CO-BENELDOPA 50 MG/12.5 MG CAPSULES

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Co-Beneldopa 50 mg/12.5 mg Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains 50 mg of levodopa and 12.5 mg of benserazide as benserazide hydrochloride. For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Capsule, hard hard gelatin capsules filled with off-white to brownish white granules, with a grey opaque cap and blue opaque body, imprinted axially in black ink 62.5 on the cap and BL on the body

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4.1

CLINICAL PARTICULARS
Therapeutic indications
Treatment of symptoms of Parkinson s disease.

4.2

Posology and method of administration
Dosage and administration are variable and no more than a guide can be given. The dose is dependent on the severity of extrapyramidal symptoms and individual tolerance. High single doses should be avoided. Treatment must be initiated and the dose increased slowly, in order to limit the adverse events and so as not to reduce the likelihood of therapeutic success. Standard dosage For doses not practicable with this strength, other strengths of this medicinal product are available.

Patients not previously treated with levodopa Levodopa dose Initial dose 100-200 mg Benserazide dose 25-50 mg 12.5-25 mg 200 mg

Increase every 50-100 mg 3rd to 7th day by Maximum dose 800 mg

Initially, each individual administration should not exceed 50 mg/12.5 mg. Subsequently, the daily dose should be divided into at least 4 administrations. If adverse events occur (see section 4.8), the dose should first not be increased any further, or may be temporarily decreased and titrated again more slowly. If gastrointestinal adverse events occur, antiemetics such as domperidone may be administered. The effective dose usually lies within the range of 400-800 mg levodopa/100-200 mg benserazide daily in divided doses, most patients requiring no more than 600 mg levodopa/150 mg benserazide daily. Optimal improvement is usually seen in one to three weeks but the full therapeutic effect may not be apparent for some time. It is advisable, therefore, to allow several weeks to elapse before contemplating dosage increments above the average dose range. If satisfactory improvement is still not achieved, the dose may be increased but with caution and on a monthly basis. It is rarely necessary to give more than 800 mg levodopa/200 mg benserazide per day. Treatment should be continued for at least six months before failure is concluded from the absence of a clinical response. Patients previously treated with levodopa Levodopa alone should be discontinued and Co-Beneldopa started after a treatmentfree period of at least 12 hours. The levodopa dose in combination with benserazide should be approximately 20% of the previous dose of levodopa, in order to achieve a similar clinical effect. Observe the patient for one week and then, if necessary, increase the dosage in the manner described for new patients. Patients previously treated with other levodopa / decarboxylase inhibitor combinations Previous therapy should be withdrawn for 12 hours. In order to minimise the potential for any effects of levodopa withdrawal, it may be beneficial to discontinue previous therapy at night and institute Co-Beneldopa therapy the following morning. Initial and increasing doses should be administered in the manner described for patients not previously treated with levodopa. Co-Beneldopa may be used concomitantly in patients already on other antiparkinsonian treatment. As soon as the therapeutic effect of Co-Beneldopa becomes apparent, the dosage of the other treatment should be evaluated, and slowly reduced and withdrawn if necessary.

Special dosage recommendations Patients who experience severe fluctuations in response may be helped by dividing the dosage into smaller, more frequent doses (i.e. more than four times daily), without, however, altering the total daily dose. Elderly patients In the elderly, the dose must be titrated slowly. Children and adolescents The experience in children and adolescents is limited (see section 4.4). Use in renal and hepatic impairment No dose adjustment is required.

Method and duration of administration Co-Beneldopa capsules, hard are for oral use. They should be swallowed whole and must not be chewed. When possible, Co-Beneldopa should be administered 30 minutes to 1 hour after meals. Gastrointestinal adverse reactions, which occur mainly in the early stages of treatment, can be controlled by taking the medicinal product with food or drink, or by slow dose titration. Co-Beneldopa must usually be taken over the long term (substitution therapy). If it is well tolerated, the treatment need not be limited in time.

4.3

Contraindications
Co-Beneldopa must not be used in the following cases: hypersensitivity to levodopa, benserazide or to any of the excipients; severe hyperthyroidism, tachycardia or phaeochromocytoma; severe endocrine, cardiac, hepatic or renal disease; endogenous or exogenous psychoses; treatment with reserpine or non-selective monoamine oxidase (MAO) inhibitors (see section 4.5). Administration of these MAO inhibitors should be discontinued at least 2 weeks before starting treatment with levodopa/benserazide;

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narrow angle glaucoma.

4.4

Special warnings and precautions for use
Use of Co-Beneldopa is not recommended in the treatment of pharmacogenic extrapyramidal reactions or Huntington s chorea. In the initial phase of treatment, hepatic, renal and haematopoietic function should be evaluated frequently, during extended therapy periodically. Circulatory function and the electrocardiogram (ECG) should be monitored regularly in patients with a history of myocardial infarction, cardiac arrhythmia or coronary arterial disorders. Close monitoring is necessary in patients with a history of orthostatic hypotension, especially at the beginning of treatment. Symptomatic orthostatic hypotension may require treatment. Patients with a history of gastrointestinal ulceration, convulsions or osteomalacia should be monitored particulary carefully. Patients with chronic wide-angle glaucoma can be treated cautiously with levodopa/benserazide, provided that intra-ocular pressure is well controlled. Patients should be carefully monitored during treatment for any changes in intra-ocular pressure. Blood sugar levels should be checked more frequently in diabetic patients, and the dosage of antidiabetic therapy adjusted accordingly. All patients should be carefully monitored for psychological changes and depression with or without suicidal ideation. Depression may occur during treatment with levodopa/benserazide, but may also be caused by the underlying disease. Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson s disease, including levodopa. The sudden withdrawal of Co-Beneldopa after long-term treatment with levodopacontaining medicinal products can lead to a malignant levodopa withdrawal syndrome (with hyperpyrexia, muscular rigidity, sometimes psychological changes and increased serum creatine phosphokinase) or akinetic crisis. Both of these conditions can be life-threatening. Therapeutically-indicated levodopa holidays should therefore only be carried out in hospital. Since Co-Beneldopa can cause tiredness and, in rare cases, excessive daytime sleepiness and sudden sleep onset, sometimes without warning signs, patients should be advised to exercise particular caution when driving or operating machinery (see

section 4.8). In such cases, a reduction of dosage or termination of therapy may be considered. If general anaesthesia is required, treatment with Co-Beneldopa may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped temporarily, Co-Beneldopa at the same dose as before may be restarted as soon as oral intake of fluid is allowed. Whenever therapy has been interrupted for longer periods, dosage should again be adjusted gradually; however, in many cases the patient can rapidly be returned to his previous therapeutic dosage. If a patient has to undergo emergency surgery, when Co-Beneldopa has not been withdrawn, anaesthesia with halothane should be avoided. Hypersensitivity reactions may occur in susceptible individuals. The experience in patients under 25 years of age is limited. Concomitant administration of antipsychotics with dopamine receptor-blocking properties, particularly D2 receptor antagonists, should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms (see section 4.5). Suspicion has arisen that levodopa may activate a malignant melanoma. Therefore, it is recommended not to use Co-Beneldopa in persons who have a history of, or who may be suffering from a malignant melanoma.

4.5

Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions Concomitant administration of the anticholinergic agent trihexyphenidyl with CoBeneldopa reduces the rate of absorption of levodopa. Ferrous sulphate reduces the peak plasma concentration and area-under-the-curve (AUC) of levodopa by 30-50%. The pharmacokinetic changes observed during concomitant treatment with ferrous sulphate appear to reach clinical significante in some but not all patients. Metoclopramide increases the rate of absorption of levodopa. Pharmacodynamic interactions Substances acting on the extrapyramidal motor system

Opioids, reserpine-containing antihypertensives and neuroleptics (except clozapine) may reduce the effect of levodopa/benserazide. The association of Co-Beneldopa and neuroleptics is not recommended. If necessary, the lowest dose of both products should be used. MAO inhibitors Co-Beneldopa must not be administered concomitantly with non-selective MAO inhibitors. The use of pure MAO-B inhibitors (e.g. selegiline, up to 10 mg daily) or selective MAO-A inhibitors (e.g. moclobemide) is not contraindicated. In certain cases, selegiline may increase the antiparkinsonian effect of levodopa, without inducing dangerous interactions. The concomitant administration of MAO-A and MAO-B inhibitors is equivalent to the action of a non-selective MAO inhibitor. Consequently, such combinations must not be administered with levodopa/benserazide. The concomitant administration of non-selective, irreversible MAO inhibitors (e.g. tranylcypromine) can cause hypertensive crisis for up to 2 weeks after the MAO inhibitor has been discontinued. Antihypertensive agents Symptomatic postural hypotension has occurred when combinations of levodopa and a decarboxylase inhibitor is added to the treatment of patients already receiving antihypertensives. Dosage adjustment of the antihypertensive agent may be required. Sympathomimetics Co-Beneldopa should not be used in combination with sympathomimetics. The combination may increase the effect of the sympathomimetic agent. If such a combination is necessary, cardiovascular function must be monitored and the dose of the sympathomimetic agent reduced. Other antiparkinsonian agents Co-Beneldopa may be combined with all other known antiparkinsonian agents (e.g. dopamine agonists, amantadine, anticholinergic agents), as long as the dosage of CoBeneldopa or the other agent is reduced as necessary. If adjuvant therapy with a catechol-O-methyl transferase (COMT) inhibitor is initiated, it may be necessary to reduce the dose of levodopa/benserazide. Anticholinergics should not be withdrawn abruptly when Co-Beneldopa therapy is instituted, as levodopa does not begin to take effect for some time. High-protein meals The concomitant ingestion of high-protein meals may reduce the effect of levodopa/benserazide. Alterations in diagnostic laboratory tests

Co-Beneldopa may interact with several diagnostic laboratory tests: - catecholamine, creatinine, uric acid, glucose, alkaline phosphatase, serum glutamic-oxaloacetic transaminase (SGOT, aspartate transaminase, AST), serum glutamic-pyruvic transaminase (SGPT, alanine transaminase, ALT), lactate dehydrogenase (LDH) and bilirubin determination; - increased blood urea nitrogen (BUN) levels have been observed with levodopa/benserazide; - false-positive ketone body determination by test strip (the reaction is unchanged if the urine is boiled); - false-negative urine glucose determination by the glucose-oxidase method; - false-positive Coombs test.

4.6

Pregnancy and lactation
Pregnancy There is insufficient data available on the use of Co-Beneldopa in pregnant women. The results of animal studies have shown teratogenicity (see section 5.3). The potential risk to the embryo or fetus is not known. Co-Beneldopa should not be used during pregnancy unless the benefits to the mother outweigh the possible risks to the fetus. It is preferable to delay the administration of levodopa after the first trimester; should it prove impossible to delay the beginning of treatment or in the absence of an alternative, pre-natal monitoring is necessary. Women of child-bearing potential must use reliable contraceptive methods. Lactation Levodopa is secreted in breast milk in significant quantities. There is evidence that lactation is suppressed during treatment with levodopa. The safety of levodopa and benserazide in the infant is not known. Women should not breast-feed during treatment with levodopa/benserazide.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Patients who experience excessive daytime sleepiness or sudden onset sleep episodes during treatment with Co-Beneldopa must be advised not to drive or operate machinery, by means of which they might put themselves or others at risk of harm, until the excessive daytime sleepiness and sudden onset sleep episodes have resolved (see section 4.4).

4.8

Undesirable effects
The frequencies of adverse events are ranked according to the following: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1000; < 1/100), rare ( 1/10000; < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data). a) Blood and lymphatic system disorders Very rare Transient leucopenia, haemolytic anaemia, thrombocytopenia

Metabolism and nutrition disorders Very rare Psychiatric disorders Rare Very rare Not known Hallucinations, disorientation in time Agitation, anxiety, sleep disturbances, delusions*, depressed mood**, anorexia Mild elation, drowsiness, aggression, 'unmasking' of psychoses Patients treated with dopamine agonists for treatment of Parkinson s disease, including levodopa, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation. Nervous system disorders Common Fluctuations of therapeutic response such as freezing , end-ofdose and on-off phenomena*, dyskinesias, involuntary movements (choreiform or athetotic)*, Excessive daytime sleepiness, sleep episodes Increased BUN (blood urea nitrogen)

Very rare Cardiac disorders Very rare Vascular disorders Very rare

Cardiac arrhythmia

Orthostatic hypotension *

Gastrointestinal disorders Very rare Not known (cannot be estimated from the available data) Taste loss, taste alterations*, nausea, vomiting, diarrhoea* Gastro-intestinal bleeding

Hepato-biliary disorders Very rare Increased hepatic transaminase levels and alkaline phosphatase

Skin and subcutaneous tissue disorders Rare Allergic skin reactions such as pruritus, rash

Renal and urinary disorders Very rare Urine discolouration*









Not known (cannot be estimated from the available data) Others Not known * **

Uraemia

Flushing and sweating

see sub-section b) see section 4.4

b) The adverse reactions typical of early treatment (loss of appetite, nausea, vomiting, taste alterations) can usually be controlled by administering Co-Beneldopa with food or drink, or by increasing the dose more slowly. Involuntary movements (e.g. choreiform or athetotic), which may develop in the later stages of the disease, can be controlled by reducing the dose. Fluctuations of the therapeutic response ( freezing , end-of-dose and on-off phenomena) may develop after prolonged treatment and are usually reduced or made tolerable by dividing the dosage into smaller, more frequent doses. The dose of levodopa may then be tentatively increased, stepwise, in order to improve efficacy. Agitation, anxiety, sleep disturbances, hallucinations, delusions and temporal disorientation occur mainly in the elderly and in patients with a corresponding history. Orthostatic hypotensive circulatory disorders can usually be improved by reducing the dose of levodopa/benserazide. Mild urine discolouration may occur. Usually red-tinged, this will turn dark on standing.

4.9

Overdose
Symptoms of overdose The symptoms of overdose correspond to a more severe adverse reaction profile, mainly increased dyskinesia, confusion, hallucinations and sleep disturbances. Nausea, vomiting and cardiac arrhythmias have rarely been observed after overdose with levodopa/benserazide. Treatment of overdose After an acute overdose with levodopa/benserazide, immediate gastric lavage, intensive monitoring, supportive measures and particular monitoring of cardiac

function are recommended. Cardiac arrhythmias may require administration of antiarrhythmic agents e.g. beta-blockers. There is no specific antidote.

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5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson drug, levodopa and decarboxylase inhibitor ATC code: N04B A02 The amino acid levodopa is used to substitute for dopamine deficiency in Parkinson s disease. Owing to the fact that at least 95% of orally administered levodopa is decarboxylated in extracerebral organs (intestines, liver, kidneys, heart, stomach), only small amounts reach the central nervous system after administration of levodopa monotherapy. The extracerebral build-up of dopamine and corresponding adrenergic substances leads to numerous gastrointestinal and cardiovascular adverse reactions with levodopa monotherapy. At therapeutic doses, the decarboxylase inhibitor benserazide does not cross into the brain in appreciable quantities (less than 6% of the plasma concentration). The concomitant administration of benserazide inhibits the peripheral decarboxylation of levodopa (notably in the intestinal mucosa) virtually completely. Consequently, the dose of levodopa required to produce a similar clinical effect can be reduced by ca. 20% compared to the monotherapeutic dose. The gastrointestinal and cardiovascular adverse effects of peripherally accumulated dopamine are also largely avoided. The benserazide component of the combination may lead to an increase in prolactin concentration, owing to decarboxylase inhibition.

5.2

Pharmacokinetic properties
Absorption Levodopa is mainly absorbed in the proximal small intestine, independent of the region thereof. Peak plasma concentrations are attained approximately 1 hour after dosing with an immediate-release dosage form. Levodopa peak plasma concentrations and AUC increase in proportion to the dose over the range of 50-200 mg of levodopa. Food intake reduces the rate and extent of levodopa absorption. Peak levodopa concentrations are reduced by ca. 30%, and delayed two or threefold, after ingestion of a standard meal. The extent of absorption is reduced by ca. 15% after

administration with food. The absorption of levodopa is influenced by changes in gastric emptying time. Distribution Levodopa crosses the blood-brain barrier (BBB) by means of a saturable transport mechanism. It is not bound to plasma protein. Its volume of distribution is 57 l. The AUC of levodopa in the cerebrospinal fluid is 12% of the value in plasma. Contrary to levodopa, benserazide does not cross the BBB at therapeutic doses. Benserazide concentrations are highest in the kidneys, lungs, small intestine and liver. Benserazide crosses the placenta. Metabolism Levodopa is mainly metabolised by decarboxylation, O-methylation, transamination and oxidation. The principal metabolic pathway for levodopa is decarboxylation to dopamine by an aromatic amino acid decarboxylase. Its main metabolites are homovanillic acid and dihydroxyphenylacetic acid. Methylation of levodopa to 3-Omethyldopa by COMT is a secondary pathway. The elimination half-life of 3-Omethyldopa is 15 hours. This metabolite therefore accumulates in patients receiving therapeutic doses of levodopa/benserazide. The concomitant administration of levodopa and benserazide reduces peripheral decarboxylation. This is manifested in increased plasma levels of amino acids (levodopa, 3-O-methyldopa) and reduced plasma levels of catecholamines (dopamine, noradrenaline) and phenylcarbonyl acids (homovanillic acid, dihydroxyphenylacetic acid). Benserazide is hydrolysed to trihydroxybenzylhydrazine in the intestinal wall and liver. This metabolite is an active inhibitor of the aromatic amino acid decarboxylase. Elimination After inhibition of peripheral levodopa decarboxylation, the elimination half-life of levodopa is ca. 1.5 hours. In elderly parkinsonian patients (65-78 years of age), the elimination half-life is increased by ca. 25%. The clearance of levodopa is 430 ml/min. Benserazide is almost entirely excreted in the form of metabolites. The metabolites are mainly excreted via the kidneys (64%), and, to a lesser extent, in the faeces (24%). Bioavailability The absolute bioavailability of levodopa when administered in combination with benserazide for inhibition of peripheral decarboxylase is 98%, on average (range, 74112%).

5.3

Preclinical safety data
Chronic toxicity In chronic toxicity studies in rats, orally administered Co-Beneldopa caused dosedependent skeletal changes, originating in the unclosed epiphyseal disks. Bone changes occurred only in growing animals and were caused by benserazide. In dogs, dose-dependent increases in liver enzymes, fatty degeneration of the liver, prolonged prothrombin times and decreased bone marrow haematopoietic tissue were observed. Genotoxicity In vitro studies in bacteria and cell cultures show that levodopa and benserazide have a weak genotoxic potential. There was no indication that clinical use would be associated with a genotoxic potential. Reproductive toxicity Studies with Co-Beneldopa in rats did not reveal any teratogenic effects. Maternotoxic doses led only to fetal weight loss. In rabbits, maternotoxic doses of Co-Beneldopa caused embryolethality and increased fetal skeletal abnormalities. These toxic effects were assigned to levodopa, based on previous results with levodopa or benserazide alone, which revealed an increase in skeletal abnormalities and cardiovascular malformations in rabbits given high (maternotoxic) doses of levodopa.

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6.1

PHARMACEUTICAL PARTICULARS
List of excipients
Capsule contents Mannitol Cellulose, microcrystalline Povidone K-30 Talc Magnesium stearate Capsule shell Gelatin Titanium dioxide (E171) Black iron oxide (E172) Erythrosin (E127)

Indigo carmine (E132) Printing ink Shellac Propylene glycol Potassium hydroxide Black iron oxide

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
White opaque HDPE bottle with a white opaque polypropylene screw cap with silica gel desiccant containing 20, 30, 50, 60, 90 & 100 capsules, hard. Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

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MARKETING AUTHORISATION HOLDER
TEVA UK Ltd, Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/0992

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/01/2008

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DATE OF REVISION OF THE TEXT
25/05/2009