PEXSON 0,75 XR

Indications

• Parkinson's disease
• Moderate to severe restless legs syndrome

Dosage

Adults: Initially 88 micrograms three times a day, increased to 350 micrograms three times a day as tolerated, with maximum daily dose of 3.3 mg. For restless legs syndrome, start at 88 micrograms once daily, increasing to a maximum of 540 micrograms per day if necessary.

Mechanism of action

Pramipexole stimulates dopamine receptors in the striatum, a brain region vital for motor control, reducing symptoms of Parkinson's disease and potentially influencing mood regulation through effects on extrastriatal dopaminergic regions. It selectively binds to D2 and D3 receptors, demonstrating a preference for the D3 subtype, which may contribute to its therapeutic effects.

Pharmacodynamics

Pramipexole alleviates motor symptoms in Parkinson's disease by compensating for reduced dopamine levels in the brain, particularly in the substantia nigra. It also restores dopaminergic balance in restless legs syndrome, alleviating uncomfortable sensations in the legs. Animal studies suggest it may block dopamine synthesis, release, and turnover while providing neuroprotection against dopaminergic neuron degeneration.

Pharmacokinetics

Pramipexole is well absorbed orally, with peak plasma concentrations occurring approximately 1-2 hours after administration. It has a half-life of about 8-12 hours, allowing for once or thrice daily dosing depending on the indication. The drug is primarily excreted unchanged in urine, and its clearance may be affected by renal function, necessitating dose adjustments in patients with renal impairment.

Contra-indications

• Hypersensitivity to pramipexole or any of its components
• Hypersensitivity to ergot alkaloids

Adverse effects

• Excessive daytime sleepiness
• Sudden onset of sleep
• Hypotension
• Nausea
• Dizziness
• Fatigue
• Hallucinations
• Peripheral edema

Interactions

• isavuconazole + pramipexole: Moderate (increases exposure)
• dolutegravir + pramipexole: Moderate (increases exposure)
• H2 receptor antagonists + pramipexole: Moderate (increases exposure)
• ranolazine + pramipexole: Moderate (increases exposure)
• trimethoprim + pramipexole: Moderate (increases exposure)
• vandetanib + pramipexole: Moderate (increases exposure)
• cimetidine + pramipexole: Moderate (increases exposure)
• memantine + pramipexole: Unknown (increases effects)
• metoclopramide + pramipexole: Unknown (decreases effects)

Precautions

• Caution in patients with hepatic impairment
• Monitor for fibrotic disease
• Monitor blood pressure after starting treatment and following dosage increases
• Management of excessive daytime sleepiness is important
• Patients should be counselled on the risk of sedation affecting driving and skilled tasks

Pregnancy

Discontinue if pregnancy occurs during treatment. Specialist advice is needed.

Breast-feeding

Avoid breastfeeding if lactation prevention fails, as pramipexole suppresses lactation.

Storage

Store in the original container (contains desiccant) at room temperature, away from moisture and light.

Formulations

• Immediate-release tablets: 125 micrograms, 250 micrograms, 500 micrograms
• Modified-release tablets: 375 micrograms, 750 micrograms, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg

Mechanism of action

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-

Pharmacodynamics

**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.