole Immediate Release Pramipexole (n=103) (n=223) (n=213) % % % Nervous system disorders Somnolence 15 36 33 Dizziness 7 12 12 Tremor 1 3 3 Balance disorder 1 2 0 Gastrointestinal disorders Nausea 9 22 24 Constipation 2 14 12 Dry mouth 1 5 4 Vomiting 0 4 4 Upper abdominal pain 1 3 4 Dyspepsia 2 3 3 Abdominal discomfort 0 2 1 Psychiatric disorders Hallucinations, including visual, auditory and mixed 1 5 6 Insomnia 3 4 4 Sleep attacks or sudden onset of sleep 1 3 6 Sleep disorder 1 2 3 Depression 0 2 0 General disorders and administration site conditions Fatigue 4 6 6 Peripheral edema 4 5 8 Asthenia 2 3 1 Musculoskeletal and connective tissue disorders Muscle spasms 3 5 3 Injury, poisoning and procedural complications Fall 1 4 4 Ear and labyrinth disorders Vertigo 1 4 2 Respiratory, thoracic and mediastinal disorders Cough 1 3 3 Metabolism and nutrition disorders Increased appetite 1 3 2 Vascular disorders Orthostatic hypotension 1 3 0 Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions.
- Adverse reactions can initially occur in either the titration or maintenance phase.
Drug interactions
Open multi-drug checker ↗- Professional use: confirm indication, dose, duration, monitoring and patient counselling points against current Kenya STG / EML and the product SmPC.
- Document allergy status and key interactions.
Mechanism & disposition
12.
Read complete mechanism
12.1 Mechanism of Action Pramipexole is a non-ergot 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. 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 D3 receptor binding in Parkinson’s disease is unknown.
Product-specific
Product-specific
See product SmPC
The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic
Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.
Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.
Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtrati...
between males and females. Age Pramipexole clearance is reduced by approximately 30% in the elderly (aged 65 years or older) compared with young, healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pr...
Pregnancy, lactation & diet
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride extended-release in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not in rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, or 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD.
8.2 Lactation Risk Summary There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole dihydrochloride extended-release and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride extended-release or from the underlying maternal condition. Data In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma.
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| Additional labeling:9 | 16. | tabs 1000's | Unavailable |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.