Levodopa + Carbidopa (CR tablet)

Uses

Idiopathic Parkinson's disease, in particular to reduce off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations.

Levodopa + Carbidopa (CR tablet) is also used to associated treatment for these conditions: Paralysis agitans, Parkinson's Disease (PD), Parkinsonism, Postencephalitic parkinsonism, Restless Legs Syndrome (RLS), Advanced Motor fluctuations

How Levodopa + Carbidopa (CR tablet) works

Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors.

Dosage

Levodopa + Carbidopa (CR tablet) dosage

Patients currently treated with conventional levodopa/decarboxylase inhibitor combinations: Dosage with Levodopa-Carbidopa prolonged-release tablet should be substituted initially at an amount that provides no more than approximately 10% more levodopa per day when higher dosages are given (more than 900 mg per day). The dosing interval between doses should be prolonged by 30 to 50% at intervals ranging from 4 to 12 hours. It is recommended to give the smaller dose, if divided doses are not equal, at the end of the day. The dose needs to be titrated further depending on clinical response, as indicated below under 'Titration'. Dosages that provide up to 30% more levodopa per day may be necessary. A guide for substitution of Levodopa Carbidopa prolonged-release tablet treatment for conventional levodopa/decarboxylase inhibitor combinations is shown in the table below:Guideline for conversion from conventional Levodopa/Carbidopa tablet to Levodopa-Carbidopa prolonged-release tablet:Conventional tablet: Daily Dosage of Levodopa 300-400 mg Controlled Release tablet: Daily Dosage of Levodopa 400 mg. Dosage Regimen: 1 tablet 2x daily. Conventional tablet: Daily Dosage of Levodopa 500-600 mg Controlled Release tablet: Daily Dosage of Levodopa 600 mg. Dosage Regimen: 1 tablet 3x daily. Conventional tablet: Daily Dosage of Levodopa 700-800 mg Controlled Release tablet: Daily Dosage of Levodopa 800 mg. Dosage Regimen: 4 tablets in 3 or 4 divided doses. Conventional tablet: Daily Dosage of Levodopa 900-1000 mg Controlled Release tablet: Daily Dosage of Levodopa 1000 mg. Dosage Regimen: 5 tablets in 3 or more divided doses. Conventional tablet: Daily Dosage of Levodopa 1100-1200 mg Controlled Release tablet: Daily Dosage of Levodopa 1200 mg. Dosage Regimen: 6 tablets in 3 or more divided doses. Conventional tablet: Daily Dosage of Levodopa 1300-1400 mg Controlled Release tablet: Daily Dosage of Levodopa 1400 mg. Dosage Regimen: 7 tablets in 3 or more divided doses. Conventional tablet: Daily Dosage of Levodopa 1500-1600 mg Controlled Release tablet: Daily Dosage of Levodopa 1600 mg. Dosage Regimen: 8 tablets in 3 or more divided doses. Patients currently treated with levodopa alone: Levodopa must be discontinued at least eight hours before therapy with this CR tablet is started. In patients with mild to moderate disease, the initial recommended dose is one tablet of this CR tablet twice daily. Patients not receiving levodopa: In patients with mild to moderate disease, the initial recommended dose is one tablet of this CR tablet twice daily. Initial dosages should not exceed 600 mg per day of levodopa, nor be given at intervals of less than six hours. Titration: Following initiation of therapy, doses and dosing intervals may be increased or decreased, depending upon therapeutic response. Most patients have been adequately treated with two to eight tablets per day of this CR tablet administered as divided doses at intervals ranging from four to twelve hours during the waking day. Higher doses (up to 12 tablets) and shorter intervals (less than four hours) have been used, but are not usually recommended. When doses of this CR tablet are given at intervals of less than four hours, or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day. In some patients the onset of effect of the first morning dose may be delayed for up to one hour compared with the response usually obtained from the first morning dose of conventional levodopa-carbidopa tablet. An interval of at least three days between dosage adjustments is recommended. Maintenance: Because Parkinson’s disease is progressive, periodic clinical evaluations are recommended and adjustment of the dosage regimen of this CR tablet may be required. Addition of other antiparkinson medication: Anticholinergic agents, dopamine agonists and amantadine can be given with this CR tablet. Dosage adjustment of this CR tablet may be necessary when these agents are added to an existing treatment regimen for this CR tablet.Interruption of therapy: Patients should be observed carefully if abrupt reduction or discontinuation of this CR tablet is required, especially if the patient is receiving antipsychotics.

Side Effects

The side-effect reported most frequently was dyskinesia (a form of abnormal involuntary movements). A greater incidence of dyskinesias was seen with Levodopa-Carbidopa prolonged-release tablet than with Levodopa-Carbidopa tablet. Other side-effects: nausea, hallucinations, confusion, dizziness, chorea, dry mouth, dream abnormalities, dystonia, insomnia, depression, asthenia, vomiting, anorexia, chest pain, palpitation, constipation, diarrhoea, dyspepsia, gastro-intestinal pain, dark saliva, angioedema, urticaria, pruritus, weight loss, neuroleptic malignant syndrome, agitation, anxiety, decreased mental acuity, paraesthesia, disorientation, fatigue, headache, extrapyramidal and movement disorders, falling, gait abnormalities, muscle cramps, on-off phenomenon, increased libido, psychotic episodes, dyspnoea, flushing, alopecia, rash, dark sweat, blurred vision, dark urine, cardiac irregularities, hypertension, phlebitis, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, gastro-intestinal bleeding, flatulence, burning sensation of tongue, development of duodenal ulcer, leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis.

Toxicity

There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment.

Precaution

When patients are receiving levodopa monotherapy, levodopa must be discontinued at least eight hours before therapy with Levodopa-Carbidopa prolonged-release tablet is started (at least 12 hours if slow-release levodopa has been administered). 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. Levodopa-Carbidopa prolonged-release tablet is not recommended for the treatment of drug-induced extrapyramidal reactions or for the treatment of Huntingdon’s chorea. Based on the pharmacokinetic profile of Levodopa-Carbidopa prolonged-release tablet the onset of effect in patients with early morning dyskinesias may be slower than with conventional Levodopa-Carbidopa tablet. The incidence of dyskinesias is slightly higher during treatment with Levodopa-Carbidopa prolonged-release tablet than with conventional Levodopa-Carbidopa tablet (16.5% vs 12.2%) in advanced patients with motor fluctuations. Levodopa-Carbidopa prolonged-release tablet 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 or of convulsions. Care should be exercised in administering Levodopa-Carbidopa prolonged-release tablet to patients with a history of 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. 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. As with levodopa, Levodopa-Carbidopa prolonged-release tablet may cause involuntary movements and mental disturbances. Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone or levodopa/decarboxylase inhibitor combination should be observed carefully when Levodopa-Carbidopa prolonged-release tablet is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa and use of Levodopa-Carbidopa prolonged-release tablet may cause recurrence. Dosage reduction may be required. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or 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, 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 tablet. Review of treatment is recommended if such symptoms develop.

Interaction

Caution should be exercised when the following drugs are administered concomitantly with Levodopa-Carbidopa prolonged-release tablet. Antihypertensive agents: Symptomatic postural hypotension has occurred when levodopa/decarboxylase inhibitor combinations were added to the treatment of patients receiving some antihypertensive drugs. Therefore when therapy with Levodopa-Carbidopa prolonged-release tablet is started, dosage adjustment of the antihypertensive drug may be required. Antidepressants: There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. Anticholinergics: Anticholinergics may affect the absorption and thus the patient’s response. Iron: Studies demonstrate a decrease in the bioavailability of carbidopa and/or levodopa when it is ingested with ferrous sulphate or ferrous gluconate. Other drugs: Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones and risperidone) and isoniazid may reduce the therapeutic effects of levodopa. The beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with Levodopa-Carbidopa prolonged-release tablet should be observed carefully for loss of therapeutic response. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone. Since levodopa competes with certain amino acids, the absorption of levodopa may be impaired in some patients on a high protein diet. The effect of simultaneous administration of antacids with Levodopa-Carbidopa prolonged-release tablet on the bioavailability of levodopa has not been studied.

Volume of Distribution

168L for orally inhaled levodopa.

Elimination Route

Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.

Half Life

2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours.

Clearance

Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.

Elimination Route

After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine

Pregnancy & Breastfeeding use

There are insufficient data to evaluate the possible harmfulness of this substance when used in human pregnancy. It is not known whether carbidopa is excreted in human milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in breast milk was reported. Levodopa-Carbidopa prolonged-release tablet should not be given during pregnancy and to nursing mothers.

Contraindication

Levodopa-Carbidopa prolonged-release tablet should not be given when administration of a sympathomimetic amine is contraindicated. Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with Levodopa-Carbidopa prolonged release tablet. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Levodopa-Carbidopa prolonged release tablet. Levodopa-Carbidopa prolonged release tablet may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g. selegiline hydrochloride). Levodopa-Carbidopa prolonged release tablet is contraindicated in patients with known hypersensitivity to any component of this medication, and in patients with narrow-angle glaucoma. Because levodopa may activate a malignant melanoma, Levodopa-Carbidopa prolonged release tablet should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

Special Warning

Use in Children: Safety and effectiveness of Levodopa-Carbidopa prolonged-release tablet in infants and children have not been established, and its use in patients below the age of 18 is not recommended.

Storage Condition

Store in a cool and dry place, protected from light.

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