Treatson

Treatson

pramipexole

Manufacturer:

Dexa Medica
Full Prescribing Info
Contents
Pramipexole dihydrochloride monohydrate.
Description
TREATSON 0.125: Each tablet contains: Pramipexole dihydrochloride monohydrate 0.125 mg equivalent to pramipexole 0.08737 mg.
TREATSON 0.25: Each tablet contains: Pramipexole dihydrochloride monohydrate 0.25 mg equivalent to pramipexole 0.1747 mg.
Action
Pharmacology: 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. Pramipexole inhibits dopamine synthesis, release, and turnover.
The mechanism of action of pramipexole as a treatment for restless legs syndrome (RLS) is not known. Although the pathophysiology of restless legs syndrome is large unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of restless legs syndrome (RLS).
Pharmacokinetics: Pramipexole is rapidly absorbed following oral administration. TREATSON tablet has been studied in a randomized, open label, two-period, two sequence, cross-over study under fasting condition which included 22 healthy adult male and female subjects.
After oral administration of a single dose of 0.25 mg TREATSON tablets, the mean of AUCt and AUCinf were 7355.76 pg·h/ml and 7996.24 pg·h/ml, respectively. The mean of maximum plasma concentration (Cmax) was 684.43 pg/ml and reached within 2 hours (0.67-4.00 hours). The mean elimination half-life (t½) of TREATSON tablets was 8.82 hours. The geometric mean ratios (90% confidence intervals) of TREATSON tablets were 95.89% (90.73-101.34%) for AUCt; 95.53% (89.75-101.68%) for AUCinf; and 92.11% (84.35-100.58%) for Cmax. The result of the study showed that the pharmacokinetic parameters of TREATSON tablets were within the acceptance range for bioequivalence, therefore, TREATSON tablets were similar or bioequivalent to the reference drug.
Indications/Uses
Parkinson's disease: Pramiprexole is indicated for the treatment of the signs and symptoms of idiopathic parkinson's 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). It may be used alone (without levodopa) or in combination with levodopa.
Pramipexole is indicated for the symptomatic treatment of idiopathic restless legs syndrome.
Dosage/Direction for Use
All dose information refers to pramipexole salt form.
Parkinson's disease: The tablets should be taken orally, swallowed with water, and can be taken either with or without food. The daily dose is administered in equally divided doses 3 times a day.
Initial treatment:
As shown as follows dosages should be increased gradually from a starting dose of 0.375 mg per day and then increased every 5-7 days. Providing patients do not experience intolerable side effects, the dosage should be titrated to achieve a maximal therapeutic effect, as shown in Table 1. (See Table 1.)


Click on icon to see table/diagram/image


If a further dose increase is necessary the daily dose should be increased by 0.75 mg at weekly intervals up to a maximum dose of 4.5 mg per day.
Maintenance treatment: The individual dose of pramipexole should be in the range of 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in pivotal studies both in early and advanced disease efficacy was observed starting at a daily dose of 1.5 mg. This does not preclude that in individual patients doses higher than 1.5 mg per day can result in additional therapeutic benefit. This applies particularly to patients with advanced disease where a reduction of the levodopa therapy is intended.
Further dose adjustments should be done based on the clinical response and tolerability. In advanced Parkinson's disease, pramipexole doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dosage of levodopa is reduced during both the dose escalation and the maintenance treatment with pramipexole, depending on reactions in individual patients.
Treatment discontinuation: Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Therefore, pramipexole should 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 should be reduced by 0.375 mg per day.
Dosing in patients with co-administration levodopa therapy: In patients with co-administration levodopa therapy it is recommended that the dosage of levodopa is reduced during both dose escalation and maintenance treatment with pramipexole. This may be necessary in order to avoid excessive dopaminergic stimulation.
Dosing in patients with renal impairment: The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested for initiation of therapy: Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing frequency.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of pramipexole should be administered in two divided doses, starting at 0.125 mg twice a day (0.25 mg daily). A maximum daily dose of pramipexole 2.25 mg should not be exceeded.
In patients with a creatinine clearance less than 20 ml/min, the daily dose of pramipexole tablets should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg pramipexole should not be exceeded.
If renal function declines during maintenance therapy reduce pramipexole daily dose by same percentage as decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce pramipexole daily dose by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min and as a single daily dose if creatinine clearance is less than 20 ml/min.
If renal function declines during maintenance therapy the recommendations given previously should be followed.
Dosing in patients with hepatic impairment: Dose adjustment in patients with hepatic failure is probably not necessary, as approximately 90% of absorbed drug is excreted through the kidneys. However, the potential influence of hepatic insufficiency on pramipexole pharmacokinetics has not been investigated.
Restless legs syndrome (RLS): The tablets should be taken orally, swallowed with water, and can be taken either with or without food.
The recommended starting dose of pramipexole is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a maximum of 0.75 mg per day, as shown in Table 2. (See Table 2.)


Click on icon to see table/diagram/image


As long-term efficacy of pramipexole in the treatment of restless legs syndrome has not been sufficiently tested, patient's response should be evaluated after 3 months 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: Pramipexole can be discontinued without tapered dose reduction.
Dosing in patients with renal impairment: The elimination of pramipexole is dependent on renal function and closely related to the creatinine clearance. Patients with a creatinine clearance above 20 ml/min require no reduction in daily dose. The use of pramipexole in restless legs syndrome patients with renal impairment has not been studied.
Dosing in patients with hepatic impairment: Dose reduction in patients with hepatic impairment is not considered necessary, as approximately 90% of absorbed drug is excreted through the kidneys.
Dosing in children and adolescent: Safety and efficacy of pramiprexole have not been established in children and adolescents up to 18 years.
Overdosage
Symptoms: There is no clinical experience with massive overdose. The expected adverse reactions should be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension.
Therapy: There is no established antidote for 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.
Hemodialysis has not been shown to be helpful.
Contraindications
Hypersensitivity to pramipexole or to any of the excipients.
Special Precautions
When prescribing pramipexole in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with Dosage & Administration.
Hallucinations: Hallucinations and confusion are known as side effects of treatment with dopamine agonists and levodopa in Parkinson's disease patients. Hallucinations were more frequent when pramipexole was given in combination with levodopa in Parkinson's disease patients with advanced disease than in monotherapy in Parkinson's disease patients with early disease. Patients should be informed that (mostly visual) hallucinations can occur. Patients should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
Patients and caregivers should be aware of the fact that abnormal behaviour (reflecting symptoms of impulse control disorders and compulsive behaviours) such as binge eating, compulsive shopping, hypersexuality and pathological gambling have been reported in patients treated with dopaminergic drugs. Dose reduction/tapered discontinuation should be considered.
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.
Patients should be alerted to the potential sedating effects associated with pramipexole including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor operate other complex machinery until they gave gained sufficient experience with pramipexole to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g. conversations, eating, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities and should contact their physician.
Patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
Patients and providers are advised to monitor for melanoma when using pramipexole or other dopaminergic drugs.
Parkinson's disease: Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy.
Augmentation in restless legs syndrome (RLS): 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.
Effects on ability to drive and use machines: Patient should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive (see Hallucinations as previously mentioned).
Use In Pregnancy & Lactation
Pregnancy: The effect on pregnancy has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses. Pramipexole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers: The excretion of pramipexole into breast milk has not been studied in women. As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. In consequence, pramipexole should not be used during breast-feeding.
Adverse Reactions
The following adverse reactions are listed under the use of pramipexole: abnormal behavior (reflecting symptoms of impulse control disorders and compulsion) such as binge eating, compulsive shopping, hypersexuality and pathological gambling; abnormal dreams, amnesia, confusion, constipation, delusion, dizziness, dyskinesia, dyspnea, fatigue, hallucinations, headache, hyperkinesia, hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral edema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual disturbance including vision blurred and visual acuity reduced, vomiting, weight decrease, weight increase.
In individual patients, hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.
Pramipexole may be associated with disorders of libido (increase or decrease).
Patients treated with pramipexole tablets have reported falling asleep during activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Some of them did not report a warning sign such as somnolence, which is a common occurrence in patients receiving pramipexole tablets at doses above 1.5 mg/day, and which, according to the current knowledge of sleep physiology, always proceeds falling asleep. There was no clear relation to the duration of treatment. Some patients were taking other medication with potentially sedative properties. In most cases where information was available, there were no further episodes following reduction of dosage or termination of therapy.
Patients treated with dopamine agonists for Parkinson's disease, including pramipexole, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.
Drug Interactions
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.
Medication that inhibit the active renal tubular secretion of basic (cationic) drugs, such as cimetidine, or are themselves eliminated by active renal tubular secretion, may interact with pramipexole resulting in reduced clearance of either or both medication. In case of co-administration treatment with these kinds of drugs (including amantadine) attention should be paid to signs of dopamine over stimulation, such as dyskinesias, agitation or hallucinations. In such cases a doses reduction is necessary.
Selegiline and levodopa do not influence the pharmacokinetics of pramipexole. The overall extent of absorption or elimination of levodopa is not changed by pramipexole. The interaction with anticholinergics and amantadine has not been examined.
As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole are rather unlikely. With amantadine, an interaction is possible via the same system of excretion in the kidney.
While increasing the dose of pramipexole in Parkinson's disease patients it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication kept constant.
Because of possible additive effects, caution should be advised when patients are taking other sedating mediation or alcohol in combination with pramipexole and when taking co-administration medication that increase plasma levels of pramipexole (e.g. cimetidine).
Co-administration of antipsychotic medicinal products with pramipexole should be avoided.
Storage
Store at temperature below 30°C.
ATC Classification
N04BC05 - pramipexole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.
Presentation/Packing
Tab 0.125 mg x 3 x 10's. 0.25 x 3 x 10's.
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