Pramipexole-NAN

Pramipexole

Tablets

White oblong tablets debossed with “P9AL 0.18”, with narrow score line on one side and wide score line on the other side.

Each tablet contains:
Active substance: 25 mg of pramipexole dihydrochloride monohydrate which is equivalent of 0.18 mg of pramipexole;
Auxiliary substances: pregelatinised amylum maidis, mannitol (E421), povidone K 29/32, colloidal anhydrous silicon dioxide, magnesium stearate.

Antiparkinsonian medications. Dopamine agonists.

N04BC05

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.

It alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Pramipexole inhibits dopamine synthesis, release, and turnover.

In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where pramipexole prolonged-release tablets were titrated faster (every 3 days) than recommended up to 3.15 mg pramipexole base (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.

Treatment of the signs and symptoms of idiopathic Parkinson’s disease in adults, 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).

The medication is indicated in adults for symptomatic treatment of moderate to severe idiopathic restless legs syndrome in dosages up to 0.75 mg of salt (0.54 mg of base).

All information regarding dosing is given below for pramipexole in the form of pramipexole dihydrochloride monohydrate (of salt).
Tablets should be taken orally with water and with or without meals.

Parkinson’s disease
The daily dose is administered in equally divided doses 3 times a day.

Initial treatment
As indicated below doses 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 undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect.

Table 1 Ascending dose schedule of Pramipexole-NAN

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. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg per day.

Supporting therapy
The individual dose should be in the range of 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.5 mg. 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. In advanced Parkinson’s disease, pramipexole doses higher than 1.5 mg per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with Pramipexole-NAN, depending on reactions in individual patients (see Section Interaction with other medicines).

Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole dose should be reduced according to the 0.75 mg per day schedule up to a dose of 0.75 mg per day. After that the dose should be reduced to 0.375 mg per day (see Section Special warnings and precautions for use).

Patients with renal impairment
The elimination of pramipexole is dependent on renal function. The following dose schedule is proposed for initial 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-NAN should be administered in two divided doses, starting at 0.125 mg twice a day. A maximum daily dose of 2.25 mg should not be exceeded.

In patients with a creatinine clearance below 20 ml/min, the initial daily dose of Pramipexole-NAN should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg should not be exceeded.

If renal function declines during maintenance therapy, the daily dose of Pramipexole-NAN should be reduced by the same percentage as the decline in creatinine clearance. So, if creatinine clearance declines by 30%, then the daily dose of Pramipexole-NAN should be reduced 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.

Patients with hepatic impairment
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys. The potential influence of hepatic insufficiency on Pramipexole-NAN pharmacokinetics has not been investigated.

Children and adolescents
The safety and efficacy of pramipexole in children below 18 years has not been established. There is no relevant use of Pramipexole-NAN in children and adolescents for the indication of Parkinson’s disease.

Restless Legs Syndrome
The recommended starting dose of Pramipexole-NAN 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 below).

Table 2 Ascending dose schedule of Pramipexole-NAN

* if needed

Patient’s response to pramipexole 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 above.

Treatment discontinuation
Since the daily dose for the treatment of restless legs syndrome will not exceed 0.75 mg, Pramipexole-NAN can be discontinued without tapering off. In a 26 week placebo controlled trial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients after abrupt discontinuation of treatment. This effect was found to be similar across all doses.

Patients with 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 pramipexole has not been studied in hemodialysis patients, or in patients with severe renal impairment.

Patients with hepatic impairment
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys.

Children and adolescents
Pramipexole-NAN is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Tourette Disorder
Children and adolescents
Pramipexole should not be used in children or adolescents with Tourette disorder because of a negative benefit-risk balance for this disorder.

Concurrent reactions are presented by classes of organ systems and occurrence rate: very common (≥ 1/10), common (≥ 1/100, but < 1/10), uncommon (≥ 1/1000, but < 1/100), rare (≥ 1/10000, but < 1/1000), very rare (< 1/10000).

Parkinson’s disease
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 pramipexole salt per day (see Section Dosage and administration). 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.

¹This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson’s disease treated with pramipexole.

Restless Legs Syndrome
The most commonly (≥ 5%) reported adverse drug reactions in patients with restless legs syndrome treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often reported in female patients treated with pramipexole (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%, respectively).

¹This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 1,395 patients with restless legs syndrome treated with pramipexole.

If any of the undesirable effects listed in the instructions worsen, or you notice any other undesirable effects not listed in the instructions, inform your doctor about it.

• Hypersensitivity to pramipexole or to any other component of Pramipexole-NAN.
• Children under 18 years of age.

If taking a larger dose than prescribed by your doctor, immediately contact specialists to provide timely medical care!

Symptoms
There is no clinical experience with massive overdosage. The expected adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension.

Treatment
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.

If you forget to take your daily dose of Pramipexole-NAN, do not take a double dose to make up for a forgotten tablet, take your next dose at its usual time.

Do not stop taking Nebivolol-NAN without consulting your doctor. Treatment with pramipexole should be discontinued gradually over several days. Abrupt discontinuation of dopaminergic therapy can lead to the development of neuroleptic malignant syndrome, which is characterized by muscle stiffness, fever, blood pressure instability, tachycardia, confusion or depression of consciousness.

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, mexiletine, zidovudine, cisplatin, quinine and procainamide may interact with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with Pramipexole-NAN.

Combination with levodopa
When pramipexole 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 pramipexole.

Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see Sections Special warnings and precautions for use, Effects on ability to drive and use potentially dangerous machines, Undesirable effects).

Antipsychotic medicinal products
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see Section Special warnings and precautions for use), e.g. if antagonistic effects can be expected.

Inform your doctor about all medications you are taking. Consult your doctor before you start taking any medication during treatment with Pramipexole-NAN.

When prescribing pramipexole in a patient with Parkinson’s disease with renal impairment a reduced dose is suggested in line with Section Dosage and 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 pramipexole. If they occur, the dose of levodopa should be decreased.

Dystonia
Inform your doctor if you have any medical conditions or symptoms, especially those described below:

• dyskinesia;
• dystonia;
• inability to keep the body and neck straight and upright (axial dystonia).

In particular, you may develop a forward tilt of the head and neck (antecollis), an involuntary forward tilt of the torso (flexion in the thoracic and lumbar spine), which increases with prolonged standing and walking, decreases or disappears in a horizontal position (camptocormia), or lateral bending of the back (Pisa Syndrome). If this happens, your doctor may change the treatment regimen.

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 Pramipexole-NAN medication. 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 (see Sections Interaction with other medicines, Effects on ability to drive and use machines, Possible side effects).

Impulse control disorders and compulsive behavior
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural 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 pramipexole. Regularly monitor the development of such manifestations while taking the medication. Dose reduction/tapered discontinuation should be considered if behavioural symptoms of impulse control disorders develop.

Severe cardiovascular diseases
In case of severe cardiovascular disease, special 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.

Mania and delirium
Patients should be regularly monitored for the development of mania and delirium. Patients and carers should be made aware that mania and delirium can occur in patients treated with pramipexole. 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 (see Section Drug-to-drug interactions).

Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.

Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy.

Dopamine agonist withdrawal syndrome (DAWS)
To discontinue treatment in patients with Parkinson’s disease, pramipexole should be tapered off (see Section Dosage and administration). Patients receiving cumulative doses of dopamine agonists, including pramipexole may be at higher risk for developing non-motor undesirable effects. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating and pain and may be of severe intensity. Prior to tapering off and discontinuing pramipexole, patients should be informed about potential withdrawal symptoms and should be closely monitored in the time following. In case of severe and/or persistent withdrawal symptoms, temporary re-administration of pramipexole may be considered. (see Section Undesirable effects).

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. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks. Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole and placebo groups.

If you have one of the diseases or conditions listed above, consult your healthcare provider before taking Pramipexole-NAN.

Inform your doctor before starting the treatment if you are pregnant or planning to become pregnant, or if you are breastfeeding.

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole-NAN should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of Pramipexole-NAN into breast milk has not been studied in women, so it is not recommended to use it during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

The safety and efficacy of Pramipexole-NAN in children under the age of 18 years have not been established, so Pramipexole-NAN is not used in children.

Pramipexole-NAN can have a major influence on the ability to drive and use machines.

Hallucinations or somnolence can occur. So patients 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.

14 tablets in a blister (PA/aluminum/PVC).
2 blisters with a patient information leaflet, packed in a carton.

Protect from light and moisture at a temperature not above 25°C. Keep away from children.

2 years. Do not use after the expiration date.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en