When carbidopa and levodopa tablets are to be given to patients who are being treated with levodopa, levodopa must be discontinued at least twelve hours before therapy with the combination product is started.
In order to reduce adverse reactions, it is necessary to individualize therapy.
See DOSAGE AND ADMINISTRATION section before initiating therapy.
The addition of carbidopa with levodopa in the form of this combination product reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.
Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse CNS effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with carbidopa and levodopa than with levodopa alone.
Levodopa alone, as well as carbidopa and levodopa, is associated with dyskinesias.
The occurrence of dyskinesias may require dosage reduction.
As with levodopa, the combination product may cause mental disturbances.
These reactions are thought to be due to increased brain dopamine following administration of levodopa.
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.
Carbidopa and levodopa should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering the combination product, to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias.
In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care.
As with levodopa, treatment with the combination product may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Neuroleptic Malignant Syndrome (NMS): Sporadic cases of a symptom complex resembling NMS have been reported in association with dose reductions or withdrawal of therapy with carbidopa and levodopa.
Therefore, patients should be observed carefully when the dosage of carbidopa and levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but 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.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential.
This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available.
Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
Management of acute overdosage with carbidopa and levodopa is the same as management of acute overdosage with levodopa.
Pyridoxine is not effective in reversing the actions of this product.
General supportive measures should be employed, along with immediate gastric lavage.
Intravenous fluids should be administered judiciously and an adequate airway maintained.
Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given.
The possibility that the patient may have taken other drugs as well as carbidopa and levodopa tablets should be taken into consideration.
To date, no experience has been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die.
A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg.
A significant proportion of rats are expected to die after treatment with similar doses of carbidopa.
The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.
Carbidopa and levodopa is a combination product for the treatment of Parkinson’s disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.25.
It is designated chemically as (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate.
Its molecular formula is C 10 H 14 N 2 O 4 .H 2 O and its structural formula is: Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.23.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.19.
It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid.
Its molecular formula is C 9 H 11 NO 4 , and its structural formula is: Carbidopa and levodopa tablets, for oral administration, are supplied in three strengths: 10 mg/100 mg, containing 10 mg of carbidopa and 100 mg of levodopa.
25 mg/100 mg, containing 25 mg of carbidopa and 100 mg of levodopa.
25 mg/250 mg, containing 25 mg of carbidopa and 250 mg of levodopa.
In addition, each tablet contains the following inactive ingredients: 10 mg/100 mg — Corn starch, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
25 mg/100 mg — Corn starch, D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake (sunset yellow lake), magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
25 mg/250 mg — Corn starch, FD&C blue #2 aluminum lake, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
Carbidopa and Levodopa Tablets USP are supplied as follows: 10 mg/100 mg — Each dark blue, mottled, round tablet imprinted with on one side and 538 and bisect on the other contains 10 mg of Carbidopa and 100 mg of Levodopa and is supplied in blistercards of 30 (NDC 0615-3537-39), and 31 (NDC 0615-3537-31).
25 mg/100 mg — Each yellow, mottled, round tablet imprinted with on one side and 539 and bisect on the other contains 25 mg of Carbidopa and 100 mg of Levodopa and is supplied in blistercards of 15 (NDC 0615-3561-05), and 30 (NDC 0615-3561-39).
25 mg/250 mg — Each light blue, mottled, round tablet imprinted with on one side and 540 and bisect on the other contains 25 mg of Carbidopa and 250 mg of Levodopa and is supplied in blistercards of 30 (NDC 0615-4504-39), and 31 (NDC 0615-4504-31).
Store at 25(C (77(F); excursions permitted to 15( to 30(C (59( to 86(F) [See USP Controlled Room Temperature].
Protect from light.
Dispense in a well-closed, light-resistant container as defined in the USP.
Manufactured by: Actavis Elizabeth LLC 200 Elmora Avenue Elizabeth, NJ 07207 USA 40-9182 Revised — September 2011 0c2b9363-figure-03 0c2b9363-figure-04 0c2b9363-figure-05
MECHANISM OF ACTION
Mechanism of Action Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum.
Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier.
However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.
INDICATIONS AND USAGE
Carbidopa and levodopa tablets are indicated in the treatment of the symptoms of idiopathic Parkinson’s disease (paralysis agitans), post-encephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.
This product is indicated in these conditions to permit the administration of lower doses of levodopa with reduced nausea and vomiting, with more rapid dosage titration, with a somewhat smoother response, and with supplemental pyridoxine (vitamin B 6 ).
In some patients a somewhat smoother antiparkinsonian effect results from therapy with carbidopa and levodopa than with levodopa.
However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from carbidopa and levodopa.
Although the administration of carbidopa permits control of parkinsonism and Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa have improved when carbidopa and levodopa was substituted.
This is most likely due to decreased peripheral decarboxylation of levodopa which results from administration of carbidopa rather than to a primary effect of carbidopa on the nervous system.
Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa in parkinsonian syndromes.
In considering whether to give this combination product to patients already on levodopa who have nausea and/or vomiting, the practitioner should be aware that, while many patients may be expected to improve, some do not.
Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy.
It should be further noted that in controlled trials comparing carbidopa and levodopa with levodopa, about half of the patients with nausea and/or vomiting on levodopa improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial.
DOSAGE AND ADMINISTRATION
The optimum daily dosage of carbidopa and levodopa must be determined by careful titration in each patient.
Carbidopa and levodopa tablets are available in a 1:4 ratio of carbidopa to levodopa (25 mg/100 mg) as well as 1:10 ratio (25 mg/250 mg and 10 mg/100 mg).
Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100 mg a day.
Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Usual Initial Dosage : Dosage is best initiated with one tablet of carbidopa and levodopa 25 mg/100 mg three times a day.
This dosage schedule provides 75 mg of carbidopa per day.
Dosage may be increased by one tablet every day or every other day, as necessary, until a dosage of eight tablets of carbidopa and levodopa 25 mg/100 mg a day is reached.
If carbidopa and levodopa 10 mg/100 mg is used, dosage may be initiated with one tablet three or four times a day.
However, this will not provide an adequate amount of carbidopa for many patients.
Dosage may be increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is reached.
How To Transfer Patients From Levodopa: Levodopa must be discontinued at least twelve hours before starting this combination product.
A daily dosage of carbidopa and levodopa should be chosen that will provide approximately 25% of the previous levodopa dosage.
Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of carbidopa and levodopa 25 mg/100 mg three or four times a day.
The suggested starting dosage for most patients taking more than 1500 mg of levodopa is one tablet of carbidopa and levodopa 25 mg/250 mg three or four times a day.
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.
When a greater proportion of carbidopa is required, one 25 mg/100 mg tablet may be substituted for each 10 mg/100 mg tablet.
When more levodopa is required, each 25 mg/250 mg tablet should be substituted for a 25 mg/100 mg tablet or a 10 mg/100 mg tablet.
If necessary, the dosage of carbidopa and levodopa 25 mg/250 mg may be increased by one-half or one tablet every day or every other day to a maximum of eight tablets a day.
Experience with total daily dosages of carbidopa greater than 200 mg is limited.
Because both therapeutic and adverse responses occur more rapidly with this combination product than with levodopa alone, patients should be monitored closely during the dose adjustment period.
Specifically, involuntary movements will occur more rapidly with carbidopa and levodopa than with levodopa.
The occurrence of involuntary movements may require dosage reduction.
Blepharospasm may be a useful early sign of excess dosage in some patients.
Addition Of Other Antiparkinsonian Medications: Standard drugs for Parkinson’s disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa is being administered, although dosage adjustments may be required.
Interruption Of Therapy: Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been associated with dose reductions and withdrawal of carbidopa and levodopa.
Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa and levodopa is required, especially if the patient is receiving neuroleptics.
(See WARNINGS .) If general anesthesia is required, carbidopa and levodopa may be continued as long as the patient is permitted to take fluids and medication by mouth.
If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient is able to take oral medication.