Oprymea

Pramipexole dihydrochloride monohydrate.

Each prolonged-release tablet contains: OPRYMEA PROLONGED-RELEASE TABLET 0.26 mg: Active substance: Pramipexole dihydrochloride monohydrate: 0.375 mg equivalent to 0.26 mg of pramipexole.
OPRYMEA PROLONGED-RELEASE TABLET 0.52 mg: Active substance: Pramipexole dihydrochloride monohydrate: 0.75 mg equivalent to 0.52 mg of pramipexole.
Excipients/Inactive Ingredient: Hypromellose, maize starch, silica, colloidal anhydrous, magnesium stearate.

Pharmacology: Pharmacodynamics: Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover.
The mechanism of action of pramipexole as a treatment for Restless Legs Syndrome is unknown. Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where OPRYMEA prolonged-release tablets were titrated faster (every 3 days) than recommended up to 4.5 mg of salt per day, an increase in blood pressure and heart rate was observed. Such an effect was not observed in patient studies.
In patients, pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease.
Pharmacokinetics: Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.
In a Phase I trial, where pramipexole immediate-release and prolonged-release tablets were assessed in a fasted state, the minimum and peak plasma concentration (Cmin, Cmax) and exposure (AUC) of the same daily dose of OPRYMEA prolonged-release tablets given once daily and OPRYMEA tablets given three times a day were equivalent.
The once-daily administration of OPRYMEA prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hours compared to the three times daily administration of pramipexole immediate-release tablets.
The maximum plasma concentrations occur at about 6 hours after administration of OPRYMEA prolonged-release tablets once daily and 1 to 3 hours after taking tablets.
A steady state of exposure is reached at the latest after 5 days of continuous dosing.
Concomitant administration with food does generally not affect the bioavailability of pramipexole. Intake of a high-fat meal-induced an increase in peak concentration (Cmax) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by concomitant food intake. The increase in Cmax is not considered clinically relevant. In the Phase III studies that established the safety and efficacy of OPRYMEA prolonged-release tablets, patients were instructed to take study medication without regard to food intake.
While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore the peak concentrations Cmax. A decreased body weight by 30 kg results in an increase in Cmax of 45%. However, in Phase III trials in Parkinson's disease patients no clinically meaningful influence of body weight on the therapeutic effect and tolerability of OPRYMEA prolonged-release tablets was detected.
Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.
In humans, the protein binding of pramipexole is very low (<20%) and the volume of distribution is large (400 L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).
Pramipexole is metabolized in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of the 14C-labelled dose is excreted through the kidneys while less than 2% is found in the feces. The total clearance of pramipexole is approximately 500 mL/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

Oprymea is indicated in adults for the treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. throughout the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur.
Oprymea prolonged-release tablets are indicated for the symptomatic treatment of moderate to severe "Restless Leg Syndrome - RLS" in doses up to 0.75 mg as salt.

Parkinson: Oprymea prolonged-release tablets are a once-a-day oral formulation of pramipexole.
The tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The tablets may be taken either with or without food and should be taken each day at about the same time.
Initial treatment: Doses should be increased gradually from a starting dose of 0.375 mg of salt per day and then increased every 5-7 days. Providing patients do not experience intolerable undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect. (See Table 1.)


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If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt at weekly intervals up to a maximum dose of 4.5 mg of salt per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg of salt per day.
Maintenance treatment: The individual dose of pramipexole should be in the range of 0.375 mg of salt to a maximum of 4.5 mg of salt per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg of salt. Further dose adjustments should be done based on the clinical response and the occurrence of adverse reactions. In clinical trials, approximately 5% of patients were treated at doses below 1.5 mg of salt. In advanced Parkinson's disease, pramipexole doses higher than 1.5 mg of salt per day can be useful in patients where a reduction of levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with OPRYMEA, depending on reactions in individual patients.
Missed dose: When the intake of a dose is missed, OPRYMEA prolonged-release tablets should be taken within 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be left out and the next dose should be taken on the following day at the next regularly scheduled time.
Treatment discontinuation: Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.75 mg of salt per day until the daily dose has been reduced to 0.75 mg of salt. Thereafter the dose should be reduced by 0.375 mg of salt per day.
Renal impairment: The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested: Patients with a creatinine clearance above 50 mL/min require no reduction in daily dose or dosing frequency.
Prolonged-release tablet: In patients with a creatinine clearance between 30 and 50 mL/min, treatment should be started with 0.375 mg of salt OPRYMEA prolonged-release tablets 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. If a further dose increase is necessary, doses should be increased by 0.375 mg of salt at weekly intervals up to a maximum dose of 2.25 mg of salt daily. The treatment of patients with a creatinine clearance below 30 mL/min with OPRYMEA prolonged-release tablets is not recommended as no data are available for this patient population.
Hepatic impairment: Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of the absorbed active substance is excreted through the kidneys.
Paediatric population: OPRYMEA is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Restless Legs Syndrome: The tablet should be taken with water and can be taken with or without food. The recommended starting dose of OPRYMEA is 0.125 mg of salt taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (interval between dosage increments) to a maximum of 0.75 mg of salt per day (as shown in the table as follows). (See Table 2.)


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The patient's response should be evaluated after 3 months of treatment and the need for treatment continuation should be reconsidered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as previously mentioned
Treatment discontinuation: Since the daily dose for the treatment of Restless Legs Syndrome will not exceed 0.75 mg of salt OPRYMEA can be discontinued without tapering off. Recovery of rebound of RLS symptoms (worsening of symptom severity as compared to baseline) after abrupt discontinuation of treatment..
Renal impairment: The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearance above 20 mL/min require no reduction in daily dose.
The use of OPRYMEA has not been studied in hemodialysis patients, or patients with severe renal impairment.
Hepatic impairment: Dose adjustment in patients with hepatic failure is not required, as approx. 90% of the absorbed active substance is excreted through the kidneys.
Paediatric population: OPRYMEA is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

There is no clinical experience with massive overdose. The expected adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation, and hypotension. There is no established antidote for an overdose of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent may be indicated. Management of the overdose may require general supportive measures, along with gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.

Hypersensitivity to the active substance or to any of the excipients.

When prescribing OPRYMEA in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with Dosage & Administration.
Hallucinations: Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia: In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of OPRYMEA. If they occur, the dose of levodopa should be decreased.
Sudden onset of sleep and somnolence: Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with OPRYMEA. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole.
Impulse control disorders: Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioral symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating can occur in patients treated with dopamine agonists including OPRYMEA. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Patients with psychotic disorders: Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole should be avoided.
Ophthalmologic monitoring: Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease: In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.
Neuroleptic malignant syndrome: Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy.
Augmentation: Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities.
Controlled trials of OPRYMEA in patients with restless legs syndrome generally did not last long enough to document this increase. The increased frequency after long-term use of OPRYMEA and the appropriate management of these events have not been evaluated in controlled clinical trials.
Effects on Ability to Drive and Use Machines: OPRYMEA can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with OPRYMEA and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved.

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rats at maternotoxic doses.
OPRYMEA should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the fetus. As pramipexole treatment inhibits the secretion of prolactin in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of active substance-related radioactivity was higher in breast milk than in plasma.
In the absence of human data, OPRYMEA should not be used during breast-feeding. However, if its use is unavoidable, breastfeeding should be discontinued.
No studies on the effect on human fertility have been conducted. These studies did not indicate direct or indirect harmful effects with respect to male fertility.

The following adverse reactions are expected under the use of Oprymea: Abnormal dreams, amnesia, behavioral symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling, confusion, constipation, delirium, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido disorders, mania, nausea, paranoia, peripheral edema, pneumonia, pruritus, rash and another hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease including decreased appetite, weight increase. (See Table 3.)


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The most commonly (≥5%) reported adverse drug reactions in patients with Parkinson's disease more frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of somnolence is increased at doses higher than 1.5 mg of pramipexole salt per day. A more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too fast.
Somnolence: Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes.
Libido disorders: Pramipexole may uncommonly be associated with libido disorders (increased or decreased).
Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including OPRYMEA, especially at high doses, usually reversible with dose reduction or discontinuation.
Cardiac failure: In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study, pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole. An association between pramipexole and heart failure has not been demonstrated.
Inform a doctor of any side effects the patient may experience while taking the drug.

Plasma protein binding: Pramipexole is bound to plasma proteins to a very low (<20%) extent, and little biotransformation is seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and levodopa.
Inhibitors/competitors of active renal elimination pathway: Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as cimetidine, amantadine may interact with pramipexole resulting in reduced clearance of one or both drugs. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with OPRYMEA.
Combination with levodopa: When OPRYMEA is given in combination with levodopa, it is recommended that the dose of levodopa is reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing the dose of OPRYMEA.
Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole.
Antipsychotic medicinal products: Co-administration of antipsychotic medicinal products with pramipexole should be avoided, e.g. if antagonistic effects can be expected.

Store in a dry place, protected from light and moisture, below 30°C.
Shelf Life: 24 months from manufacturing date.

Antiparkinsonian Drugs

N04BC05 - pramipexole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.