OPRYMEA 0.18mg tablets medication leaflet

Oprymea 0.088 mg tablets

Oprymea 0.18 mg tablets

Oprymea 0.35 mg tablets

Oprymea 0.7 mg tablets

Oprymea 1.1 mg tablets

Oprymea 0.088 mg tablets

Each tablet contains 0.088 mg pramipexole (as 0.125 mg pramipexole dihydrochloride monohydrate).

Oprymea 0.18 mg tablets

Each tablet contains 0.18 mg pramipexole (as 0.25 mg pramipexole dihydrochloride monohydrate).

Oprymea 0.35 mg tablets

Each tablet contains 0.35 mg pramipexole (as 0.5 mg pramipexole dihydrochloride monohydrate).

Oprymea 0.7 mg tablets

Each tablet contains 0.7 mg pramipexole (as 1 mg pramipexole dihydrochloride monohydrate).

Oprymea 1.1 mg tablets

Each tablet contains 1.1 mg pramipexole (as 1.5 mg pramipexole dihydrochloride monohydrate).

Please note:

Pramipexole doses as published in the literature refer to the salt form.

Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (inbrackets).

For the full list of excipients, see section 6.1.

Tablet

Oprymea 0.088 mg tablets

White, round, with bevelled edges and imprint 'P6' on one side of the tablet.

Oprymea 0.18 mg tablets

White, oval, with bevelled edges, both sides scored, with imprint 'P7' on both halves of one side ofthe tablet. The tablet can be divided into equal doses.

Oprymea 0.35 mg tablets

White, oval, with bevelled edges, both sides scored, with imprint 'P8' on both halves of one side ofthe tablet. The tablet can be divided into equal doses.

Oprymea 0.7 mg tablets

White, round, with bevelled edges, both sides scored, with imprint 'P9' on both halves of one side ofthe tablet. The tablet can be divided into equal doses.

Oprymea 1.1 mg tablets

White, round, with bevelled edges, both sides scored. The tablet can be divided into equal doses.

Oprymea is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson'sdisease, 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 fluctuationsof the therapeutic effect occur (end of dose or “on off” fluctuations).

Oprymea is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless

Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).

Parkinson’s disease

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

Initial treatment

Doses should be increased gradually from a starting-dose of 0.264 mg of base (0.375 mg of salt) perday and then increased every 5 - 7 days. Providing patients do not experience intolerable undesirableeffects, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending - Dose Schedule of Oprymea

Week Dose Total Daily Dose Dose Total Daily Dose(mg of base) (mg of base) (mg of salt) (mg of salt)1 3 x 0.088 0.264 3 x 0.125 0.3752 3 x 0.18 0.54 3 x 0.25 0.753 3 x 0.35 1.1 3 x 0.5 1.50

If a further dose increase is necessary the daily dose should be increased by 0.54 mg of base (0.75 mgof 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 1.1 mgof base (1.5 mg of salt) per day (see section 4.8).

The individual dose of pramipexole should be in the range of 0.264 mg of base (0.375 mg of salt) to amaximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies,efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). Further doseadjustments should be done based on the clinical response and the occurrence of adverse reactions. Inclinical trials approximately 5% of patients were treated at doses below 1.1 mg of base (1.5 mg ofsalt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1 mg of base (1.5 mg of salt)per day can be useful in patients where a reduction of the levodopa therapy is intended. It isrecommended that the dose of levodopa is reduced during both the dose escalation and themaintenance treatment with Oprymea, depending on reactions in individual patients (see section 4.5).

Abrupt discontinuation of dopaminergic therapy can lead to the development of a neurolepticmalignant syndrome or a dopamine agonist withdrawal syndrome. Pramipexole should be tapered offat 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 mgof base (0.75 mg of salt). Thereafter the dose should be reduced by 0.264 mg of base (0.375 mg ofsalt) per day (see section 4.4). Dopamine agonist withdrawal syndrome could still appear whiletapering and a temporary increase of the dose could be necessary before resuming tapering (seesection 4.4).

The elimination of pramipexole is dependent on renal function. The following dose schedule issuggested for initiation of therapy:

Patients with a creatinine clearance above 50 mL/min require no reduction in daily dose or dosingfrequency.

In patients with a creatinine clearance between 20 and 50 mL/min, the initial daily dose of Oprymeashould be administered in two divided doses, starting at 0.088 mg of base (0.125 mg of salt) twice aday (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 Oprymea should beadministered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily. A maximum dailydose of 1.1 mg pramipexole base (1.5 mg of salt) should not be exceeded.

If renal function declines during maintenance therapy the Oprymea daily dose should be reduced bythe same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%,then the Oprymea daily dose should be reduced by 30%. The daily dose can be administered in twodivided doses if creatinine clearance is between 20 and 50 mL/min, and as a single daily dose ifcreatinine clearance is less than 20 mL/min.

Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbedactive substance is excreted through the kidneys. However, the potential influence of hepaticinsufficiency on Oprymea pharmacokinetics has not been investigated.

The safety and efficacy of Oprymea in children below 18 years has not been established. There is norelevant use of Oprymea in the paediatric population for the indication of Parkinson’s Disease.

Restless Legs Syndrome

The recommended starting dose of Oprymea is 0.088 mg of base (0.125 mg of salt) taken once daily2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may beincreased every 4-7 days to a maximum of 0.54 mg of base (0.75 mg of salt) per day (as shown in thetable below). The lowest effective dose should be used (see section 4.4 Restless legs augmentationsyndrome).

Dose Schedule of Oprymea

Titration Step Once Daily Evening Dose Once Daily Evening Dose(mg of base) (mg of salt)1 0.088 0.1252* 0.18 0.253* 0.35 0.504* 0.54 0.75

* if needed

Patient’s response should be evaluated after 3 months treatment and the need for treatmentcontinuation should be reconsidered. If treatment is interrupted for more than a few days it should bere-initiated by dose titration carried out as above.

Since the daily dose for the treatment of Restless Legs Syndrome will not exceed 0.54 mg of base(0.75 mg of salt) Oprymea can be discontinued without tapering off. In a 26 week placebo controlledtrial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) wasobserved in 10% of patients (14 out of 135) after abrupt discontinuation of treatment. This effect wasfound to be similar across all doses.

The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearanceabove 20 mL/min require no reduction in daily dose.

The use of pramipexole has not been studied in haemodialysis patients, or in patients with severe renalimpairment.

Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed activesubstance is excreted through the kidneys.

Oprymea is not recommended for use in children and adolescents below 18 years due to a lack of dataon safety and efficacy.

Tourette Disorder

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

The tablets should be taken orally, swallowed with water, and can be taken either with or withoutfood.

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

When prescribing Oprymea in a patient with Parkinson’s disease with renal impairment a reduceddose is suggested in line with section 4.2.

Hallucinations

Hallucinations are known as a side-effect of treatment with dopamine agonists and levodopa. Patientsshould be informed that (mostly visual) hallucinations can occur.

Dyskinesia

In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesia can occur duringthe initial titration of Oprymea. If they occur, the dose of levodopa should be decreased.

Dystonia

Axial dystonia including antecollis, camptocormia and pleurothotonus (Pisa Syndrome) hasoccasionally been reported in patients with Parkinson’s disease following initiation or incrementaldose increase of pramipexole. Although dystonia may be a symptom of Parkinson’s disease, thesymptoms in these patients have improved after reduction or withdrawal of pramipexole. If dystoniaoccurs, the dopaminergic medication regimen should be reviewed and an adjustment in the dose ofpramipexole considered.

Sudden onset of sleep and somnolence

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly inpatients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases withoutawareness or warning signs, has been reported uncommonly. Patients must be informed of this andadvised 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 fromdriving or operating machines. Furthermore a reduction of the dose or termination of therapy may beconsidered. Because of possible additive effects, caution should be advised when patients are takingother sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7and section 4.8).

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients andcarers should be made aware that behavioural symptoms of impulse control disorders includingpathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eatingand 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 carersshould be made aware that mania and delirium can occur in patients treated with pramipexole. Dosereduction/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 potentialbenefits outweigh the risks.Co-administration of antipsychotic medicinal products with pramipexoleshould 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 bloodpressure, especially at the beginning of treatment, due to the general risk of postural hypotensionassociated with dopaminergic therapy.

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawalof dopaminergic therapy (see section 4.2).

Dopamine agonist withdrawal syndrome (DAWS)

DAWS has been reported with dopamine agonists, including pramipexole (see section 4.8). Todiscontinue treatment in patients with Parkinson’s disease, pramipexole should be tapered off (seesection 4.2). Limited data suggests that patients with impulse control disorders and those receivinghigh daily dose and/or high cumulative doses of dopamine agonists may be at higher risk fordeveloping DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweatingand pain and do not respond to levodopa. Prior to tapering off and discontinuing pramipexole, patientsshould be informed about potential withdrawal symptoms. Patients should be closely monitored duringtapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary re-administration of pramipexole at the lowest effective dose may be considered.

Restless legs augmentation syndrome

Treatment of Restless Legs Syndrome with pramipexole can result in augmentation. Augmentationrefers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms,and spread of symptoms to involve other extremities. The risk of augmentation may increase withhigher dose. Prior to treatment, patients should be informed that augmentation may occur and shouldbe advised to contact their physician if they experience symptoms of augmentation. If augmentation issuspected, dose adjustment to the lowest effective dose, or discontinuation of pramipexole should beconsidered (see section 4.2 and 4.8).

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low (<20%) extent, and little biotransformation isseen in man. Therefore, interactions with other medicinal products affecting plasma protein binding orelimination by biotransformation are unlikely. As anticholinergics are mainly eliminated bybiotransformation, the potential for an interaction is limited, although an interaction withanticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline andlevodopa.

Inhibitors/competitors of active renal elimination pathway

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably byinhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal productsthat are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such ascimetidine,amantadine mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact withpramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose shouldbe 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 isreduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasingthe dose of Oprymea.

Because of possible additive effects, caution should be advised when patients are taking other sedatingmedicinal products or alcohol in combination with pramipexole (see sections 4.4, 4.7 and 4.8).

Antipsychotic medicinal products

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (seesection 4.4), e.g. if antagonistic effects can be expected.

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was notteratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).

Oprymea should not be used during pregnancy unless clearly necessary, i.e. if the potential benefitjustifies the potential risk to the foetus.

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, theconcentration of active substance-related radioactivity was higher in breast milk than in plasma. In theabsence of human data, Oprymea should not be used during breast-feeding. However, if its use isunavoidable, breast-feeding should be discontinued.

No studies on the effect on human fertility have been conducted. In animal studies, pramipexoleaffected 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.

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 episodesmust be informed to refrain from driving or engaging in activities where impaired alertness may putthemselves or others at risk of serious injury or death (e.g. operating machines) until such recurrentepisodes and somnolence have resolved (see also sections 4.4, 4.5, and 4.8).

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

The majority of adverse drug reactions usually start early in therapy and most tend to disappear evenas therapy is continued.

Within the system organ classes, adverse reactions are listed under headings of frequency (number ofpatients expected to experience the reaction), using the following categories: very common (≥1/10);common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare(<1/10 000); not known (cannot be estimated from the available data).

Parkinson’s disease, most common adverse reactions

The most commonly (≥5%) reported adverse drug reactions in patients with Parkinson’s disease morefrequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence ofsomnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). Amore frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension mayoccur at the beginning of treatment, especially if pramipexole is titrated too fast.

Table 1: Parkinson’s disease

Body System Very Common Uncommon Rare Not knowncommon (≥1/100 to (≥1/1 000 to (≥1/10 000(≥1/10) <1/10) <1/100) to<1/1 000)

Infections and pneumoniainfestations

Endocrine inappropriatedisorders antidiuretichormonesecretion1

Psychiatric insomnia compulsive maniadisorders hallucinations shoppingabnormal pathologicaldreams gamblingconfusion restlessnesshypersexualitybehavioural delusionsymptoms of libido disorderimpulse control paranoiadisorders and deliriumcompulsions binge eating1hyperphagia1

Nervous somnolence headache sudden onset ofsystem dizziness sleepdisorders dyskinesia amnesiahyperkinesiasyncope

Eye disorders visualimpairmentincludingdiplopia visionblurredvisual acuityreduced

Cardiac cardiac failure1disorders

Vascular hypotensiondisorders

Respiratory, dyspnoeathoracic, and hiccupsmediastinaldisorders

Gastrointestinal nausea constipationdisorders vomiting

Skin and hypersensitivitysubcutaneous pruritustissue disorders rash

Reproductive spontaneoussystem and penilebreast disorders erection

General fatigue dopaminedisorders and peripheral agonistadministration oedema withdrawalsite conditions syndromeincludingapathy,anxiety,depression,fatigue,sweatingand pain.

Investigations weight decrease weight increaseincludingdecreasedappetite1 This side effect has been observed in post-marketing experience. With 95 % certainty, thefrequency category is not greater than uncommon, but might be lower. A precise frequencyestimation is not possible as the side effect did not occur in a clinical trial database of 2 762patients with Parkinson’s Disease treated with pramipexole.

Restless Legs Syndrome, most common adverse reactions

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

Table 2: Restless legs syndrome

Body System Very Common Uncommon Rare Not knowncommon (≥1/100 to (≥1/1 000 to (≥1/10 000(≥1/10) <1/10) <1/100) to<1/1 000)

Infections and pneumonia1infestations

Endocrine inappropriatedisorders antidiuretic hormonesecretion1

Psychiatric insomnia restlessnessdisorders abnormal confusiondreams hallucinationslibido disorderdelusion1hyperphagia1paranoia1mania1delirium1behaviouralsymptoms ofimpulse controldisorders andcompulsions1 (suchas:compulsiveshopping,pathologicalgambling,hypersexuality,binge eating)

Nervous restless legs headache sudden onset ofsystem augmentation dizziness sleepdisorders syndrome somnolance syncopedyskinesiaamnesia1hyperkinesia1

Eye disorders visual impairmentincludingvisual acuity reduceddiplopiavision blurred

Cardiac cardiac failure1disorders

Vascular hypotensiondisorders

Respiratory, dyspnoeathoracic, and hiccupsmediastinaldisorders

Gastrointestinal nausea constipationdisorders vomiting

Skin and hypersensitivitysubcutaneous pruritustissue disorders rash

Reproductive spontaneoussystem and penilebreast disorders erection

General fatigue peripheral oedema dopaminedisorders and agonistadministration withdrawalsite conditions syndromeincludingapathy,anxiety,depression,fatigue,sweatingand pain

Investigations weight decreaseincluding decreasedappetiteweight increase1 This side effect has been observed in post-marketing experience. With 95 % certainty, thefrequency category is not greater than uncommon, but might be lower. A precise frequencyestimation is not possible as the side effect did not occur in a clinical trial database of 1 395patients with Restless Legs Syndrome treated with pramipexole.

Somnolence

Pramipexole is commonly associated with somnolence and has been associated uncommonly withexcessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).

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 eatingand compulsive eating can occur in patients treated with dopamine agonists including Oprymea (seesection 4.4).

In a cross-sectional, retrospective screening and case-control study including 3 090 Parkinson’sdisease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment hadsymptoms of an impulse control disorder during the past six months. Manifestations observed includepathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour(hypersexuality). Possible independent risk factors for impulse control disorders includeddopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤65 years), notbeing married and self-reported family history of gambling behaviours.

Dopamine agonist withdrawal syndrome

Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists includingpramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see section4.4).

Cardiac failure

In clinical studies and post-marketing experience cardiac failure has been reported in patients withpramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increasedrisk of cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95% CI, 1.21-2.85).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamilyof dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsicactivity.

Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in thestriatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, andturnover.

The mechanism of action of pramipexole as 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.

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 1 800 patients of Hoehn and Yahr stages I - V treatedwith pramipexole. Out of these, approximately 1 000 were in more advanced stages, receivedconcomitant levodopa therapy, and suffered from motor complications.

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

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

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

Clinical efficacy and safety in Restless Legs Syndrome

The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately1 000 patients with moderate to very severe idiopathic Restless Legs Syndrome.

The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical

Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For bothprimary endpoints statistically significant differences have been observed for the pramipexole dosegroups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks oftreatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4;

- 2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005).

Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week oftreatment.

In a placebo-controlled polysomnography study over 3 weeks pramipexole significantly reduced thenumber of periodic limb movements during time in bed.

Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment,there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexoleand placebo group, respectively, with a statistically significant (p = 0.008) mean treatment differenceof -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5%(111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed totreat (NNT) of 6 patients (95%CI: 3.5, 13.4).

The European Medicines Agency has deferred the obligation to submit the results of studies withpramipexole in one or more subsets of the paediatric population in Restless Legs Syndrome (seesection 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 flexibledose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primaryendpoint 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 theprimary 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% ofpatients in the pramipexole group and more common in the pramipexole-treated patients than inpatients 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%), sleepdisorder (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 medicationfor patients receiving pramipexole were confusional state, speech disorder and aggravated condition(see section 4.2).

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

In humans, the protein binding of pramipexole is very low (<20%) and the volume of distribution islarge (400 L). High brain tissue concentrations were observed in the rat (approx. 8-fold compared toplasma).

Pramipexole is metabolised in man only to a small extent.

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The totalclearance of pramipexole is approximately 500 mL/min and the renal clearance is approximately400 mL/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

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

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

The potential effects of pramipexole on reproductive function have been investigated in rats andrabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat atmaternally 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 cellhyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding isnot clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) andhigher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was notobserved in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other speciesinvestigated.

Mannitol

Maize starch

Pregelatinised maize starch

Povidone K25

Colloidal anhydrous silica

Magnesium stearate

Not applicable.

3 years

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

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

Not all pack sizes may be marketed.

No special requirements for disposal.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Oprymea 0.088 mg tablets20 tablets: EU/1/08/469/00130 tablets: EU/1/08/469/00260 tablets: EU/1/08/469/00390 tablets: EU/1/08/469/004100 tablets: EU/1/08/469/005

Oprymea 0.18 mg tablets20 tablets: EU/1/08/469/00630 tablets: EU/1/08/469/00760 tablets: EU/1/08/469/00890 tablets: EU/1/08/469/009100 tablets: EU/1/08/469/010

Oprymea 0.35 mg tablets20 tablets: EU/1/08/469/01130 tablets: EU/1/08/469/01260 tablets: EU/1/08/469/01390 tablets: EU/1/08/469/014100 tablets: EU/1/08/469/015

Oprymea 0.7 mg tablets20 tablets: EU/1/08/469/01630 tablets: EU/1/08/469/01760 tablets: EU/1/08/469/01890 tablets: EU/1/08/469/019100 tablets: EU/1/08/469/020

Oprymea 1.1 mg tablets20 tablets: EU/1/08/469/02130 tablets: EU/1/08/469/02260 tablets: EU/1/08/469/02390 tablets: EU/1/08/469/024100 tablets: EU/1/08/469/025

Date of first authorisation: 12 September 2008

Date of latest renewal: 9 April 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.