Get your patient on Carbidopa And Levodopa - Carbidopa And Levodopa tablet (Carbidopa And Levodopa)

Carbidopa and levodopa tablets are indicated in the treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that  may follow carbon monoxide intoxication or manganese intoxication.

Carbidopa allows patients treated for Parkinson's disease to use much lower doses of levodopa. Some patients who responded poorly to levodopa have improved on carbidopa and levodopa. This is most likely due to decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.

Carbidopa may also reduce nausea and vomiting and permit more rapid titration of  levodopa.

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 four times a day) 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 1,500 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 1,500 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 hyperpyrexia and confusion 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.

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with this combination product. Carbidopa and levodopa may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS , Drug Interactions).

Carbidopa and levodopa is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.

The most common adverse reactions reported with carbidopa and levodopa have included dyskinesias, such as choreiform, dystonic, and other involuntary movements, and nausea.

The following other adverse reactions have been reported with carbidopa and levodopa:

Body as a Whole

Chest pain, asthenia.

Cardiovascular

Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation.

Gastrointestinal

Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations.

Hematologic

Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia.

Hypersensitivity

Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions).

Musculoskeletal

Back pain, shoulder pain, muscle cramps.

Nervous System/Psychiatric

Psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes ("on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with carbidopa and levodopa has not been established.

Respiratory

Dyspnea, upper respiratory infection.

Skin

Rash, increased sweating, alopecia, dark sweat.

Urogenital

Urinary tract infection, urinary frequency, dark urine.

Laboratory Tests

Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in the urine.

Other adverse reactions that have been reported with levodopa alone and with various carbidopa and levodopa formulations, and may occur with this combination product are:

Body as a Whole

Abdominal pain and distress, fatigue.

Cardiovascular

Myocardial infarction.

Gastrointestinal

Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups.

Metabolic

Edema, weight gain, weight loss.

Musculoskeletal

Leg pain.

Nervous System/Psychiatric

Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral neuropathy.

Respiratory

Pharyngeal pain, cough.

Skin

Malignant melanoma, flushing.

Special Senses

Oculogyric crises, diplopia, blurred vision, dilated pupils.

Urogenital

Urinary retention, urinary incontinence, priapism.

Miscellaneous

Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation.

Laboratory Tests

Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine.

To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Carbidopa and levodopa tablets, USP are a combination product for the treatment of Parkinson's disease and syndrome.

Carbidopa, USP an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.24. 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, USP 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, USP for oral administration, are supplied in three strengths:

10 mg/100 mg, containing 10 mg of carbidopa, USP and 100 mg of levodopa, USP.

25 mg/100 mg, containing 25 mg of carbidopa, USP and 100 mg of levodopa, USP.

25 mg/250 mg, containing 25 mg of carbidopa, USP and 250 mg of levodopa, USP.

In addition, each tablet contains the following inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, pregelatinized starch (maize). In addition, the 25 mg/100 mg strength contain D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake (sunset yellow lake). The 10 mg/100 mg and 25 mg/250 mg strengths contain FD&C blue #2 aluminum lake.

Mechanism of Action

Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.

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.

Pharmacodynamics

When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect, and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.

Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet.

Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system.

The incidence of levodopa-induced nausea and vomiting is less with the combination product than with levodopa. In many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.

Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.

Pharmacokinetics

Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.

The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady state, the bioavailability of carbidopa from carbidopa and levodopa tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa.

In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times.

Pyridoxine hydrochloride (vitamin B ₆ ), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, carbidopa and levodopa can be given to patients receiving supplemental pyridoxine (vitamin B ₆ ).

Special Populations
Geriatric: A study in eight young healthy subjects (21 to 22 yr) and eight elderly healthy subjects (69 to 76 yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study in forty patients with Parkinson’s disease, there was a correlation between age of patients and the increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. AUC of levodopa was increased by 28% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr). Additionally, mean value of C _max for levodopa was increased by 24% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr) (see PRECAUTIONS , Geriatric Use ).

The AUC of carbidopa was increased in elderly subjects (n=10, 65 to 76 yr) by 29% compared to young subjects (n=24, 23 to 64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This increase is not considered a clinically significant impact.

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 side contains 10 mg of carbidopa, USP and 100 mg of levodopa, USP and is supplied in bottles of 100 (NDC 0228-2538-10) and 500 (NDC 0228-2538-50).

25 mg/100 mg — Each yellow, mottled, round tablet imprinted with on one side and 539 and bisect on the other side contains 25 mg of carbidopa, USP and 100 mg of levodopa, USP and is supplied in bottles of 100 (NDC 0228-2539-10), 500 (NDC 0228-2539-50) and 1,000 (NDC 0228-2539-96).

25 mg/250 mg — Each light blue, mottled, round tablet imprinted with on one side and 540 and bisect on the other side contains 25 mg of carbidopa, USP and 250 mg of levodopa, USP and is supplied in bottles of 100 (NDC 0228-2540-10), 500 (NDC 0228-2540-50) and 1,000 (NDC 0228-2540-96).

Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured by:
Teva Pharmaceuticals USA, Inc.
Parsippany, NJ 07054

Rev. B 9/2020