Pramipexole

211.33

211.33

1806241-263-5

83619PEU5T

DTXSID6023496

N04BC05|N - Nervous system

2934999090

79.2

1.9

Solid

1.17±0.1 g/cm3(Predicted)

288-290°C

378°C

182.4±27.9 °C

1.583

1.40e-01 g/L

-20°C Freezer

1.55X10-5 mm Hg at 25 deg C (est)

5.6, 9.5

Henry's Law constant = 5.1X10-13 atm-cu m/mol at 25 °C (est)

5.6, 9.5|pKa1 = 4.65 (imine); pKa2 = 10.31 (secondary amine); pKa3 = 17.66 (primary amine) (est)

White to off-white powder, mp 296-301 °C (decomposes). Specific optical rotation: -67.2 deg at 20 °C/D(c = 1 in methanol). Solubility: water >20%; methanol ~8 %; ethanol ~0.5%. Practically insoluble in dichloromethane. /Pramipexole dihydrochloride monohydrate/|Hydroxyl radical reaction rate constant = 1.1X10-10 cu cm/molec-sec at 25 °C (est)

3

R36/37/38:Irritating to eyes, respiratory system and skin .

S26-S36

Xi

Stable under recommended storage conditions. /Pramipexole dihydrochloride/

P261, P264, P270, P271, P272, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P321, P322, P330, P333+P313, P363, P501

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Pramipexole dihydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pramipexole dihydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pramipexole dihydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P272, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P321, P322, P330, P333+P313, P363, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Skin protection: Handle with gloves. /Pramipexole dihydrochloride/|Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Pramipexole dihydrochloride/|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Pramipexole dihydrochloride/|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Pramipexole dihydrochloride/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Pramipexole dihydrochloride/|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Pramipexole dihydrochloride/

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Pramipexole dihydrochloride/

Appropriate engineering controls: General industrial hygiene practice. /Pramipexole dihydrochloride/|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. /Pramipexole dihydrochloride/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Pramipexole dihydrochloride/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

**LD50** Rat Oral LD 50 >800 mg/kg. **Carcinogenicity, mutagenicity, impact on fertility** Pramipexole was not found to be carcinogenic in 2-year studies on mice and rats at 0.3, 2.2, and 11 times the maximum recommended human dose (MRHD). No increased incidence of tumors was observed. No mutagenicity was detected in various assays, including the Ames test. Finally, pramipexole given to rat models at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose), increased estrus cycles and inhibited implantation of a fertilized ovum. Decreased levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy, were measured. The significance of these findings in humans is unknown. **Pregnancy** This drug is considered a pregnancy category C drug, showing teratogenic effects in animals. Currently, there no studies of pramipexole in human pregnancy. Animal reproduction studies are not always predictive of human response. This drug should only be used in pregnancy if the potential benefit outweighs the possible fetal risks. **Nursing** Whether pramipexole is excreted in human milk is unknown. A decision should be made regarding the administration pramipexole during nursing, or whether to discontinue it during nursing, as many drugs are excreted in human milk. The potential exists for risk to the infant if pramipexole is, in fact, excreted in the milk.|IDENTIFICATION AND USE: Pramipexole, a synthetic benzothiazolamine derivative, is a nonergot-derivative dopamine receptor agonist. It is used for the symptomatic management of idiopathic parkinsonian syndrome. It is also used for the symptomatic management of moderate-to-severe primary restless legs syndrome. HUMAN EXPOSURE AND TOXICITY: There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose. Postmarketing reports with medication used to treat Parkinson's disease, including pramipexole, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole or after starting or increasing the dose of pramipexole. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including pramipexole, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. ANIMAL STUDIES: Single dose toxicity of pramipexole after oral administration was studied in rodents, dogs and monkeys. In rodents, CNS-related signs at high doses included ataxia, dyspnea and tremor/convulsions. In dogs, vomiting occurred at 0.0007 mg/kg and above. Monkeys displayed major excitation at 3.5 mg/kg. Pramipexole was administered to mice for two years at drug in-diet-doses of 0.3, 2, or 10 mg/kg/day. With the exception of statistically significant decreases in adrenal cortical adenomas in males at 10 mg/kg and malignant lymphomas in females at 2 and 10 mg/kg, the incidence of neoplastic changes was similar in treated and control animals. Pramipexole was administered to rats for two years by drug-in-diet, at doses of 0.3, 2, or 8 mg/kg/day. A statistically significant increase in the incidence of Leydig cell adenomas was noted in males at 2 and 8 mg/kg. The following neoplasms were significantly decreased in rats at 2 and 8 mg/kg: mammary gland neoplasia in females, pituitary adenomas in both sexes, total number of primary neoplasms in females. Additionally, a decrease in the incidence of benign adrenal medullary neoplasms was observed in female rats at 0.3, 2, and 8 mg/kg/day. Although retinal degeneration was observed in albino rats given 2 or 8 mg/kg/day, no retinal degeneration was noted at the low dose of 0.3 mg/kg/day. No retinal degeneration was seen in the two year carcinogenicity study in mice, in the one year drug-in-diet rat study, or in any other study in any species. The treatment of albino rats with pramipexole clearly reduced the rate of disk shedding from photoreceptor cells. This change was associated with increased sensitivity of the retina of albino rats to the damaging effects of light. In contrast, pigmented rats had absolutely no degeneration of any portion of the retina. When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos. 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). 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. Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day or greater during the latter part of pregnancy and throughout lactation. In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day, prolonged estrus cycles and inhibited implantation. Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

Pramipexole has been reported to cause serum aminotransferase elevations in a small proportion of patients, but these abnormalities are usually mild, asymptomatic and self-limiting even without dose adjustment. Pramipexole has not been implicated in cases of clinically apparent acute liver injury which must be rare, if it occurs at all.

Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with Mirapex and when taking concomitant medication that increase plasma levels of pramipexole (e.g. cimetidine).|Concomitant therapy with drugs secreted by the renal cationic transport system (e.g., amantadine, cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine), may decrease the oral clearance of Mirapex and thus, may necessitate an adjustment in the dosage of Mirapex. In case of concomitant treatment with these kinds of drugs (incl. amantadine) attention should be paid to signs of dopamine overstimulation, such as dyskinesias, agitation or hallucinations. In such cases a dose reduction is necessary. Concomitant therapy with drugs secreted by the renal anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide and chlorpropamide) are not likely to have any effect on the oral clearance of Mirapex.|Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, increased Mirapex AUC by 50% and increased its half-life by 40% in volunteers (N = 12).|In volunteers (N = 11), selegiline did not influence the pharmacokinetics of pramipexole. Population pharmacokinetic analysis suggests that amantadine may alter the oral clearance of pramipexole (N = 54). Levodopa/carbidopa did not influence the pharmacokinetics of pramipexole in volunteers (N = 10). Pramipexole did not alter the extent of absorption (AUC) or elimination of levodopa/carbidopa, although it increased levodopa Cmax by about 40%, and decreased Tmax from 2.5 to 0.5 hours. While increasing the dose of Mirapex in Parkinson's disease patients it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication is kept constant.|Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Mirapex tablets.

LD50 Rat iv 210 mg/kg|LD50 Rat (female) oral >548 mg/kg|LD50 Rat (male) oral >800 mg/kg|LD50 Mouse (female) iv 188.3 (151.9-194.9) mg/kg|For more Non-Human Toxicity Values (Complete) data for PRAMIPEXOLE (6 total), please visit the HSDB record page.

Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including Mirapex, because of the risk of exacerbating the psychosis.|The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering Miraoex tablets to patients with renal disease

About 15% bound to plasma proteins.

This drug is indicated for the symptomatic treatment of Parkinson’s disease. This drug can be administered as monotherapy or in conjunction with levodopa. It is also indicated for symptomatic treatment of moderate to severe primary Restless Legs Syndrome (RLS).|FDA Label|Sifrol is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, though to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end-of-dose or 'on-off' fluctuations).Sifrol is indicated for symptomatic treatment of moderate to severe idiopathic restless-legs syndrome in dosages up to 0.54 mg of base (0.75 mg of salt).|Mirapexin is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end-of-dose or 'on-off' fluctuations).Mirapexin is indicated for symptomatic treatment of moderate to severe idiopathic restless-legs syndrome in dosages up to 0.54 mg of base (0.75 mg of salt).|Oprymea is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or "on off" fluctuations).Oprymea is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).|Pramipexole Teva is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end-of-dose or 'on-off' fluctuations).Pramipexole Teva is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).|Pramipexole Accord is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end-of-dose or 'on-off' fluctuations).|DAQUIRAN tablets are indicated for treatment of the signs and symptoms of advanced idiopathic Parkinson's disease in combination with levodopa, i.e. over the course of the disease, when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or "on off" fluctuations).

Pramipexole is a selective dopamine receptor agonist used in the therapy of Parkinson disease. Pramipexole therapy is associated with a low rate of transient serum enzyme elevations during treatment, but has not been implicated in cases of clinically apparent acute liver injury.

Antiparkinson Agents

Antioxidants; Antiparkinson Agents; Dopamine Agonists|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health(NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Pramipexole is included in the database.|Mirapex tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). /Included in US product label/|Mirapex tablets are indicated for the treatment of Parkinson's disease. /Included in US product label/|For more Therapeutic Uses (Complete) data for PRAMIPEXOLE (7 total), please visit the HSDB record page.

Postmarketing reports with medication used to treat Parkinson's disease, including Mirapex, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Mirapex or after starting or increasing the dose of Mirapex. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.|Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including Mirapex, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Mirapex.|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 Mirapex, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.|There are no adequate and well-controlled studies in pregnant women. Mirapex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.|For more Drug Warnings (Complete) data for PRAMIPEXOLE (13 total), please visit the HSDB record page.

**Parkinson's Disease** Through the stimulation of dopamine receptors, pramipexole is thought to relieve the symptoms of Parkinson's Disease. The motor symptoms of Parkinson's disease occur partly due to a reduction of dopamine in the substantia nigra of the brain. Dopamine is an essential neurotransmitter that has major effects on motor movements in humans. **Restless Legs Syndrome** Pramipexole likely restores balance to the dopaminergic system, controlling the symptoms of this condition. Restless legs syndrome is thought to occur, in part, through dysfunction of the dopaminergic system, resulting in unpleasant lower extremity symptoms,. **Other effects** In addition to the abovementioned effects, animal studies demonstrate that pramipexole blocks dopamine synthesis, release, and turnover. Additionally, this drug is neuroprotective to dopamine neuron degeneration after ischemia or methamphetamine neurotoxicity.

Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues. (See all compounds classified as Antioxidants.)|Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)|Drugs that bind to and activate dopamine receptors. (See all compounds classified as Dopamine Agonists.)

The bioavailability of pramipexole is higher than 90%, indicating a high level of absorption.|The main route of pramipexole elimination, with 90% of a pramipexole dose found in the urine, almost entirely as unchanged drug.|This drug is extensively distributed in the body with a volume of distribution of approximately 500 L.|Renal clearance is about 400 mL/min, indicating heavy secretion by the renal tubules.|Pramipexole is extensively distributed, having a volume of distribution of about 500 L. Protein binding is less than 20% in plasma; with albumin accounting for most of the protein binding in human serum. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately 2.0 and a blood to plasma ratio of approximately 1.5. Consistent with the large volume of distribution in humans, whole body autoradiography and brain tissue levels in rats indicated that pramipexole was widely distributed throughout the body, including the brain.|Urinary excretion is the major route of pramipexole elimination. Approximately 88% of a 14C-labelled dose was recovered in the urine and less than 2% in the faeces following single intravenous and oral doses in healthy volunteers. The terminal elimination half-life was about 8.5 hours in young volunteers (mean age 30 years) and about 12 hours in elderly volunteers (mean age 70 years). Approximately 90% of the recovered (14)C-labelled dose was unchanged drug; with no specific metabolites having been identified in the remaining 10% of the recovered radio-labelled dose. Pramipexole is the levorotational (-) enantiomer, and no measurable chiral inversion or racemization occurs in vivo.|Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.|The objective of the study was to investigate the anodal iontophoretic delivery of pramipexole (PRAM), a dopamine agonist used for the treatment of Parkinson's disease, in order to determine whether therapeutic amounts of the drug could be delivered across the skin. Preliminary iontophoretic experiments were performed in vitro using porcine ear and human abdominal skin. These were followed by a pharmacokinetic study in male Wistar rats to determine the drug input rate in vivo. Stability studies revealed that after current application (0.5 mA/cm(2) for 6h), the solution concentration of PRAM was only 60.2 + or - 5.3% of its initial value. However, inclusion of sodium metabisulfite (0.5%), an antioxidant, increased this to 97.2 + or - 3.1%. Iontophoretic transport of PRAM across porcine skin in vitro was studied as a function of current density (0.15, 0.3, 0.5 mA/cm(2)) and concentration (10, 20, 40 mM). Increasing the current density from 0.15 to 0.3 and 0.5 mA/cm(2), resulted in 2.5- and 4-fold increases in cumulative permeation, from 309.5 + or - 80.2 to 748.8 + or - 148.1 and 1229.1 + or - 138.6 ug/sq cm, respectively. Increasing the PRAM concentration in solution from 10 to 20 and 40 mM resulted in a 2-fold increase in cumulative permeation (816.4 + or - 123.3, 1229.1 + or - 138.6 and 1643.6 + or - 201.3 u g/sq cm, respectively). Good linearity was observed between PRAM flux and both the applied current density (r(2)=0.98) and drug concentration in the formulation (r(2)=0.99). Co-iontophoresis of acetaminophen showed that electromigration was the dominant electrotransport mechanism (accounting for >80% of delivery) and that there was no inhibition of electroosmotic flow at any current density. Cumulative iontophoretic permeation across human and porcine skin (after 6 hr at 0.5 mA/sq cm) was also shown to be statistically equivalent (1229.1 + or- 138.6 and 1184.8 + or- 236.4 ug/sq cm, respectively). High transport and delivery efficiencies were achieved for PRAM (up to 7% and 58%, respectively). The plasma concentration profiles obtained in the iontophoretic studies in vivo (20 mM PRAM; 0.5 mA/sq cm for 5 hr) were modelled using constant and time-variant input models; the latter gave a superior quality fit. The drug input rate in vivo suggested that PRAM electrotransport rates would be sufficient for therapeutic delivery and the management of Parkinsonism.|For more Absorption, Distribution and Excretion (Complete) data for PRAMIPEXOLE (7 total), please visit the HSDB record page.

This drug undergoes little metabolism in humans.|Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.

About 8.5-12 hours.|The terminal elimination half-life was about 8.5 hours in young volunteers (mean age 30 years) and about 12 hours in elderly volunteers (mean age 70 years).

The exact mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown at this time. It is thought, however, that the ability of pramipexole to cause stimulation of the dopamine receptors in the striatum of the brain, a region that receives a vast array of neurological input and is responsible for a wide variety of functions, may be involved. Studies performed in animals show that pramipexole influences striatal neuronal transmission rates following activation of dopamine receptors. Pramipexole is considered a non-ergot dopamine agonist that shows specificity and strong activity at the D2 subfamily of dopamine receptors in vitro, binding selectively and dopamine D2 receptors and showing a preference for the dopamine D3 receptor subtype rather than other subtypes. The clinical significance of this binding specificity is unknown,.|The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D(2) receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using (11)C-FLB 457 for quantification of D(2)/D(3) receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D(2)/D(3) receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects.|Pramipexole dihydrochloride, a synthetic benzothiazolamine derivative, is a nonergot-derivative dopamine receptor agonist. In in vitro binding studies, pramipexole demonstrated high binding specificity for and intrinsic activity at dopamine D2 receptors compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide), having a higher affinity for the D3 receptor subtype than for the D2 or D4 subtypes. Pramipexole binds with moderate affinity to alpha2-adrenergic receptors but has little or no affinity for alpha1- or beta-adrenergic, acetylcholine, dopamine D1, or serotonin (5-hydroxytryptamine (5-HT)) receptors.|Our aim was to determine if pramipexole, a D3 preferring agonist, effectively reduced dopamine neuron and fiber loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model when given at intraperitoneal doses corresponding to clinical doses. We also determined whether subchronic treatment with pramipexole regulates dopamine transporter function, thereby reducing intracellular transport of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+). Ten 12-month old C57BL/6 mice were treated with MPTP (or saline) twice per day at 20 mg/kg s.c. (4 injections over 48 h). Mice were pretreated for 3 days and during the 2-day MPTP regimen with pramipexole (0.1 mg/kg/day) or saline. Stereological quantification of dopamine neuron number and optical density measurement of dopamine fiber loss were carried out at 1 week after treatment, using immunostaining for dopamine transporter (DAT) and tyrosine hydroxylase (TH). Additional wild-type (WT) and D3 receptor knockout (KO) mice were treated for 5 days with pramipexole (0.1 mg/kg/day) or vehicle. The kinetics of (3)H-MPP+ and (3)H-DA uptake (Vmax and Km) were determined 24 hr later; and at 24 hr and 14 days dopamine transporter density was measured by quantitative autoradiography. Pramipexole treatment completely antagonized the neurotoxic effects of MPTP, as measured by substantia nigra and ventral tegmental area TH-immunoreactive cell counts. MPTP- induced loss of striatal innervation, as measured by DAT-immunoreactivity, was partially prevented by pramipexole, but not with regard to TH-IR. Pramipexole also reduced DAT- immunoreactivity in non-MPTP treated mice. Subchronic treatment with pramipexole lowered the Vmax for (3)H-DA and (3)H-MPP+ uptake into striatal synaptosomes of WT mice. Pramipexole treatment lowered Vmax in WT but not D3 KO mice; however, D3 KO mice had lower Vmax for (3)H-DA uptake. There was no change in DAT number in WT with pramipexole treatment or D3 KO mice at 24 hr post-treatment, but there was a reduction in WT-pramipexole treated and not in D3 KO mice at 14 days post-treatment. These results suggest that protection occurs at clinically suitable doses of pramipexole. Protection could be due to a reduced amount of MPP+ taken up into DA terminals via DAT. D3 receptor plays an important role in this regulation of transporter uptake and availability.

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.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective beta-1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a beta-1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.|/HUMAN EXPOSURE STUDIES/ The effects and tolerability of pramipexole, a new dopamine D2-receptor agonist, on prolactin, human growth hormone, thyrotropin, cortisol, and corticotropin levels were investigated in a randomized, double-blind, crossover study in 12 healthy volunteers. Single oral doses of 0.1, 0.2, and 0.3 mg pramipexole and placebo were studied over a period of 24 hours. Pramipexole decreased serum prolactin levels in a dose-dependent manner, with a maximum effect after 2 to 4 hours. Serum levels of human growth hormone were dose-dependently increased; however, this effect was only significant 2 hours after drug administration. Furthermore, a slight increase in serum cortisol levels and a slight decrease in serum thyrotropin levels was observed. Our findings show for the first time pharmacodynamic effects of pramipexole after single oral doses in healthy volunteers. The compound was well tolerated and showed an endocrine profile similar to other dopamine D2-agonists.|/HUMAN EXPOSURE STUDIES/ Pramipexole and ropinirole are ... dopamine agonists, both of which have proven efficacy in the treatment of Parkinson's disease. There is, however, uncertainty regarding differences in the adverse event profiles associated with each drug. ... We systematically reviewed the medical literature to identify randomised controlled trials of pramipexole and ropinirole used in the management of Parkinson's disease. Computerised databases (including Medline, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts) were used to identify pertinent articles for inclusion in this study. Trials that compared the dopamine agonists to either levodopa or placebo were included. Adverse events with these drugs included dizziness, nausea, hypotension, hallucinations, and somnolence. We made two separate analyses. In the first analysis, we estimated the pooled relative risk (RR) of adverse events with either pramipexole or ropinirole as compared with levodopa. In the second analysis, the pooled RRs of adverse events with pramipexole and ropinirole were compared with placebo. We used the random-effects model of DerSimonian and Laird to estimate the RRs and their corresponding 95% CIs. We tested for study heterogeneity using Q statistics. RESULTS: There was no significant difference in the risk of dizziness, nausea, or hypotension with either drug individually or in combination when compared with levodopa. The risk of hypotension was approximately four times higher with ropinirole than pramipexole when each drug was individually compared with placebo (6.46 [95% CI 1.47-28.28] for ropinirole, and 1.65 [0.88-3.08] for pramipexole). The pooled RR (for pramipexole and ropinirole combined) of hallucinations was 1.92 (95% CI 1.08-3.43) when compared with levodopa. Relative to placebo, pramipexole had a significantly higher risk of hallucinations than ropinirole (pramipexole 5.2 (95% CI 1.97-13.72) vs ropinirole 2.75 (95% CI 0.55-13.73)). There was no significant difference in the risk of somnolence between the two drugs when each was individually compared with levodopa. When compared with placebo, the pooled RR (pramipexole and ropinirole combined) of somnolence was 3.16 (95% CI 1.62-6.13). Relative to placebo, the risk of somnolence was 2.01 (95% CI 2.17-3.16) with pramipexole and 5.73 (95% CI 2.34-14.01) with ropinirole. Use of ropinirole seems to be associated with a higher risk of hypotension and somnolence than use of pramipexole when compared with placebo. Use of pramipexole seems to be associated with a higher risk of hallucinations than use of ropinirole when compared with placebo.|/SIGNS AND SYMPTOMS/ Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including Mirapex, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Mirapex. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Mirapex.|For more Human Toxicity Excerpts (Complete) data for PRAMIPEXOLE (22 total), please visit the HSDB record page.

2 Amino 6 propylaminotetrahydrobenzothiazole

Mirapexin is presented as tablets containing pramipexole dihydrochloride monohydrate. There are 5 tablet strengths containing 0.088 mg, 0.18 mg, 0.35 mg, 0.7 mg, and 1.1 mg of the active substance pramipexole, respectively corresponding to 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg, and 1.5 mg of pramipexole dihydrochloride monohydrate. /Pramipexole dihydrochloride monohydrate/|Table: Ropinirole Hydrochloride Preparations [Table#8248]

A highly sensitive and specific LC-MS/MS method has been developed and validated for the estimation of pramipexole (PPX) with 500 uL human plasma using memantine as an internal standard (IS). The API-4000 was operated under multiple-reaction monitoring mode (MRM) using the electrospray ionization technique. Solid-phase extraction was used to extract PPX and IS from human plasma. The resolution of peaks was achieved with 0.01 m ammonium acetate buffer (pH 4.4):acetonitrile (30:70, v/v) on a Discovery CN column. The total chromatographic run time was 3.0 min and the elution of PPX and IS occurred at approximately 2.32 and 2.52, respectively. The MS/MS ion transitions monitored were 212.10 --> 153.10 for PPX and 180.20 --> 107.30 for IS. The method was proved to be accurate and precise at linearity range of 20-3540 pg/mL with a correlation coefficient (r) of > or =0.999. The intra- and inter-day precision and accuracy values found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a pharmacokinetic study in human volunteers following oral administration of 0.25 mg PPX tablet.|A simple, rapid and sensitive method has been developed and validated for the determination of pramipexole in rat plasma by using gas chromatography mass spectrometry. The lower limit of quantification (LLOQ) is superior to the other reported LC-MS/MS methods. After being made alkaline with NaOH, plasma samples (0.1 mL) were subjected to liquid-liquid extraction using methyl-t-butyl ether. Analytes were determined using electron impact ionization in a single quadrupole mass spectrometer. GC/MS was performed in the selected ion monitoring mode using target ions at m/z 211, 212 and 152 for pramipexole and m/z 194 and 165 for caffeine as internal standard. A linear calibration curve was plotted over the range of 20-1000 pg/mL for pramipexole (r(2) > 0.996). The LLOQ was 20.0 pg/mL, respectively, which offered high sensitivity and selectivity enough for bioanalytical investigation. Inter- and intraday precisions ranged from 0.3 to 8.8% and from 0.9 to 11.33%, respectively. The recovery of pramipexole from plasma ranged from 82.4 + or - 7.1 to 87.8 + or - 5.7%. The method fulfills all standards required for bioanalytical methods and can be successfully applied to a pharmacokinetic study of pramipexole in rats.

Human drugs -> Sifrol -> EMA Drug Category|Anti-Parkinson drugs -> Human pharmacotherapeutic group|Human drugs -> Mirapexin -> EMA Drug Category|Human drugs -> Oprymea -> EMA Drug Category|Human drugs -> Pramipexole Teva -> EMA Drug Category|Human drugs -> Pramipexole Accord -> EMA Drug Category|Human drugs -> Daquiran -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients