1. Name of The Medicinal Products

Pramipixole Dihydrochloride Tablets 0.125mg Taj Pharma
Pramipixole Dihydrochloride Tablets 0.25mg Taj Pharma
Pramipixole Dihydrochloride Tablets 1.5mg Taj Pharma

2. Qualitative and Quantitative Composition

a) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)             0.125mg
Excipients                           q.s

b) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)               0.25mg
Excipients                             q.s

c) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)                1.5mg
Excipients                              q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

4. Clinical particulars

4.1 Therapeutic indications

Pramipixole 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).

4.2 Posology and method of administration

Posology

Parkinson’s disease

The daily dosage is administered in equally divided doses 3 times a day.

Initial treatment

Dosages should be increased gradually from a starting-dose of 0.264 mg of base (0.375 mg of salt) per day and then increased every 5 – 7 days. Providing patients do not experience intolerable undesirable effects, the dosage should be titrated to achieve a maximal therapeutic effect.

If a further dose increase is necessary the daily dose should be increased by 0.54 mg base (0.75 mg salt) at weekly intervals up to a maximum dose of 3.3 mg of base (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/day (see section 4.8).

Maintenance treatment

The individual dose should be in the range of 0.264 mg of base (0.375 mg of salt) to a maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in three pivotal studies, efficacy was observed starting at a daily dose of 1.1 mg of base (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 1.1 mg (1.5 mg of salt). In advanced Parkinson’s disease, 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 Pramipixole, depending on reactions in individual patients (see section 4.5).

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 0.54 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).

Patients with renal impairment

The elimination of pramipexole is dependent on renal function. The following dosage 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 Pramipixole should be administered in two divided doses, starting at 0.088 mg of base (0.125 mg of salt) twice a day (0.176 mg of base/0.25 mg of salt daily). A maximum daily dose of 1.57 mg pramipexole base (2.25 mg of salt) should not be exceeded.

In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipixole should be administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily. A maximum daily dose of 1.1 mg pramipexole base (1.5 mg of salt) should not be exceeded.

If renal function declines during maintenance therapy reduce Pramipixole daily dose by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce the Pramipixole 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.

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. However, the potential influence of hepatic insufficiency on Pramipixole pharmacokinetics has not been investigated.

Paediatric population

The safety and efficacy of Pramipixole in children below 18 years has not been established. There is no relevant use of Pramipixole in the paediatric population in Parkinson’s Disease.

Tourette Disorder

Paediatric population

Pramipixole is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipixole should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder (see section 5.1).

Method of administration

The tablets should be taken orally, swallowed with water, and can be taken either with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

When prescribing Pramipixole in a patient with Parkinson’s disease with renal impairment a reduced dose is suggested in line with section 4.2.

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.

Dyskinesias

In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur during the initial titration of Pramipixole. 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 Pramipixole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole (see sections 4.5, 4.7 and section 4.8).

Impulse control disorders

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. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

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.

Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).

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 (see section 4.2).

Augmentation

Reports in the literature indicate that treatment of another indication with dopaminergic medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Combination with levodopa

When Pramipixole is given in combination with levodopa, it is recommended that the dosage of levodopa is reduced and the dosage of other anti-parkinsonian medicinal products is kept constant while increasing the dose of Pramipixole.

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

Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4), e.g. if antagonistic effects can be expected.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 rat at maternotoxic doses (see section 5.3). Pramipixole should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

As pramipexole treatment inhibits 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, Pramipixole should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

Fertility

No studies on the effect on human fertility have been conducted. In animal studies, pramipexole affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However, these studies did not indicate direct or indirect harmful effects with respect to male fertility.

4.7 Effects on ability to drive and use machines

Pramipixole can have a major influence on the ability to drive and use machines.

Hallucinations or somnolence can occur.

Patients being treated with Pramipixole 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 (see also sections 4.4, 4.5, and 4.8).

4.8 Undesirable effects

Expected adverse effects

The following adverse reactions are expected under the use of pramipexole: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling; cardiac failure, confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other 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.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both groups. 63 % of patients on pramipexole and 52% of patients on placebo reported at least one adverse drug reaction.

Tables 1 and 2 display the frequency of adverse reactions from placebo-controlled clinical trials. The adverse reactions reported in these tables are those events that occurred in 0,1% or more of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. However, the majority of common adverse reactions were mild to moderate, they usually start early in therapy, and most tended to disappear even as therapy was continued.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Parkinson’s disease, most common adverse effects

The most commonly (≥5%) reported adverse 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/day (see section 4.2). 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.

Table 1: Parkinson’s disease

¹ This 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.

Other indication, most common adverse effects

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

Table 2: Other indication

¹ This 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 other indication treated with pramipexole.

Somnolence

Pramipexole is associated with somnolence (8.6%) and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (0.1%). (See also section 4.4).

Libido disorders

Pramipexole may 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 Pramipixole (see section 4.4).

In a cross-sectional, retrospective screening and case-control study including 3090 Parkinson’s disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder during the past six months. Manifestations observed include pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), not being married and self-reported family history of gambling behaviours.

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 (observed risk ratio 1.86; 95% CI, 1.21-2.85).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

There is no clinical experience with massive overdose. The expected adverse events 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 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists.

Mechanism of action

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.

Pharmacodynamic effects

In human volunteers, a dose-dependent decrease in prolactin was observed.

Clinical efficacy and safety in Parkinson’s disease

In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson’ s disease. Placebo-controlled clinical trials included approximately 1800 patients of Hoehn and Yahr stages stages I – IV. Out of these, approximately 1000 were in more advanced stages, received concomitant levodopa therapy, and suffered from motor complications.

In early and advanced Parkinson’s disease, efficacy of pramipexole in the controlled clinical trials was maintained for approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy.

In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole significantly delayed the onset of motor complications, and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However there was no significant difference during the maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson´s disease.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with pramipexole in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for information on paediatric use).

Clinical efficacy and safety in Tourette Disorder

The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of patients in the pramipexole group and more common in the pramipexole-treated patients than in patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%), nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication for patients receiving pramipexole were confusional state, speech disorder and aggravated condition (see section 4.2).

5.2 Pharmacokinetic properties

Absorption

Pramipexole is rapidly and completely absorbed following oral administration. The absolute bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3 hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.

Distribution

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).

Biotransformation

Pramipexole is metabolised in man only to a small extent.

Elimination

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of ¹⁴C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t_½) varies from 8 hours in the young to 12 hours in the elderly.

5.3 Preclinical safety data

Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving the CNS and female reproductive system, and probably resulting from an exaggerated pharmacodynamic effect of pramipexole.

Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.

The potential effects of pramipexole on reproductive function have been investigated in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the selection of animal species and the limited parameters investigated, the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.

A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.

Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species investigated.

6. Pharmaceutical particulars

6.1 List of excipients

Mannitol, Maize starch, Pregelatinised maize starch, Povidone, Colloidal anhydrous silica & Magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Blister pack (Al/Al foil): 10, 20, 30, 60, 90 or 100 tablets, in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of  Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com

Pramipixole Dihydrochloride Tablets 0.125mg, 0.25mg, 1.5mg Taj Pharma

Package leaflet: Information for the patient

(Pramipexole)

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Pramipixole is and what it is used for
2. What you need to know before you take Pramipixole
3. How to take Pramipixole
4. Possible side effects
5. How to store Pramipixole
6. Contents of the pack and other information

1.What Pramipixole is and what it is used for

Pramipixole contains the active substance pramipexole and belongs to a group of medicines known as dopamine agonists which stimulate dopamine receptors in the brain. Stimulation of the dopamine receptors triggers nerve impulses in the brain that help to control body movements.

Pramipixole is used to treat the symptoms of primary Parkinson’s disease in adults. It can be used alone or in combination with levodopa (another medicine for Parkinson’s disease).

2. What you need to know before you take Pramipixole

Do not take Pramipixole:

• if you are allergic to pramipexole or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor before taking Pramipixole. Tell your doctor if you have or have had or develop any medical conditions or symptoms, especially any of the following:

• Kidney disease.
• Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.
• Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs). If you have advanced Parkinson’s disease and are also taking levodopa, you might develop dyskinesia during the uptitration of Pramipixole.
• Sleepiness and episodes of suddenly falling asleep.
• Psychosis (e.g. comparable with symptoms of schizophrenia).
• Vision impairment. You should have regular eye examinations during treatment with Pramipixole.
• Severe heart or blood vessels disease. You will need to have your blood pressure checked regularly, especially at the beginning of treatment. This is to avoid postural hypotension (a fall

in blood pressure on standing up).

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose.

Tell your doctor if you or your family/carer notices that you are developing mania (agitation, feeling elated or over-excited) or delirium (decreased awareness, confusion, loss of reality). Your doctor may need to adjust or stop your dose.

Children and adolescents

Pramipixole is not recommended for use in children or adolescents under 18 years.

Other medicines and Pramipixole

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines, herbal remedies, health foods or supplements that you have obtained without a prescription.

You should avoid taking Pramipixole together with antipsychotic medicines.

Take care if you are taking the following medicines:

• cimetidine (to treat excess stomach acid and stomach ulcers);
• amantadine (which can be used to treat Parkinson’s disease);
• mexiletine (to treat irregular heartbeats, a condition known as ventricular arrhythmia);
• zidovudine (which can be used to treat the acquired immune deficiency syndrome (AIDS), a disease of the human immune system);
• cisplatin (to treat various types of cancers);
• quinine (which can be used for the prevention of painful night-time leg cramps and for the treatment of a type of malaria known as falciparum malaria (malignant malaria));
• procainamide (to treat irregular heart beat).

If you are taking levodopa, the dose of levodopa is recommended to be reduced when you start treatment with Pramipixole.

Take care if you are using any medicines that calm you down (have a sedative effect) or if you drink alcohol. In this cases Pramipixole may effect your ability to drive and operate machinery.

Pramipixole with food, drink and alcohol

You should be cautious while drinking alcohol during treatment with Pramipixole.

Pramipixole can be taken with or without food.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will then discuss with you if you should continue to take Pramipixole.

The effect of Pramipixole on the unborn child is not known. Therefore, do not take Pramipixole if you are pregnant unless your doctor tells you to do so.

Pramipixole is not recommended during breast-feeding. Pramipixole can reduce the production of breast milk. Also, it can pass into the breast milk and can reach your baby. If treatment with Pramipixole is unavoidable, breast-feeding must be stopped.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Pramipixole can cause hallucinations (seeing, hearing or feeling things that are not there). If affected, do not drive or use machines.

Pramipixole has been associated with sleepiness and episodes of suddenly falling asleep, particularly in patients with Parkinson’s disease. If you experience these side effects, you must not drive or operate machinery. Please tell your doctor if this occurs.

   3.How to take Pramipixole

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The doctor will advise you on the right dosing.

You can take Pramipixole with or without food. Swallow the tablets with water.

Parkinson’s disease

The daily dose is to be taken divided into 3 equal doses.

During the first week, the usual dose is 1 tablet Pramipixole 0.088 mg three times a day (equivalent to

0.264 mg daily):

This will be increased every 5 – 7 days as directed by your doctor until your symptoms are controlled (maintenance dose).

The usual maintenance dose is 1.1 mg per day. However, your dose may have to be increased even further. If necessary, your doctor may increase your tablet dose up to a maximum of 3.3 mg of pramipexole a day. A lower maintenance dose of three Pramipixole 0.088 mg tablets a day is also possible.

Patients with kidney disease

If you have moderate or severe kidney disease, your doctor will prescribe a lower dose. In this case, you will have to take the tablets only once or twice a day. If you have moderate kidney disease, the usual starting dose is 1 tablet Pramipixole 0.088 mg twice a day. In severe kidney disease, the usual starting dose is just 1 tablet Pramipixole 0.088 mg a day.

If you take more Pramipixole than you should

If you accidentally took too many tablets:

• Contact your doctor or nearest hospital casualty department immediately for advice.
• You may experience vomiting, restlessness, or any of the side effects as described in section 4.

“Possible side effects”.

If you forget to take Pramipixole

Do not worry. Simply leave out that dose completely and then take your next dose at the right time.

Do not take a double dose to make up for a forgotten tablet.

If you stop taking Pramipixole

Do not stop taking Pramipixole without first talking to your doctor. If you have to stop taking this medicine, your doctor will reduce the dose gradually. This reduces the risk of worsening symptoms.

If you suffer from Parkinson’s disease you should not stop treatment with Pramipixole abruptly. A sudden stop could cause you to develop a medicinal condition called neuroleptic malignant syndrome which may represent a major health risk. The symptoms include:

• akinesia (loss of muscle movement),
• rigid muscles,
• fever,
• unstable blood pressure,
• tachycardia (increased heart rate),
• confusion,
• depressed level of consciousness (e.g. coma).

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Evaluation of these side effects is based on the following frequencies:

If you suffer from Parkinson’s disease, you may experience the following side effects:

Very common:

• Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
• Sleepiness
• Dizziness
• Nausea (sickness)

Common:

• Urge to behave in an unusual way
• Hallucinations (seeing, hearing or feeling things that are not there)
• Confusion
• Tiredness (fatigue)
• Sleeplessness (insomnia)
• Excess of fluid, usually in the legs (peripheral oedema)
• Headache
• Hypotension (low blood pressure)
• Abnormal dreams
• Constipation
• Visual impairment
• Vomiting (being sick)
• Weight loss including decreased appetite

Uncommon:

• Paranoia (e.g. excessive fear for one’s own well-being)
• Delusion
• Excessive daytime sleepiness and suddenly falling asleep
• Amnesia (memory disturbance)
• Hyperkinesia (increased movements and inability to keep still)
• Weight increase
• Allergic reactions (e.g. rash, itching, hypersensitivity)
• Fainting
• Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*
• Inappropriate antidiuretic hormone secretion*
• Restlessness
• Dyspnoea (difficulties to breathe)
• Hiccups
• Pneumonia (infection of the lungs)
• Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include:
  • Strong impulse to gamble excessively despite serious personal or family consequences.
  • Altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive.
  • Uncontrollable excessive shopping or spending
  • Binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger)*
• Delirium (decreased awareness, confusion, loss of reality)

Rare:

• Mania (agitation, feeling elated or over-excited)

Tell your doctor if you experience any of these behaviors; he will discuss ways of managing or reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side effects were not observed in clinical studies among 2,762 patients treated with pramipexole. The frequency category is probably not greater than “uncommon”.

If you suffer from other indication, you may experience the following side effects:

Very common:

• Nausea (sickness).

Common:

• Changes in sleep pattern, such as sleeplessness (insomnia) and sleepiness
• Tiredness (fatigue)
• Headache
• Abnormal dreams
• Constipation
• Dizziness
• Vomiting (being sick)

Uncommon:

• Urge to behave in an unusual way*
• Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*
• Inappropriate antidiuretic hormone secretion*
• Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
• Hyperkinesia (increased movements and inability to keep still)*
• Paranoia (e.g. excessive fear for one’s own well-being)*
• Delusion*
• Amnesia (memory disturbance)*
• Hallucinations (seeing, hearing or feeling things that are not there)
• Confusion
• Excessive daytime sleepiness and suddenly falling asleep
• Weight increase
• Hypotension (low blood pressure)
• Excess of fluid, usually in the legs (peripheral oedema)
• Allergic reactions (e.g. rash, itching, hypersensitivity)
• Fainting
• Restlessness
• Visual impairment
• Weight loss including decreased appetite
• Dyspnoea (difficulties to breathe)
• Hiccups
• Pneumonia (infection of the lungs)*
• Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include:
  • Strong impulse to gamble excessively despite serious personal or family consequences.
  • Altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive.
  • Uncontrollable excessive shopping or spending
  • Binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger)*
• Mania (agitation, feeling elated or over-excited)*
• Delirium (decreased awareness, confusion, loss of reality)*

Tell your doctor if you experience any of these behaviors; he will discuss ways of managing or reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side effects were not observed in clinical studies among 1,395 patients treated with pramipexole. The frequency category is probably not greater than “uncommon”.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Pramipixole

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry date refers to the last day of that month.

Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Pramipixole contains

• The active substance is pramipexole.

a) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)             0.125mg
Excipients                           q.s

b) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)               0.25mg
Excipients                             q.s

c) Each uncoated Tablet contains:
Pramipixole Dihydrochloride USP
(as Monohydrate)                1.5mg
Excipients                              q.s

• The other ingredients are mannitol, maize starch, pregelatinised maize starch, povidone, colloidal anhydrous silica and magnesium stearate.

What Pramipixole looks like and contents of the pack

Blister pack (Al/Al foil): 10, 20, 30, 60, 90 or 100 tablets, in a box.

Not all pack sizes may be marketed.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of  Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com