Lavida

Levodopa, carbidopa.

Each tablet contains: Levodopa 100 mg, Carbidopa 25 mg or Levodopa 250 mg, Carbidopa 25 mg.

Pharmacology: Pharmacodynamics: Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is converted to dopamine in the basal ganglia. It is believed to act principally by increasing dopamine concentration in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
Carbidopa inhibits decarboxylation of peripheral levodopa, resulting to more levodopa available for transport to the brain. Carbidopa does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system (CNS). In doses that effectively inhibit peripheral decarboxylation of levodopa, carbidopa has little effect on the CNS, cardiovascular or gastrointestinal (GI) systems.
Levodopa + carbidopa improves overall therapeutic response compared with levodopa alone.
Pharmacokinetics: Levodopa is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the CNS. Thus, large doses of levodopa are required for adequate therapeutic effect.
Carbidopa reduces the amount of levodopa required to produce a given response by about 75%. When administered with levodopa, carbidopa increases both levodopa's plasma levels and half-life, and decreases plasma and urinary dopamine and homovanillic acid (HVA). Levodopa + carbidopa provides effective long lasting levodopa plasma levels at doses that are approximately 70% to 80% lower than those needed with levodopa alone.
The plasma-half-life of levodopa is about 50 minutes; it is increased to 1.5 hours when carbidopa and levodopa are administered together. At steady state, the bioavailability of carbidopa from levodopa + carbidopa is approximately 99% relative to the concomitant administration of levodopa and carbidopa.
Levodopa is widely distributed into most body tissues and the total volume of distribution is about 65% of body weight. There is considerable uptake of levodopa by the pancreas, liver, GI tract, salivary glands, kidneys, and skin. Levodopa is approximately 10% to 30% bound to plasma proteins. Carbidopa crosses the placenta and is distributed into milk.
Substantial amounts of levodopa are metabolized in the lumen of the stomach and intestines and on first pass through the liver. Most absorbed levodopa is decarboxylated to dopamine; more than 95% of the drug is decarboxylated peripherally by aromatic L-amino acid decarboxylase, a widely distributed enzyme. Small amounts of levodopa are metabolized to norepinephrine, epinephrine and 3-methoxytyramine. Dopamine is further metabolized to 3, 4- dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) and is excreted in urine. HVA, DOPAC and dopamine are the metabolites of levodopa present in cerebrospinal fluid (CSF). Carbidopa is not extensively metabolized; about 30% of an oral dose of carbidopa is excreted in urine unchanged within 24 hours.
When carbidopa and levodopa are administered concurrently, the urinary excretion of dopamine, DOPAC and HVA is substantially diminished, and the amount of unchanged levodopa excreted in urine has been reported to be increased by 6%.

Treatment of Parkinson's disease and syndrome.

The optimum daily dosage of levodopa + carbidopa must be determined by careful titration according to individual requirements, response and tolerance. Titration and dosage adjustment should be made in small steps and the dosage ranges recommended should usually not be exceeded. Treatment with levodopa should not be stopped abruptly.
Levodopa + carbidopa tablets are available in a ratio of 4:1 or 10:1 of levodopa to carbidopa to provide facility for fine dosage titration for each patient.
General Dosing Recommendation: Studies show that peripheral dopa decarboxylase is saturated by carbidopa at doses between 70 and 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Patients should be carefully monitored during the dosage adjustment period since both therapeutic and adverse effects are seen more rapidly with levodopa + carbidopa than with levodopa alone. Involuntary movements, particularly blepharospasm, are a useful early sign of excess dosage in some patients, thus requiring dose reduction.
Since parkinsonian syndrome is progressive, the patient's clinical condition should be evaluated periodically and therapy should be adjusted as necessary.
Patients not receiving levodopa: Usual Initial Dose: One tablet (levodopa 100 mg + carbidopa 25 mg) three times a day; Dosage may be increased by one tablet every day or every other day, as necessary, until a dosage equivalent of eight tablets of levodopa 100 mg + carbidopa 25 mg a day is reached.
Maximum Recommended Dose: 2 g of levodopa and 200 mg of carbidopa.
Some patients, including those with postencephalitic parkinsonism, are more sensitive to levodopa and require specially careful dosage adjustment.
Maintenance: Therapy should be individualized and adjusted according to the desired therapeutic response. At least 70 to 100 mg of carbidopa per day should be provided for optimal inhibition of extracerebral decarboxylation of levodopa.
When more levodopa is required, levodopa 250 mg + carbidopa 25 mg should be substituted at a dosage of one tablet three or four times a day. If necessary, the dosage of levodopa 250 mg + carbidopa 25 mg may be increased by half to one tablet every other day to a maximum of eight tablets a day. Clinical experience with a total daily dose greater than 200 mg carbidopa is limited.
Patients receiving levodopa: Discontinue levodopa at least 12 hours (24 hours for slow-release preparations) before starting therapy with levodopa + carbidopa.
Levodopa + carbidopa should be given as the first morning dose after a night without any levodopa. The dose of levodopa + carbidopa should be approximately 20% of the previous daily dose of levodopa.
Patients taking less than 1,500 mg of levodopa a day should be started on one tablet of levodopa 100 mg + carbidopa 25 mg three or four times a day based on patient need. The recommended starting dose for most patients taking more than 1,500 mg levodopa a day is one tablet of levodopa 250 mg + carbidopa 25 mg tablet three or four times a day.
Patients receiving levodopa with another decarboxylase inhibitor: When transferring a patient to levodopa + carbidopa from levodopa combined with another decarboxylase inhibitor, discontinue dosage at least 12 hours before levodopa + carbidopa is started.
Start with a dosage of levodopa + carbidopa that will provide the same amount of levodopa as contained in the other levodopa + decarboxylase inhibitor combination.
Patients receiving other antiparkinsonian agents: Current data indicate that other antiparkinsonian agents may be continued when levodopa + carbidopa is introduced, although dosage adjustment of levodopa + carbidopa may be necessary.
Or, as prescribed by a physician.

Levodopa + carbidopa overdosage requires general supportive measures along with immediate gastric lavage. Intravenous fluids should be given judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if necessary, appropriate antiarrhythmic therapy should be given.
The value of hemodialysis in the management of levodopa + carbidopa overdosage is not known. The usefulness of pyridoxine administration during overdosage has not been established, but pyridoxine is not effective in reversing the actions of levodopa + carbidopa combination.
The possibility that the patient may have taken drugs other than levodopa + carbidopa should be taken into consideration.

Hypersensitivity to levodopa, carbidopa or any ingredient of the product.
Concomitant use with nonselective monoamine oxidase inhibitors (MAOIs). These inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa + carbidopa. Levodopa + carbidopa may be administered concomitantly with the manufacturer's recommended dose of a MAO inhibitor with selectivity for MAO type B (e.g., selegiline hydrochloride).
Clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary (including bronchial asthma), or renal disease.
Narrow angle glaucoma.
When administration of a sympathomimetic amine is contraindicated (e.g., epinephrine, norepinephrine or isoproterenol).
Severe psychoses.
Suspicious undiagnosed skin lesions or a history of melanoma since levodopa may activate a malignant melanoma.

General: When levodopa + carbidopa is to be given to patients who are being treated with levodopa, levodopa must be discontinued at least 12 hours before therapy with levodopa + carbidopa is started. In order to reduce adverse reactions, it is necessary to individualize therapy.
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy.
Levodopa + carbidopa is not recommended for the treatment of medicine-induced extrapyramidal reactions.
Patients who improve while on therapy with levodopa + carbidopa should increase physical activities gradually, with caution, consistent with other medical considerations such as the presence of osteoporosis or phlebothrombosis.
Cardiovascular: Care should be exercised when giving levodopa + carbidopa to patients with a history of myocardial infarction who have residual atrial, nodal or ventricular arrhythmia. Monitoring of cardiac function should be done with particular care during the initial dosage administration and titration period.
Nervous System: Dyskinesia: Certain adverse CNS effects such as dyskinesia may occur at lower dosages sooner with levodopa + carbidopa than with levodopa alone. Dosage reduction may be necessary when dyskinesia develops.
Mental Disturbance: Patients, particularly those who have psychological problems or a medical history of such disorders, should be monitored for the development of depression and suicidal tendencies, and other serious antisocial behavior. Patients with past or current psychoses should be treated with caution.
Somnolence: Levodopa + carbidopa may cause somnolence and rare episodes of sudden onset of sleep (sleep episodes occurring without awareness or warning during daily activities). Patients should be advised to avoid performing tasks which require complete mental alertness such as driving or operating machines.
Neuroleptic Malignant Syndrome (NMS): NMS or a symptom complex resembling NMS may occur in association with dosage reductions or withdrawal of therapy with levodopa + carbidopa. Patients should be observed carefully when the dosage of levodopa + carbidopa is reduced abruptly or discontinued, particularly if the patient is receiving neuroleptics.
Although uncommon, NMS may be a life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin have been reported.
Early diagnosis is important for appropriate management of NMS which should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available.
Behavioral Disturbances: Long-term use of levodopa and dopamine agonists has been associated with hypersexuality, punding (purposeless repetitive acts), excessive gambling or shopping, and other obsessive behavior such as compulsive eating. Healthcare professionals should inform patients to seek help from their doctor if they, their family or their caregiver notice that their behavior is unusual.
Hallucinations: Patients should be aware that hallucinations (mostly visual) can occur when undergoing treatment with dopaminergic agents, including levodopa.
Ophthalmologic: Glaucoma: Pupillary dilatation and activation of latent Horner's syndrome have been reported during levodopa treatment. Levodopa + carbidopa should be given with caution to patients with chronic wide-angle glaucoma. It is important that intraocular pressure is well-controlled and periodically monitored in these patients.
Dermatologic: Melanoma: Patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Periodic skin examinations should be done frequently and on a regular basis by appropriately qualified individuals(e.g., dermatologist).
Peri-Operative Considerations: In cases when general anesthesia is required, levodopa + carbidopa may be continued as long as patients are allowed to take fluids and medication orally. If treatment is interrupted temporarily, the usual daily dose may be given as soon as the patient is able to take oral medication.
Use in Patients with Concomitant Illness: Exercise caution when giving levodopa + carbidopa to patients with severe cardiovascular or pulmonary disease; bronchial asthma; renal, hepatic or
endocrine disease; history of peptic ulcer disease (because of the possibility of upper gastrointestinal hemorrhage); history of seizures, conditions associated with seizure, or have a lowered seizure threshold.
Advice for Patients: Levodopa + carbidopa should be taken at regular intervals according to the schedule outlined by the physician. Sometimes a "wearing off" effect may occur at the end of the dosing interval. The physician should be notified if such a response poses a problem to lifestyle.
Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva, urine or sweat after taking levodopa + carbidopa. Although it appears to be clinically insignificant, garments may become discolored.
Use in Children (< 18 years old): The use of levodopa + carbidopa in patients below 18 years old is not recommended.

Use in Pregnancy: Pregnancy Category C. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Levodopa + carbidopa should be administered to pregnant women or women who might become pregnant only when the benefits to the mother outweigh the possible risks to the mother and fetus since there are no adequate or well-controlled studies available.
Use in Lactation: Caution should be exercised since excretion of levodopa in human breast milk was reported in a study of one breastfeeding mother with Parkinson's disease and levodopa inhibits prolactin excretion, interfering with breastfeeding.

Body as a whole: Unknown: Asthenia, fatigue, malaise, sense of stimulation.
Cardiovascular: Common: Orthostatic hypotension. Uncommon: Cardiac irregularities and/or palpitation (i.e., sinus tachycardia, ventricular tachycardia or extra systole, atrial flutter or fibrillation, or block of atrioventricular conduction), hypertension. Rare: Phlebitis. Unknown: Hypotension, syncope, chest pain, myocardial infarction.
Dermatologic and Hypersensitivity: Unknown: Rash, increased sweating, alopecia, dark sweat, malignant melanoma, angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions (including pemphigus-like reactions), flushing, pigmentation of the skin and teeth.
Endocrine/Metabolic: Common: Anorexia (may be accompanied with weight loss). Very Rare: Increased libido including hypersexuality. Unknown: Edema, weight gain or loss, priapism, elevated serum glucose, decreased serum potassium, increased uric acid.
Gastrointestinal: Common: Nausea, vomiting. Uncommon: Dark saliva. Rare: Epigastric and abdominal pain and distress, diarrhea, constipation. Unknown: GI bleeding, development of duodenal ulcer, vomiting, dyspepsia, dry mouth, GI pain, dysphagia, sialorrhea, flatulence, burning sensation of the tongue, hiccups, heartburn, hoarseness, trismus.
Hematologic: Rare: Leukopenia, agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, decreased hemoglobin and hematocrit.
Musculoskeletal: Very Common: Involuntary movements (e.g., grimacing, bruxism, gnawing, chewing, twisting and protrusion of the tongue, rhythmic opening and closing of the mouth, bobbling and wave-like motions of the head with or without gesticulation, slow rhythmic movements of the neck, hands or feet, jerky movements of the shoulder or pelvic girdle, and opisthotonos or ballismus), intermittent myoclonic body jerks during sleep. Unknown: Back pain, shoulder pain, muscle cramps, leg pain.
Nervous system: Very Common: Dyskinesia (e.g., choreiform, dystonic), increased hand tremor, ataxia, agitation, anxiety, euphoria). Common: Dream abnormalities including nightmares, insomnia, drowsiness. Very Rare: Somnolence (e.g., excessive daytime somnolence and sudden sleep onset episodes, pathological gambling. Rare: Headache, paresthesia. Unknown: Decreased attention span, insouciance, aggression, psychotic episodes (e.g., delusions, hallucinations, paranoid ideation), NMS, bradykinetic episodes (the "on-off" phenomenon), confusion, dizziness, depression with or without development of suicidal tendencies, dementia, impulse control symptoms (e.g., compulsive spending or buying, binge or compulsive eating), convulsions, extrapyramidal disorder, falling, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, numbness, activation of latent Horner's syndrome, peripheral neuropathy, faintness, toxic delirium.
Respiratory: Rare: Stridor, episodic hyperventilation. Unknown: dyspnea, upper respiratory infection, pharyngeal pain, cough, bizarre breathing patterns, excessive nasal discharge.
Special Senses: Common: Blepharospasm. Rare: Dilated or constricted pupils, diplopia, blurred vision, precipitation of glaucoma. Unknown: Oculogyric crises, taste alterations, widening of the palpebral fissures.
Urogenital: Uncommon: Polyuria, urinary retention, urinary incontinence, dark urine. Unknown: Urinary tract infection, hot flashes, white blood cells, bacteria, and blood in the urine, increased serum creatinine, protein and glucose in urine, postmenopausal bleeding.

Caution should be exercised when the following drugs are administered concomitantly with levodopa + carbidopa: Anticholinergics: May affect the absorption of levodopa and thus, the patient's response.
Antihypertensive agents: Concomitant use may be associated with symptomatic postural hypotension. Dosage adjustment of the antihypertensive agent may be required.
Tricyclic Antidepressants: Hypertension and dyskinesia have been reported with concomitant use.
Selegiline: Concomitant use may be associated with severe orthostatic hypotension not attributable to levodopa + carbidopa alone (see Contraindications).
Dopamine D₂ receptor antagonists (e.g., phenothiazine, butyrophenones, risperidone) and isoniazid: May reduce the therapeutic effects of levodopa.
Dopamine-depleting agents (e.g., reserpine and tetrabenazone) and other drugs depleting monoamine stores: Concomitant use is not recommended.
Phenytoin and papaverine: The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine, requiring close observation for possible loss of therapeutic response.
Metoclopramide: Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.
Iron salts: Reduced bioavailability of levodopa and/or carbidopa when it is ingested with ferrous sulfate or ferrous gluconate.
Other interactions: The absorption of levodopa + carbidopa may be impaired in some patients on a high protein diet since levodopa competes with certain amino acids.
Levodopa + carbidopa may be given to patients with Parkinson's disease and syndrome who are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B₆). While pyridoxine hydrochloride is known to accelerate the peripheral metabolism of levodopa to dopamine, carbidopa prevents this action.
The effect of simultaneous administration of antacids with levodopa + carbidopa on the bioavailability of levodopa has not been studied.
Laboratory Test Alterations: Elevation of liver function tests such as alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of BUN, creatinine, and uric acid are lower during administration of levodopa + carbidopa than with levodopa.
Levodopa + carbidopa may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. False-negative tests may result with the use of glucose-oxidase methods for testing for glucosuria.
Exercise caution when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa + carbidopa therapy. Cases of falsely diagnosed pheochromocytoma in patients on levodopa + carbidopa therapy have been reported very rarely.

Store at temperatures not exceeding 30°C.

Antiparkinsonian Drugs

N04BA02 - levodopa and decarboxylase inhibitor ; Belongs to the class of dopa and dopa derivative dopaminergic agents. Used in the management of Parkinson's disease.

Rx