CORBILTA 150mg / 37.5mg / 200mg tablets medication leaflet

Corbilta 50 mg/12.5 mg/200 mg film-coated tablets

Corbilta 75 mg/18.75 mg/200 mg film-coated tablets

Corbilta 100 mg/25 mg/200 mg film-coated tablets

Corbilta 125 mg/31.25 mg/200 mg film-coated tablets

Corbilta 150 mg/37.5 mg/200 mg film-coated tablets

Corbilta 175 mg/43.75 mg/200 mg film-coated tablets

Corbilta 200 mg/50 mg/200 mg film-coated tablets

50 mg/12.5 mg/200 mg

Each tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.2 mg of sucrose.

75 mg/18.75 mg/200 mg

Each tablet contains 75 mg of levodopa, 18.75 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.4 mg of sucrose.

100 mg/25 mg/200 mg

Each tablet contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.6 mg of sucrose.

125 mg/31.25 mg/200 mg

Each tablet contains 125 mg of levodopa, 31.25 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.6 mg of sucrose.

150 mg/37.5 mg/200 mg

Each tablet contains 150 mg of levodopa, 37.5 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.9 mg of sucrose and 2.6 mg sodium as a constituent of an excipient.

175 mg/43.75 mg/200 mg

Each tablet contains 175 mg of levodopa, 43.75 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 1.89 mg of sucrose.

200 mg/50 mg/200 mg

Each tablet contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg of entacapone.

Each tablet contains 2.3 mg of sucrose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)50 mg/12.5 mg/200 mg

Brownish or greyish red, round, convex, unscored film-coated tablets marked with “LCE 50” on oneside.

75 mg/18.75 mg/200 mg

Light brownish red, oval film-coated tablets marked with “LCE 75” on one side.

100 mg/25 mg/200 mg

Brownish or greyish red, oval, unscored film-coated tablets marked with “LCE 100” on one side.

125 mg/31.25 mg/200 mg

Light brownish red, oval film-coated tablets marked with “LCE 125” on one side.

150 mg/37.5 mg/200 mg

Brownish or greyish red, elongated-ellipse shaped, unscored film-coated tablets marked with “LCE150” on one side.

175 mg/43.75 mg/200 mg

Light brownish red, oval, unscored film-coated tablets marked with “LCE 175” on one side.

200 mg/50 mg/200 mg

Dark brownish red, oval, unscored film-coated tablets marked with “LCE 200” on one side.

Corbilta is indicated for the treatment of adult patients with Parkinson’s disease and end-of-dosemotor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

The optimum daily dose must be determined by careful titration of levodopa in each patient. The dailydose should be preferably optimised using one of the seven available tablet strengths(50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg,150 mg/37.5 mg/200 mg, 175 mg/43.75 mg/200 mg or 200 mg/50 mg/200 mglevodopa/carbidopa/entacapone).

Patients should be instructed to take only one Corbilta tablet per dose administration. Patientsreceiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting.

While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximumrecommended daily dose of entacapone is 2 000 mg and therefore the maximum dose is 10 tablets perday for the Corbilta strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of

Corbilta 150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopadose, the maximum recommended daily dose of Corbilta 175 mg/43.75 mg/200 mg is 8 tablets per dayand Corbilta 200 mg/50 mg/200 mg dose is 7 tablets per day.

Usually Corbilta is to be used in patients who are currently treated with corresponding doses ofstandard release levodopa/DDC inhibitor and entacapone.

How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations andentacapone tablets to Corbilta

a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa indoses equal to Corbilta tablet strengths can be directly transferred to corresponding Corbilta tablets.

For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet ofentacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Corbilta tablet four timesdaily in place of their usual levodopa/carbidopa and entacapone doses.

b. When initiating Corbilta therapy for patients currently treated with entacapone andlevodopa/carbidopa in doses not equal to Corbilta tablets (50 mg/12.5 mg/200 mg or75 mg/18.75 mg/200 mg or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or150 mg/37.5 mg/200 mg or 175 mg/43.75 mg/200 mg or 200 mg/50 mg/200 mg), Corbilta dosingshould be carefully titrated for optimal clinical response. At the initiation, Corbilta should be adjustedto correspond as closely as possible to the total daily dose of levodopa currently used.

c. When initiating Corbilta in patients currently treated with entacapone and levodopa/benserazide ina standard release formulation, the dosing of levodopa/benserazide should be discontinued in theprevious night, and Corbilta should be started in the next morning. The starting dose of Corbiltashould provide either the same amount of levodopa or slightly (5-10%) more.

How to transfer patients not currently treated with entacapone to Corbilta

Initiation of Corbilta may be considered at corresponding doses to current treatment in some patientswith Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their currentstandard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDCinhibitor to Corbilta is not recommended for patients who have dyskinesias or whose daily levodopadose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separatetreatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Corbilta.

Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patientswith dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks afterinitiating Corbilta treatment. The daily dose of levodopa can be reduced by extending the dosingintervals and/or by reducing the amount of levodopa per dose, according to the clinical condition ofthe patient.

Dose adjustment during the course of the treatment

When more levodopa is required, an increase in the frequency of doses and/or the use of an alternativestrength of Corbilta should be considered, within the dose recommendations.

When less levodopa is required, the total daily dose of Corbilta should be reduced either bydecreasing the frequency of administration by extending the time between doses, or by decreasing thestrength of Corbilta at an administration.

If other levodopa products are used concomitantly with a Corbilta tablet, the maximum doserecommendations should be followed.

Discontinuation of Corbilta therapy: If Corbilta treatment (levodopa/carbidopa/entacapone) isdiscontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, itis necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achievea sufficient level of control of the parkinsonian symptoms.

Paediatric population: The safety and efficacy of Corbilta in children aged below 18 years have notbeen established. No data are available.

Elderly: No dose adjustment of Corbilta is required for elderly.

Hepatic impairment: It is advised that Corbilta should be administered cautiously to patients withmild to moderate hepatic impairment. Dose reduction may be needed (see section 5.2). For severehepatic impairment see section 4.3.

Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. Noparticular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients withrenal insufficiency, therefore Corbilta therapy should be administered cautiously to patients in severerenal impairment including those receiving dialysis therapy (see section 5.2).

Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains onetreatment dose and the tablet may only be administered as whole tablets.

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

- Severe hepatic impairment.

- Narrow-angle glaucoma.

- Pheochromocytoma.

- Coadministration of Corbilta with non-selective monoamine oxidase (MAO-A and MAO-B)inhibitors (e.g. phenelzine, tranylcypromine).

- Coadministration with a selective MAO-A inhibitor and a selective MAO-B inhibitor (seesection 4.5).

- A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumaticrhabdomyolysis.

- Corbilta is not recommended for the treatment of drug-induced extrapyramidal reactions.

- Corbilta therapy should be administered cautiously to patients with ischemic heart disease,severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease,history of peptic ulcer disease or history of convulsions.

- In patients with a history of myocardial infarction who have residual atrial nodal or ventriculararrhythmias; cardiac function should be monitored with particular care during the period ofinitial dose adjustments.

- All patients treated with Corbilta should be monitored carefully for the development of mentalchanges, depression with suicidal tendencies, and other serious antisocial behaviour. Patientswith past or current psychosis should be treated with caution.

- Concomitant administration of antipsychotics with dopamine receptor-blocking properties,particularly D2 receptor antagonists should be carried out with caution, and the patient carefullyobserved for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.

- Patients with chronic wide-angle glaucoma may be treated with Corbilta with caution, providedthe intra-ocular pressure is well controlled and the patient is monitored carefully for changes inintra-ocular pressure.

- Corbilta may induce orthostatic hypotension. Therefore Corbilta should be given cautiously topatients who are taking other medicinal products which may cause orthostatic hypotension.

- Entacapone in association with levodopa has been associated with somnolence and episodes ofsudden sleep onset in patients with Parkinson’s disease and caution should therefore beexercised when driving or operating machines (see section 4.7).

- In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common inpatients who received entacapone and dopamine agonists (such as bromocriptine), selegiline oramantadine compared to those who received placebo with this combination. The doses of otherantiparkinsonian medicinal products may need to be adjusted when Corbilta treatment issubstituted for a patient currently not treated with entacapone.

- Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) hasbeen observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose reductionor withdrawal of levodopa should be carefully observed, particularly in patients who are alsoreceiving neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterised bymotor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g., agitation, confusion,coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevatedserum creatine phosphokinase. In individual cases, only some of these symptoms and/orfindings may be evident. The early diagnosis is important for the appropriate management of

NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity,elevated body temperature, mental changes and increased serum creatine phosphokinase hasbeen reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS norrhabdomyolysis have been reported in association with entacapone treatment from controlledtrials in which entacapone was discontinued abruptly. Since the introduction of entacapone intothe market, isolated cases of NMS have been reported, especially following abrupt reduction ordiscontinuation of entacapone and other concomitant dopaminergic medicinal products. Whenconsidered necessary, the replacement of Corbilta with levodopa and DDC inhibitor withoutentacapone or other dopaminergic treatment should proceed slowly and an increase in levodopadose may be necessary.

- If general anaesthesia is required, therapy with Corbilta may be continued for as long as thepatient is permitted to take fluids and medicinal products by mouth. If therapy has to be stoppedtemporarily, Corbilta may be restarted as soon as oral medicinal products can be taken at thesame daily dose as before.

- Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function isrecommended during extended therapy with Corbilta.

- For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoidpotential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use ofentacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drugshould be discontinued and appropriate medical therapy and investigations considered.

- Patients should be regularly monitored for the development of impulse control disorders.

Patients and carers should be made aware that behavioural symptoms of impulse controldisorders including pathological gambling, increased libido, hypersexuality, compulsivespending or buying, binge eating and compulsive eating can occur in patients treated withdopamine agonists and/or other dopaminergic treatments containing levodopa including

Corbilta. Review of treatment is recommended if such symptoms develop.

- Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use ofthe product seen in some patients treated with carbidopa/levodopa. Before initiation oftreatment, patients and caregivers should be warned of the potential risk of developing DDS(see also section 4.8).

- For patients who experience progressive anorexia, asthenia and weight decrease within arelatively short period of time, a general medical evaluation including liver function should beconsidered.

- Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinaryketone and this reaction is not altered by boiling the urine sample. The use of glucose oxidasemethods may give false negative results for glycosuria.

- Corbilta contains sucrose, and therefore patients with rare hereditary problems of fructoseintolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should nottake this medicine.

- Corbilta 150 mg/37.5 mg/200 mg contains 2.6 mg sodium per tablet. The maximumrecommended daily dose (10 tablets) contains 26 mg sodium, equivalent to 1.3% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

- Corbilta 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg,125 mg/31.25 mg/200 mg, 175 mg/43.75 mg/200 mg and 200 mg/50 mg/200 mg film-coatedtablets contain less than 1 mmol (23 mg) sodium per maximum recommended daily dose, that isto say essentially ‘sodium-free’.

Other antiparkinsonian medicinal products: To date there has been no indication of interactions thatwould preclude concurrent use of standard antiparkinsonian medicinal products with Corbilta therapy.

Entacapone in high doses may affect the absorption of carbidopa. However, no interaction withcarbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to10 times daily). Interactions between entacapone and selegiline have been investigated in repeateddose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interactionwas observed. When used with Corbilta, the daily dose of selegiline should not exceed 10 mg.

Caution should be exercised when the following active substances are administered concomitantlywith levodopa therapy.

Antihypertensives: Symptomatic postural hypotension may occur when levodopa is added to thetreatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensiveagent may be required.

Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with theconcomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacaponeand imipramine and between entacapone and moclobemide have been investigated in single dosestudies in healthy volunteers. No pharmacodynamic interactions were observed. A significant numberof Parkinson's disease patients have been treated with the combination of levodopa, carbidopa andentacapone with several active substances including MAO-A inhibitors, tricyclic antidepressants,noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinalproducts that are metabolised by COMT (e.g. catechol-structured compounds, paroxetine). Nopharmacodynamic interactions have been observed. However, caution should be exercised when thesemedicinal products are used concomitantly with Corbilta (see sections 4.3 and 4.4).

Other active substances: Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking thesemedicinal products with Corbilta should be carefully observed for loss of therapeutic response.

Due to entacapone's affinity to cytochrome P450 2C9 in vitro (see section 5.2), Corbilta maypotentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as

S-warfarin. However, in an interaction study with healthy volunteers, entacapone did not change theplasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11-26%]. The INR values increased on average by 13% [CI90 6-19%]. Thus, a control of INR isrecommended when Corbilta is initiated for patients receiving warfarin.

Other forms of interactions: Since levodopa competes with certain amino acids, the absorption of

Corbilta may be impaired in some patients on high protein diet.

Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore,

Corbilta and iron preparations should be taken at least 2-3 hours apart (see section 4.8).

In vitro data: Entacapone binds to human albumin binding site II which also binds several othermedicinal products, including diazepam and ibuprofen. According to in vitro studies, significantdisplacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly,to date there has been no indication of such interactions.

There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone inpregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (seesection 5.3). The potential risk for humans is unknown. Corbilta should not be used during pregnancyunless the benefits for the mother outweigh the possible risks to the foetus.

Levodopa is excreted in human breast milk. There is evidence that breast-feeding is suppressed duringtreatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is notknown whether they are excreted in human breast milk. The safety of levodopa, carbidopa orentacapone in the infant is not known. Women should not breast-feed during treatment with Corbilta.

No adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa orlevodopa alone. Fertility studies in animals have not been conducted with the combination ofentacapone, levodopa and carbidopa.

Corbilta may have a major influence on the ability to drive and use machines. Levodopa, carbidopaand entacapone together may cause dizziness and symptomatic orthostatism. Therefore, cautionshould be exercised when driving or using machines.

Patients being treated with Corbilta and presenting with somnolence and/or sudden sleep onsetepisodes must be instructed to refrain from driving or engaging in activities where impaired alertnessmay put themselves or others at risk of serious injury or death (e.g. operating machines) until suchrecurrent episodes have resolved (see section 4.4).

The most frequently reported adverse reactions with Corbilta are dyskinesias occurring inapproximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurringin approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connectivetissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration ofurine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinalhaemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with

Corbilta or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainlycholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Corbiltaalthough no cases have been identified from the clinical trial data.

The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data ofeleven double-blind clinical trials consisting of 3 230 patients (1 810 treated with Corbilta orentacapone combined with levodopa/DDC inhibitor, and 1 420 treated with placebo combined withlevodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-marketing data since the introduction of entacapone into the market for the combination use ofentacapone with levodopa/DDC inhibitor.

Adverse reactions are ranked under headings of frequency, the most frequent first, using the followingconvention: 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 theavailable data, since no valid estimate can be derived from clinical trials or epidemiological studies).

Table 1. Adverse reactions

Common: Anaemia

Uncommon: Thrombocytopenia

Common: Weight decreased*, decreased appetite*

Common: Depression, hallucination, confusional state*, abnormal dreams*, anxiety,insomnia

Uncommon: Psychosis, agitation*

Not known: Suicidal behaviour, Dopamine dysregulation syndrome

Very common: Dyskinesia*

Common: Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off phenomenon,dystonia, mental impairment (e.g. memory impairment, dementia), somnolence,dizziness*, headache

Not known: Neuroleptic malignant syndrome*

Common: Blurred vision

Common: Ischemic heart disease events other than myocardial infarction (e.g. anginapectoris)**, irregular heart rhythm

Uncommon: Myocardial infarction**

Common: Orthostatic hypotension, hypertension

Uncommon: Gastrointestinal haemorrhage

Common: Dyspnoea

Very common: Diarrhoea*, nausea*

Common: Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*

Uncommon: Colitis*, dysphagia

Uncommon: Hepatic function test abnormal*

Not known: Hepatitis with mainly cholestatic features (see section 4.4)*

Common: Rash*, hyperhidrosis

Uncommon: Discolourations other than urine (e.g. skin, nail, hair, sweat)*

Rare: Angioedema

Not known: Urticaria*

Very common: Muscle, musculoskeletal and connective tissue pain*

Common: Muscle spasms, arthralgia

Not known: Rhabdomyolysis*

Very common: Chromaturia*

Common: Urinary tract infection

Uncommon: Urinary retention

Common: Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue

Uncommon: Malaise

*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequencydifference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitoralone. See section c.

**The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2 082 patientswith end-of-dose motor fluctuations receiving entacapone.

c. Description of selected adverse reactions

Adverse reactions that are mainly attributable to entacapone or are more frequent with entacaponethan levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some ofthese adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea andvomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dosedecreases the severity and frequency of these dopaminergic reactions. Few adverse reactions areknown to be directly attributable to the active substance entacapone including diarrhoea and reddish-brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin,nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are markedbased on either their more frequent occurring (by the frequency difference of at least 1%) in theclinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reportsreceived after the introduction of entacapone into the market.

Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship tolevodopa/carbidopa therapy has not been established.

Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsivespending or buying, binge eating and compulsive eating can occur in patients treated with dopamineagonists and/or other dopaminergic treatments containing levodopa including Corbilta (see section4.4).

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated withcarbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse abovedoses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (seealso section 4.4).

Entacapone in association with levodopa has been associated with isolated cases of excessive daytimesomnolence and sudden sleep onset episodes.

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.

The post-marketing data includes isolated cases of overdose in which the reported highest daily dosesof levodopa and entacapone have been at least 10 000 mg and 40 000 mg, respectively. The acutesymptoms and signs in these cases of overdose included agitation, confusional state, coma,bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue andconjunctiva, and chromaturia. Management of acute overdose with Corbilta therapy is similar to acuteoverdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Corbilta.

Hospitalisation is advised and general supportive measures should be employed with immediategastric lavage and repeated doses of charcoal over time. This may hasten the elimination ofentacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy ofthe respiratory, circulatory and renal systems should be carefully monitored and appropriatesupportive measures employed. ECG monitoring should be started and the patient carefully monitoredfor the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy shouldbe given. The possibility that the patient has taken other active substances in addition to Corbiltashould be taken into consideration. The value of dialysis in the treatment of overdose is not known.

Pharmacotherapeutic group: anti-parkinson drugs, dopa and dopa derivatives, ATC code: N04BA03

According to the current understanding, the symptoms of Parkinson’s disease are related to depletionof dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, theprecursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. Aslevodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches thecentral nervous system when levodopa is administered without metabolic enzyme inhibitors.

Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism oflevodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation oflevodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can beused and the incidence of adverse reactionssuch as nausea is reduced.

With inhibition of the decarboxylase by a DDC inhibitor, catechol-O-methyltransferase (COMT)becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible,specific and mainly peripherally acting COMT inhibitor designed for concomitant administration withlevodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increasedarea under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinicalresponse to each dose of levodopa is enhanced and prolonged.

The evidence of the therapeutic effects of Corbilta is based on two phase III double-blind studies, inwhich 376 Parkinson’s disease patients with end-of-dose motor fluctuations received eitherentacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and withoutentacapone was recorded in home-diaries by patients. In the first study, entacapone increased themean daily ON time by 1 h 20 min (CI 95% 45 min, 1 h 56 min) from baseline. This corresponded to an8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF timewas 24% in the entacapone group and 0% in the placebo group. In the second study, the meanproportion of daily ON time increased by 4.5% (CI95% 0.93%, 7.97%) from baseline. This is translatedto a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by18% on entacapone and by 5% on placebo. Because the effects of Corbilta tablets are equivalent withentacapone 200 mg tablet administered concomitantly with the commercially available standardrelease carbidopa/levodopa preparations in corresponding doses these results are applicable todescribe the effects of Corbilta as well.

General characteristics of the active substances

Absorption/distribution: There are substantial inter- and intra-individual variations in the absorptionof levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed andeliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. Whengiven separately without the two other active substances, the bioavailability for levodopa is 15-33%,for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutralamino acids may delay and reduce the absorption of levodopa. Food does not significantly affect theabsorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 l/kg) andentacapone (Vdss 0.27 l/kg) is moderately small while no data for carbidopa are available.

Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is boundapproximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) -mainly toserum albumin. At therapeutic concentrations, entacapone does not displace other extensively boundactive substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to anysignificant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation and elimination: Levodopa is extensively metabolised to various metabolites:decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase(COMT) being the most important pathways.

Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides andunconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces(80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite,the cis-isomer, which accounts for about 5% of plasma total amount.

Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of0.70 l/kg/h. The elimination-half life is (t1/2) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopaand 0.4-0.7 hours for entacapone, each given separately.

Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs onrepeated administration.

Data from in vitro studies using human liver microsomal preparations indicate that entacaponeinhibits cytochrome P450 2C9 (IC50 ~ 4 µM). Entacapone showed little or no inhibition of othertypes of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); seesection 4.5.

Elderly: When given without carbidopa and entacapone, the absorption of levodopa is greater andelimination is slower in elderly than in young people. However, after combination of carbidopa withlevodopa, the absorption of levodopa is similar between the elderly and the young people, but the

AUC is still 1.5 fold greater in the elderly due to decreased DDC activity and lower clearance byaging. There are no significant differences in the AUC of carbidopa or entacapone between younger(45-64 years) and elderly (65-75 years).

Gender: Bioavailability of levodopa is significantly higher in women than in men. In thepharmacokinetic studies with Corbilta the bioavailability of levodopa is higher in women than in men,primarily due to the difference in body weight, while there is no gender difference with carbidopa andentacapone.

Hepatic impairment: The metabolism of entacapone is slowed in patients with mild to moderatehepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration ofentacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particularstudies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment arereported, however, it is advised that Corbilta should be administered cautiously to patients with mildor moderate hepatic impairment.

Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. Noparticular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients withrenal impairment. However, a longer dosing interval of Corbilta may be considered for patients whoare receiving dialysis therapy (see section 4.2).

Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed nospecial hazard for humans based on conventional studies of safety pharmacology, repeated dosetoxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone,anaemia most likely due to iron chelating properties of entacapone was observed. Regardingreproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone developmentwere noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa andcombinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.

Croscarmellose sodium

Magnesium stearate

Maize starch

Mannitol (E421)

Povidone K 30 (E1201)

Film-coating of 50/12.5/200 mg, 100/25/200 mg and 150/37.5/200 mg:

Glycerol (85 per cent) (E422)

Hypromellose

Magnesium stearate

Polysorbate 80

Red iron oxide (E172)

Sucrose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Film-coating of 75/18.75/200 mg, 125/31.25/200 mg, 175/43.75/200 mg and 200/50/200 mg:

Glycerol (85 per cent) (E422)

Hypromellose

Magnesium stearate

Polysorbate 80

Red iron oxide (E172)

Sucrose

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

HDPE bottle with a child resistant PP-closure.

Pack sizes of 50/12.5/200 mg, 100/25/200 mg and 150/37.5/200 mg:10, 30, 100, 130, 175 and 250 tablets.

Pack sizes of 75/18.75/200 mg, 125/31.25/200 mg, 175/43.75/200 mg and 200/50/200 mg:10, 30, 100, 130 and 175 tablets.

Not all pack sizes may be marketed.

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

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

50 mg/12.5 mg/200 mg

EU/1/13/859/001-00675 mg/18.75 mg/200 mg

EU/1/13/859/007-011100 mg/25 mg/200 mg

EU/1/13/859/012-017125 mg/31.25 mg/200 mg

EU/1/13/859/018-022150 mg/37.5 mg/200 mg

EU/1/13/859/023-028175 mg/43.75 mg/200 mg

EU/1/13/859/029-033200 mg/50 mg/200 mg

EU/1/13/859/034-038

Date of first authorisation: 11 November 2013

Date of latest renewal: 6 July 2018

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

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