SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-Careldopa 25/100 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Carbidopa monohydrate 27 mg (corresponding to 25 mg carbidopa anhydrous) Levodopa 100 mg

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets.

Mottled yellow, round flat, bevelled tablet, 9.1 mm in diameter, plain and breakline on each side.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For treatment of Parkinson's disease.

4.2 Posology and method of administration

Posology

The optimum daily dosage of Co-Careldopa must be determined by careful titration for each patient.

Because both therapeutic and adverse effects are seen more rapidly with Co-Careldopa than with levodopa, patients should be carefully monitored during the dosage adjustment period. Involuntary movements, particularly blepharospasm, are a useful early sign of excess dosage in some patients.

If general anaesthesia is required, therapy with Co-Careldopa may be continued for as long as the patient is permitted to take fluids and medicines by mouth. If therapy has to be stopped temporarily, Co-Careldopa may be restarted as soon as oral medication can be taken at the same daily dosage as before.

Co-Careldopa tablets are available in a ratio of 1:4 or 1:10 of carbidopa to levodopa to provide facility for fine dosage titration for each patient.

-    Patients not receiving levodopa: For patients starting with Co-Careldopa 25/250, the initial dose is one-half tablet taken once or twice daily. However, this may not provide the optimal amount of carbidopa needed by many patients. If necessary, add one-half tablet every day or every other day until optimal response is reached. Response has been observed in one day, and sometimes after one dose. Fully effective doses usually are reached within seven days as compared to weeks or months with levodopa alone.

-    Patients receiving levodopa: Discontinue levodopa at least 12 hours (24 hours for slow release preparations) before starting therapy with Co-Careldopa. The easiest way to do this is to give Co-Careldopa as the first morning dose after a night without any levodopa. The dose of Co-Careldopa should be approximately 20% of the previous daily dosage of levodopa.

-    Patients taking less than 1,500 mg levodopa a day should be started on a lower strength, with a regimen providing 75-100mg of carbidopa and 300-400mg of levodopa in three to four daily doses, dependent on patient need. The suggested starting dose for most patients taking more than 1,500 mg levodopa a day is one tablet of Co-Careldopa 25/250 three or four times a day.

-    Maintenance: Therapy with Co-Careldopa should be individualised and adjusted gradually according to response.

When more levodopa is required, Co-Careldopa 25/250 should be substituted at a dosage of one tablet three or four times a day. If necessary, the dosage of Co-Careldopa 25/250 may be increased by half to one tablet every other day to a maximum of eight tablets a day. Experience with a total daily dosage greater than 200 mg carbidopa is limited.

When transferring a patient to Co-Careldopa from levodopa combined with another decarboxylase inhibitor, dosage should be discontinued at least 12 hours before Co-Careldopa is started. Begin with a dosage of Co-Careldopa that will provide the same amount of levodopa as contained in the other levodopa/decarboxylase inhibitor combination.

-    Patients receiving other antiparkinsonian agents: The combination of Co-Careldopa with MAO-B inhibitors (e.g. selegiline) has been reported to improve the efficacy of Co-Careldopa in controlling episodes of akinesia and/or dyskinesia.

Standard anti-parkinsonism drugs other than levodopa alone, may be continued while Co-Careldopa is being administered, although their dosage or the levodopa dosage may have to be adjusted. Anticholinergics: (See below under Interaction with other Medicinal Products and other Forms of Interaction)

Pediatric population

-    Use in children: The safety of Co-Careldopa in patients under 18 years of age has not been established. (See under Contra-Indications)

Older people

-    Use in the older people: There is wide experience in the use of this product in elderly patients. The recommendations set out above reflect the clinical data derived from this experience.

4.3 Contraindications

MAO inhibitors (except low doses of selective MAO-B inhibitors) and Co-Careldopa should not be given concomitantly (these must be discontinued at least two weeks before starting Co-Careldopa); narrow angle glaucoma; hypersensitivity to the active substances or to any of the excipients listed in section 6.1; severe heart failure; psychoses; children under 18 years of age; pregnancy. Because levodopa may activate a malignant melanoma, it should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma. Carbidopa/Levodopa should not be given in situations in which a sympathomimetic compound is contra-indicated.

4.4 Special warnings and precautions for use

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

Co-Careldopa should be administered cautiously to patients with cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease; or a history of peptic ulcer disease (because of the possibility of upper gastrointestinal haemorrhage).

Care should be exercised when Co-Careldopa is administered to patients with a history of myocardial infarction who have atrial, nodal, or ventricular arrhythmias. Cardiac function should be monitored with particular care in such patients during the period of initial dosage adjustment.

All patients should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients with current psychoses should be treated with caution.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa, including Co-careldopa. Review of treatment is recommended if such symptoms develop.

Dyskinesias may occur in patients previously treated with levodopa alone, because carbidopa permits more levodopa to reach the brain and thus, more dopamine to be formed. The occurrence of dyskinesias may require dosage reduction.

As with levodopa, Co-Careldopa may cause involuntary movements and mental disturbances. Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone should be observed carefully when Co-Careldopa is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa, and use of Co-Careldopa may cause a recurrence. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agent especially when the patient also is treated with antipsychotic agents. Therefore, any abrupt dosage reduction or withdrawal of Co-Careldopa should be carefully observed, particularly in patients who are also receiving neuroleptics.

Concomitant administration of psycho-active drugs such as phenothiazines or butyrophenones should be carried out with caution, and the patients carefully observed for loss of antiparkinsonian effect. Patients with a history of convulsions should be treated with caution.

As with levodopa, periodic evaluations of hepatic, haematopoietic, cardiovascular and renal functions are recommended during extended therapy.

Patients with chronic wide-angle glaucoma may be treated cautiously with Co Careldopa, provided the intra-ocular pressure is well controlled and the patients monitored carefully for changes in intra-ocular pressure during therapy.

- Laboratory tests: Commonly, levels of blood urea, creatinine and uric acid are lower during administration of Co-Careldopa than with levodopa. Transient abnormalities include elevated levels of blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin, alkaline phosphatase, and protein-bound iodine.

Decreased haemoglobin, haematocrit, elevated serum glucose, and white blood cells, bacteria and blood in the urine have been reported.

Positive Coombs tests have been reported, both with Co-Careldopa and levodopa alone, but haemolytic anaemia is extremely rare.

Co-Careldopa may cause a false positive result when a dipstick is used to test for urinary ketone; and this reaction is not altered by boiling the urine. The use of glucose oxidase methods may give false negative results for glycosuria.

Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Caution should be exercised when the following drugs are administered concomitantly with Co-Careldopa:

Antihypertensive agents: Postural hypotension can occur when Co-Careldopa is added to the treatment of patients already receiving antihypertensive drugs. Dosage adjustments of the hypertensive agent may be required.

Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants. (See the ContraIndications for patients receiving MAOIs).

The concomitant use of anaesthetics can induce arrhythmias.

Other drugs: Phenothiazines, benzodiazepines, butyrophenones, phenytoin and papaverine may reduce the therapeutic effect of levodopa. The metabolism of levodopa is increased by anticonvulsive drugs. Patients taking these drugs with Co-Careldopa should be carefully observed for loss of therapeutic response.

Anticholinergic drugs: they may act synergistically with levodopa to decrease tremor and this interaction is often used to therapeutic advantage; however they can exacerbate abnormal involuntary movements. They may also in high dosage diminish the beneficial effects of levodopa by delaying its absorption thus increasing gastric metabolism of the drug.

Since levodopa competes with certain amino acids, the absorption of Co-Careldopa may be impaired in some patients on a high protein diet.

4.6 Fertility, pregnancy and lactation

Pregnancy

Although the effects of Co-Careldopa on human pregnancy are unknown, both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits. Therefore, Co-Careldopa should not be used during pregnancy. Any woman of child bearing potential who is receiving Co-Careldopa must practise effective contraception.

Breast-feeding

It is not known whether carbidopa or levodopa is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in infants, a decision should be made whether to discontinue breastfeeding or to discontinue the use of Co-Careldopa taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

There are no data on the effect of these products on the ability to drive.

Some of the adverse events mentioned in the relevant Section could interfere with the ability to drive or use machines.

Patients being treated with levodopa and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also Section 4.4).

4.8 Undesirable effects

Side-effects that occur frequently with Co-Careldopa are those due to neuropharmacological activity of dopamine. These reactions can usually be diminished by dosage reduction. The most common are dyskinesias including choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be taken a early signs to consider dosage reduction.

Other serious side-effects are mental changes, including paranoid ideation and psychotic episodes; depression with or without development of suicidal tendencies; and dementia.

Impulse control disorders

Pathological gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating or compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including carbidopa+levodopa.(see section 4.4 “Special warnings and precautions for use”).

A common but less serious side-effect is nausea.

Less frequent side effects are cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, bradykinetic episodes (the 'on-off' phenomenon), anorexia, vomiting, dizziness and somnolence.

Gastro-intestinal bleeding, development of duodenal ulcer, hypertension, phlebitis, leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis, chest pain, dyspnoea and paraesthesia have occurred rarely. Convulsions have occurred rarely; however, a causal relationship with Co-Careldopa has not been established.

Other side-effects that have been reported with levodopa and may be potential side-effects include:

Neurological: ataxia, numbness, increased hand tremor, muscle twitching, muscle cramp, trismus, activation of latent Horner's syndrome.

Psychiatric: confusion, insomnia, nightmares, hallucinations, delusions, agitation, anxiety, euphoria.

Gastro-intestinal: dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, abdominal pain and distress, constipation, diarrhoea, flatulence, burning sensation of the tongue.

Metabolic: weight gain or loss, oedema.

Integumentary: flushing, increased sweating, dark sweat, rash, hair loss. Genito-urinary: urinary retention, urinary incontinence, dark urine, priapism.

Special senses: diplopia, blurred vision, dilated pupils, oculogyric crises. Miscellaneous: weakness, faintness, fatigue, headache, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, neuroleptic malignant syndrome, malignant melanoma (see Contra-Indications).

Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Other side-effects that have been reported with Co-Careldopa CR and may be potential side-effects with Co-Careldopa include:

Neurological: falling, gait abnormalities.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Management of acute overdosage with Co-Careldopa is basically the same as management of acute overdosage with levodopa; however, pyridoxine is not effective in reversing the actions of Co-Careldopa. ECG monitoring should be

instituted, and the patient carefully observed for the possible development of arrhythmias; if required appropriate anti-arrhythmic therapy should be given.

The possibility that the patient may have taken other drugs as well as Co-Careldopa should be taken into consideration. To date, no experience has been reported with dialysis, and hence its value in the treatment of overdosage is not known.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson Drug. Dopaminergic agent. Levodopa and decarboxylase inhibitor.

ATC Code: NO4B AO2

Levodopa is the metabolic precursor of dopamine. The latter is severely depleted in the striatum, pallidum and substantia nigra of Parkinsonian patients and it is considered that administration of levodopa raises the level of available dopamine in these centres. However, conversion of levodopa into dopamine by the enzyme dopa decarboxylase also takes place in extracerebral tissues. As a consequence the full therapeutic effect may not be obtained and side-effects occur.

Administration of a peripheral decarboxylase inhibitor, which blocks the extracerebral decarboxylation of levodopa, in conjunction with levodopa has significant advantages; these include reduced gastro-intestinal side effects, a more rapid response at the initiation of therapy and a simpler dosage regimen.

By reducing some of the adverse reactions produced by levodopa alone, Co-Careldopa permits more patients to obtain adequate relief of the symptoms of Parkinson's disease.

General Considerations: Studies show that peripheral enzyme dopa-decarboxylase is fully inhibited (saturated) by carbidopa at doses between 70 and 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.

Co-Careldopa may be given to patients with Parkinson's disease who are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B6).

Addition of carbidopa prevents the increase in the rate of levodopa metabolism to dopamine known to be induced by pyridoxine hydrochloride (Vitamin B₆).

5.2 Pharmacokinetic properties

Levodopa and carbidopa are well absorbed, reaching maximum plasma concentrations after 1 to 3 hours. The terminal half-life of levodopa is about two hours in the presence of carbidopa. As an effect of carbidopa, the plasma clearance of levodopa is reduced to about 50%. In the presence of carbidopa, levodopa is mainly metabolised to amino acids and, to a lesser extent, to catecholamine derivatives. All the metabolites of carbidopa and levodopa are excreted renally.

5.3 Preclinical safety data

It can be concluded from the findings of mutagenicity testing that carbidopa/levodopa will not exert mutagenic effects under conditions of clinical use. In a two-year study in rats with carbidopa/levodopa no evidence of carcinogenicity was found.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet contains: Pregelatinised maize starch Maize starch

Microcrystalline cellulose E132 indigo carmine Magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Bottles 4 years Blisters 3 years

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

HDPE bottles with metal screw cap: 100, 500 and 1000 tablets.

HDPE bottles with child resistant tamper evident screw cap: 100 tablets

Cardboard boxes with PVC/aluminium blister strips: 20, 30, 50, 60, 100 and 200 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0784

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 25/09/2008

10 DATE OF REVISION OF THE TEXT

09/09/2014