Summary of medicine characteristics - CARAMET 25 MG / 100 MG CR TABLETS
Caramet 25 mg/100 mg Prolonged Release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 25 mg carbidopa (as monohydrate) and 100 mg levodopa
For a full list of excipients see section 6.1
Prolonged-release tablet
Orange-brown, round, biconcave prolonged-release tablet
4.1 Therapeutic indications
Idiopathic Parkinson’s disease in particular to shorten the ‘“off” period in patients who
have previously been treated with immediate-release levodopa/decarboxylase inhibitors or with just levodopa and who showed motor fluctuations.
Experience with Caramet 25 mg/100 mg Prolonged Release Tablets is limited in patients, who have not been previously treated with levodopa.
4.2 Posology and method of administration
The daily dose of Caramet 25 mg/100 mg Prolonged Release Tablets should be carefully determined. Patients should be closely monitored during the period of dose adjustment, especially with regard to the occurrence or exacerbation of nausea and abnormal involuntary movements such as dyskinesias, chorea and dystonia.
Blepharospasm could be an early sign of overdosing.
The pharmacokinetic properties of the prolonged-release tablets may be altered if the tablets are broken or chewed. Therefore the tablets must be swallowed whole.
Most other medicines, used to treat Parkinson's Disease, except for levodopa, can be continued during administration of Caramet 25 mg/100 mg Prolonged Release Tablets. However their dosage may need to be adjusted.
Sudden withdrawal of Levodopa therapy should be avoided wherever possible.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, Caramet 25 mg/100 mg Prolonged Release Tablets can be administered to patients who receiving supplemental pyridoxine (vitamin B6).
Precaution:
In order to maintain the prolonged-release effect of the medicinal product, the prolonged-release tablets may only be taken whole and may not be divided.
Starting dose
Patients who have never before received levodopa therapy
Caramet 25 mg/100 mg Prolonged Release Tablets is designed for use in patients, who have not previously had levodopa treatment or to aid titration in patients who receive Caramet 50 mg/200 mg Prolonged Release Tablets.
The recommended starting dose is one prolonged-release tablet of Caramet 25 mg/100 mg Prolonged Release Tablets, two times a day.
In patients who need more levodopa a daily dose of three to four tablets of Caramet 25 mg/100 mg Prolonged Release Tablets is usually well tolerated.
The starting dose should not be higher than 600 mg levodopa per day and the doses should be administered with minimum intervals six hours.
Dose adjustments should occur with intervals of at least two to four days.
Depending upon the severity of disease, six months of treatment may be required to achieve optimal disease control.
A guide to substitution for patients who are treated with the immediate-release combination of levodopa and decarboxylase inhibitor
Transferring to Caramet 25 mg/100 mg Prolonged Release Tablets, should initially occur in a dose that supplies at most about 10% more levodopa/day, when higher doses are indicated (more then 900 mg daily).
Levodopa and decarboxylase inhibitor should be discontinued at least 12 hours before the administration of Caramet 25 mg/100 mg Prolonged Release Tablets.
The dose interval should be prolonged by 30%-50% at intervals of ranging from 4–12 hours.
If the divided doses are not equal it is recommended to administer the lowest dose at the end of the day. The dose should be adjusted depending on the clinical reaction, as indicated below in Dose Adjustment. It could be that doses which supply maximally 30% more levodopa per day are necessary.
A guide for the substitution of Caramet 25 mg/100 mg Prolonged Release Tablets for immediate-release levodopa/carbidopa combinations is shown in the table below:
Daily dose of Daily dose of Number of prolonged-
levodopa (mg)levodopa (mg) release tablets
100–200 200 1 tablet, twice daily
300–400 400 1 tablet, three to four times daily
For higher doses, Caramet 50 mg/200 mg Prolonged Release Tablets are also available.
Patients who are currently treated with just levodopa
Levodopa must be discontinued at least twelve hours before therapy with Caramet 25 mg/100 mg Prolonged Release Tablets is started. In patients with mild to moderate disease, the recommended initial dose is 2 prolonged-release tablets of Caramet 25 mg/100 mg Prolonged Release Tablets twice daily.
Dose adjustment
Once the dosage has been established, the dose or the dosing interval can be increased or decreased, according to patient response. For higher doses, Caramet 50 mg/200 mg Prolonged Release Tablets is also available.
Most patients are adequately treated with 400 mg Levodopa/100 mg Carbidopa to 1600 mg Levodopa/400 mg Carbidopa per day, administered in divided doses at intervals ranging from four to twelve hours during the waking day. Higher doses (up to 2400 mg Levodopa/600 mg Carbidopa) and shorter intervals (less than four hours) have been used, but are generally not recommended.
When doses of Caramet 25 mg/100 mg Prolonged Release Tablets are given at intervals of less than four hours or if the divided doses are not equal, it is recommended to administer the lowest dose at the end of the day.
The effect of the first morning dose can be delayed in some patients for up to one hour compared to the usual reaction of the first morning dose of immediate-release Levodopa/Carbidopa.
Adjustments of the dosage should occur in intervals of at least three days.
Maintenance dose
Because Parkinson’s disease is progressive, periodic clinical check-ups are recommended and an adjustment of the dose schedule of Caramet 25 mg/100 mg Prolonged Release Tablets may be needed.
Addition of other anti-Parkinson medications
Anti-cholinergic agents, dopamine agonists and amantadine can be administered concomitantly with Caramet 25 mg/100 mg Prolonged Release Tablets. It might be necessary to adjust the dose Caramet 25 mg/100 mg Prolonged Release Tablets when these medications are added to an ongoing treatment of Caramet 25 mg/100 mg Prolonged Release Tablets.
Interruption of the therapy
Patients should be carefully observed in case of a sudden reduction of the dose or if it is necessary to discontinue treatment with Caramet 25 mg/100 mg Prolonged Release Tablets, particularly in the patient who is receiving anti-psychotics (see section 4.4).
If anaesthesia is necessary, the administration of Caramet 25 mg/100 mg Prolonged Release Tablets can be continued as long as the patient is allowed to take oral medications. In case of a temporary interruption of the therapy, the usual dose can be administered as soon as the patient is able to take the oral medications.
Use in children and adolescents
The safety in patients under 18 years of age has not been established.
Use in Older people
There is a wide experience in the use of levodopa/carbidopa in elderly patients. The recommendations set out above reflect the clinical data derived from this experience. Use in renal and hepatic impairment
No dose adjustment is necessary.
4.3 Contraindications
– Hypersensitivity to levodopa, carbidopa or any of the excipients
– Narrow-angle glaucoma
– Severe heart failure
– Severe cardiac arrhythmia
– Acute stroke
Caramet prolonged-release tablets should not be given, when administration of a sympathomimetics is contraindicated.
Non- selective mono-amino-oxydase (MAO) inhibitors and selective MAO type A inhibitors are contraindicated for concomitant use with Caramet 25 mg/100 mg Prolonged Release Tablets. The administration of these inhibitors should have been discontinued at least two weeks before starting treatment with Caramet 25 mg/100 mg Prolonged Release Tablets. Caramet 25 mg/100 mg Prolonged Release Tablets can be taken concomitantly with the recommended dose of an MAO inhibitor, which is selective for MAO type B (for instance selegiline-HCl) (see section 4.5).
4.4 Special warnings and precautions for use
In patients who are treated with just levodopa, treatment should have been discontinued for at 12 hours before starting with the therapy of Caramet 25 mg/100 mg Prolonged Release Tablets.
Based on the pharmacokinetic profile of Caramet 25 mg/100 mg Prolonged Release Tablets the onset of effect in patients with early morning dyskinesia may be slower than with immediate-release levodopa/carbidopa. The incidence of dyskinesia is greater during treatment with Caramet 25 mg/100 mg Prolonged Release Tablets in patients with an advanced stage of motor fluctuations than it is with an immediate-release tablet with a combination levodopa/carbidopa (16.5% versus 12.2%).
Dyskinesia can occur in patients who previously were treated with just levodopa, because carbidopa makes it possible for more levodopa to reach the brain, which causes more dopamine to be formed. The occurrence of dyskinesia may make it necessary to reduce the dose (see section 4.8).
Caramet 25 mg/100 mg Prolonged Release Tablets can, just like levodopa, cause involuntary movements and mental disturbances. Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone or with carbidopa-levodopa combination should be observed carefully when Caramet 25 mg/100 mg Prolonged Release Tablets is substituted. It is suspected that these reactions are the result of the increased dopamine in the brain after administration of levodopa, and the use of Caramet 25 mg/100 mg Prolonged Release Tablets can cause a recurrence. It may be necessary to reduce the dose. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychosis should be treated with caution.
Caramet 25 mg/100 mg Prolonged Release Tablets should be discontinued when there is deterioration of any pre-exiting psychotic condition.
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 or an episode of sudden sleep onset must refrain from driving or operating machines. A reduction of dosage or termination of therapy may be considered.
Caramet 25 mg/100 mg Prolonged Release Tablets should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease or with a history of peptic ulcer disease, haematemesis or of convulsions. Levodopa/Carbidopa should be administered cautiously to patients who have had a recent myocardial infarction, who have residual atrial, nodal or ventricular arrhythmia. In such patients cardiac function should be monitored with particular care during the period of initial dosage administration and titration.
Patients with chronic wide-angle glaucoma may be treated cautiously with Caramet 25 mg/100 mg Prolonged Release Tablets provided the intraocular pressure is well controlled and the patient is monitored carefully for changes in eye pressure during the therapy.
A symptom complex resembling the neuroleptic malignant syndrome, including muscular rigidity, increased body temperature, mental changes and increased serum creatine phosphokinase, has been reported when anti Parkinsonian medication was withdrawn abruptly. Therefore patients should be carefully observed when the dose of carbidopa/levodopa combinations is abruptly reduced or discontinued, especially if the patient is receiving anti-psychotics.
The use of Caramet 25 mg/100 mg Prolonged Release Tablets is not advised during treatment for pharmacogenic extra-pyramidal reactions or Huntington's chorea.
Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function are recommended during extended therapy.
The safety and efficacy of Caramet 25 mg/100 mg Prolonged Release Tablets has not been determined in infants and children and use in patients under the age of eighteen is not advised.
Patients with Parkinson’s disease show a possible increased risk of melanoma but no confirmed association with levodopa therapy has been established.
Therefore caution should be exercised during treatment.
Laboratory tests
Carbidopa/levodopa preparations have given rise to abnormalities in several laboratory tests and these can also occur with Caramet 25 mg/100 mg Prolonged Release Tablets. These include elevations of liver function tests, such as alkaline phosphatase, SGOT, SGPT, lactic acid dehydrogenase, bilirubin, blood urea nitrogen and a positive Coombs test.
Decreased haemoglobin and haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have also been reported with
Levodopa/Carbidopa.
When a test strip is used to determine ketonuria, carbidopa/levodopa preparations can show a false positive result for urinary ketone bodies. This reaction is not altered by boiling the urine sample. False negative results can also occur in the examination of glycosuria with the use of glucose oxidase methods.
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 levodopa/carbidopa. Review of treatment is recommended if such symptoms develop.
Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/levodopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).
Excipient(s)
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per prolonged release tablet, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Caution is needed in concomitant administration of Caramet 25 mg/100 mg
Prolonged Release Tablets with the following medicines:
Anti-hypertensives
Symptomatic orthostatic dysregulation has occurred when levodopa is added with a decarboxylase inhibitor to certain antihypertensives, Dose adjustment of tantihypertensives may be necessary during the titration phase of treatment with Caramet 25 mg/100 mg Prolonged Release Tablets.
Anti-depressants
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant administration of tricyclic anti-depressants and carbidopa/levodopa preparations (see section 4.3 for patients receiving monoamine oxidase inhibitors).
Anti-cholinergics
Anti-cholinergics may act synergistically with levodopa to decrease tremor. However combined use may exacerbate abnormal involuntary movements. Anticholinergics may decrease the effects of levodopa by delaying its absorption. An adjustment of the dose of levodopa/carbidopa may be needed.
Other medicines
Dopamine-D2-receptor antagonists (for instance phenothiazines, butyrophenons, risperidone), benzodiazepines and isoniazide can reduce the therapeutic effect of levodopa. The beneficial effects of levodopa in Parkinson’s disease may be reduced by phenytoin and papaverine. Patients taking these medications together with Caramet 25 mg/100 mg Prolonged Release Tablets should be observed carefully for loss of therapeutic response.
Concomitant use of selegiline and Caramet 25 mg/100 mg Prolonged Release Tablets may be associated with severe orthostatic hypotension (see section 4.3).
COMT inhibitors (tolcapone, entacapone)
Concomitant use of COMT (catechol-O-methyltransferase) inhibitors and Caramet 25 mg/100 mg Prolonged Release Tablets can increase the bioavailability of levodopa. The dose of levodopa/carbidopa may need adjusting.
Amantadine has a synergistic effect with levodopa and may increase levodopa-related side events. An adjustment of the dose of Caramet 25 mg/100 mg Prolonged Release may be needed.
Metoclopramide increases gastric emptying and may increase the bioavailability of levodopa/carbidopa.
Sympathomimetics may increase cardiovascular side events related to levodopa.
Concomitant use of ferrous sulphate and levodopa/carbidopa can lead to a reduction in the bioavailability of levodopa.
As levodopa competes with certain amino acids, levodopa absorption may be impaired in some patients who are on a protein rich diet.
The effect of administration of antacids and levodopa/carbidopa on the bioavailability of levodopa has not been studied.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are insufficient data available on the use of Caramet 25 mg/100 mg Prolonged Release Tablets in pregnant women. The results of animal studies have shown reproduction toxicity (see section 5.3). The potential risk to embryo or the foetus is not known.
Caramet 25 mg/100 mg Prolonged Release Tablets should not be used during pregnancy. Any women of child-bearing potential who is receiving Caramet 25 mg/100 mg Prolonged Release Tablets must practice effective contraception.
Lactation
Significant amounts of levodopa are excreted into the breast milk. While using Caramet 25 mg/100 mg Prolonged Release Tablets women should not breastfeed.
4.7 Effects on ability to drive and use machines
There are no known data on the effect of this product on the ability to drive. Certain side effects such as sleepiness and dizziness may influence the ability to drive or use machines.
Patients being treated with levodopa and presenting with somnolence or an episode of sudden sleep onset must be advised 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
During controlled clinical trials in patients with moderate to severe motor fluctuations, levodopa/carbidopa caused no side effects which were unique to the modified release formulations.
The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency. Frequencies are defined as 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).
Blood and lymphatic system disorders
Rare: leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia
Very rare: agranulocytosis
Metabolism and nutrition disorders
Common: anorexia
Uncommon: weight loss or gain
Psychiatric disorders
Common: hallucinations, confusion, dizziness, nightmares, sleepiness, fatigue, sleeplessness, depression, very rarely with attempted suicide, euphoria, dementia, psychotic episodes, feeling of stimulation
Rare: agitation, fear, reduced thinking capacity, disorientation, headache, increased libido, numbness, convulsions
Not known: dopamine dysregulation syndrome
Nervous system disorders
Common: dyskinesias (during use of levodopa/carbidopa prolonged-release tablets, dyskinesias have been observed more frequently than with use of immediate-release levodopa/carbidopa dosage forms), chorea, dystonia, extrapyramidal and movement disorders, the „on-off“ -appearance
An (on-off episodes) bradykinesia may occur some months or years after beginning treatment with levodopa and is probably associated with progression of the disease. Adjustment of the dosage regimen and dosing interval may be required.
Uncommon: ataxia, increased tremor of the hands
Rare: neuroleptic malignant syndrome, paraesthesias, falling, walking defects, trismus Levodopa/carbidopa has been associated with somnolence and has been associated very rarely with extreme daytime somnolence and sudden onset of sleep.
Eye disorders
Rare: blurred vision, blepharospasm, activation of a latent Horner’s syndrome, diplopia, pupil dilation, oculogyric crises
Blepharospasm can be an early symptom of overdose.
Cardiac disorders
Common: palpitations, irregular heart beat
Vascular disorders
Common: orthostatic hypotension, tendency to fainting, syncope
Uncommon: hypertension
Rare: phlebitis
Respiratory, thoracic and mediastinal disorders
Uncommon: hoarseness, chest pain
Rare: dyspnoea, abnormal breathing pattern
Gastrointestinal disorders
Common: nausea, vomiting, dry mouth, bitter taste
Uncommon: constipation, diarrhoea, sialorrhoea, dysphagia, flatulence
Rare: dyspepsia, gastrointestinal pain, dark discolouration of the saliva, bruxism, hiccups, gastrointestinal bleeding, burning sensation on the tongue, duodenal ulcers
Skin and subcutaneous tissue disorders
Uncommon: oedema
Rare: angioedema, urticaria, pruritus, facial redness, hair loss, exanthema, increased sweating, dark discolouration of the sweat, activation of malignant melanoma (see section 4.3), Schonlein-Henoch purpura
Musculoskeletal, connective tissue and bone disorders
Uncommon: myospasm
Renal and urinary disorders
Uncommon: dark discolouration of the urine
Rare: urinary retention, urinary incontinence, priapism
General disorders and administration site conditions
Uncommon: feeling of weakness, malaise, “flare ups”
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”).
Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with carbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section 4.4).
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 Website: www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseThe treatment of an acute overdose of Caramet 25 mg/100 mg Prolonged Release Tablets is in general the same as that of an acute overdose of levodopa. However, pyridoxine has no effect on the reversal of the action of Caramet 25 mg/100 mg Prolonged Release Tablets. Electrocardiographic monitoring should be used and the patient observed carefully for the development of cardiac arrhythmias. If necessary an appropriate antiarrhythmic therapy should be given.
The possibility that the patient took other medications together with Caramet 25 mg/100 mg Prolonged Release Tablets should be taken into consideration. To date experience with dialysis has not been reported. Therefore its value in the treatment of overdose is unknown.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: levodopa: dopaminergics; carbidopa: dopadecarboxylase ATC-Code: N04BA02
Caramet 25 mg/100 mg Prolonged Release Tablets is a combination of carbidopa, an aromatic amino acid decarboxylase inhibitor, and levodopa, the metabolic precursor of dopamine, in the form of a prolonged-release tablet on a polymer base for use in the treatment of Parkinson’s Disease. Caramet 25 mg/100 mg Prolonged Release Tablets is particularly useful in the reduction of the “off” period in patients previously treated with the immediate-release levodopa/decarboxylase inhibitor combination who have had dyskinesia and motor fluctuations.
Patients with Parkinson’s Disease who were treated with preparations that contained levodopa, can develop motor fluctuations which are characterized by the wearing off effect of a dose, dyskinesia in the peak dose and akinesia. The advanced form of motor fluctuations (“on-off” phenomenon) is characterized by unpredictable fluctuations from mobility to immobility. Although the causes of the motor fluctuations are not completely clear, it has been shown that they can be reduced by treatment schedules that provide a stable plasma concentration of levodopa.
Levodopa relieves the symptoms of Parkinson’s disease by being decarboxylated to dopamine in the brain. Carbidopa, which does not pass the blood/brain barrier, inhibits only the extra-cerebral decarboxylation of levodopa, making more levodopa available for transport to the brain and subsequent conversion to dopamine. Therefore it is normally not necessary to administer high doses of levodopa at frequent intervals. Gastro-intestinal and cardio-vascular side-effects, in particular those which can be attributed to the dopamine formed in the extra-cerebral tissues, are avoided totally or partially by the reduced dose.
During clinical trials patients with motor fluctuations experienced a shorter “off” period with levodopa and carbidopa in retard form in comparison with an immediate-release tablet of a combination of levodopa and carbidopa. The reduction of the “off” time is rather small (about 10%) and the incidence of dyskinesia was slightly increased after administration of levodopa+carbidopa prolonged release tablet compared to treatment with an immediaterelease tablet of a combination of levodopa and carbidopa. In patients without motor fluctuations levodopa+carbidopa prolonged release tablet provided, under controlled circumstances, the same therapeutic advantage in less frequent doses than the immediate-release tablet with a combination of levodopa and carbidopa. Improvement of other symptoms of Parkinson’s Disease did not generally take place.
5.2 Pharmacokinetic properties
Absorption
The pharmacokinetics of levodopa after administration of Levodopa+Carbidopa 200+50 mg in prolonged release form compared to an immediate release Levodopa+Carbidopa 200+50 mg tablet has been studied in young healthy volunteers. After administration of Levodopa+Carbidopa 200+50 mg prolonged release tablet it took approximately two hours before maximal levodopa plasma levels were reached in comparison to 0.75 hours for the immediate-release tablet. The mean maximal levodopa plasma levels were reduced 60% in Levodopa+Carbidopa 200+50 mg prolonged release tablets compared in immediate-release tablets. The absorption of levodopa after the administration of Levodopa+Carbidopa 200+50 mg prolonged release tablets occurred continuously for four to six hours. In these studies the levodopa plasma concentrations fluctuated within closer margins than with the immediate-release tablet of levodopa and carbidopa. As the bio-availability of levodopa from Levodopa+Carbidopa 200+50 mg prolonged release tablet in comparison to an immediate-release tablet with a combination of levodopa and carbidopa is approximately 70%, the daily dose of levodopa in the modified release formulation should as a rule be higher than that of the immediate-release product.
The mean maximal plasma concentration of levodopa after the administration of a single dose Levodopa+Carbidopa 100+25 mg prolonged release tablet was approximately 70% of Levodopa+Carbidopa 200+50 mg prolonged release tablet.
The mean time to reach the maximal plasma concentrations was reduced a little with Levodopa+Carbidopa 100+25 mg prolonged release tablet over Levodopa+Carbidopa 200+50 mg prolonged release tablet.
The pharmacokinetics of levodopa after administration of Levodopa+Carbidopa prolonged release tablet was also studied in patients with Parkinson’s Disease. Regular twice daily administering of Levodopa+Carbidopa 100+25 mg prolonged release tablet (varying from 50 mg carbidopa and 200 mg levodopa to 150 mg carbidopa and 600 mg levodopa) for three months showed no accumulation of levodopa in the plasma.
Intake of food had no influence on the absorption of levodopa. With regard to carbidopa the simultaneous intake of food resulted in a 50% AUC reduction and a 40% Cmax reduction. The reduced plasma levels of carbidopa have no clinical relevance.
Distribution
Levodopa is widely distributed to most body tissues, but not to the central nervous because of extensive metabolism in the periphery. Levodopa is not bound to proteins. Levodopa crosses the blood-brain barrier by an active but saturable transport system for large neutral amino acids.
Carbidopa does not cross the blood brain barrier. Both Levodopa and carbidopa cross the placenta and are excreted in breast milk.
Metabolism and elimination
In the presence of carbidopa, levodopa is mainly metabolised to aminoacids and, to a less extent, to catecholamine derivates. All metabolites are excreted renally.
Following an oral dose approximately 50% is recorded in the urine.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Fumaric acid
Hypromellose
Sodium stearyl fumarate
Silica colloidal anhydrous
Quinoline yellow (E104)
Coating:
Hypromellose
Iron oxide yellow (E172)
Iron oxide red (E172)
Titanium dioxide (E171)
Macrogol 6000
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/Aluminium blister pack with 20, 30, 50, 60 and 100 prolonged-release tablets.
Not all package sizes may be marketed