CARBIDOPA AND LEVODOPA- carbidopa and levodopa tablet, extended release
Carbidopa and levodopa extended-release tablets USP are 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 244.3. It is designated chemically as (—)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10 H14 N2 O4 •H2 O and its structural formula is:
Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9 H11 NO4 and its structural formula is:
Each extended-release tablet, for oral administration, contains either 50 mg of carbidopa USP and 200 mg of levodopa USP, or 25 mg of carbidopa USP and 100 mg of levodopa USP. Inactive ingredients: microcrystalline cellulose, lactose monohydrate, hydroxypropyl methyl cellulose, hypromellose, colloidal anhydrous silica, magnesium stearate, ferric oxide red and ferric oxide yellow.
The 50 mg/200 mg tablet is supplied as an oval, scored, biconvex, compressed tablet that is peach to light peach colored. The 25 mg/100 mg tablet is supplied as an oval, biconvex, compressed tablet that is peach to light peach colored. Carbidopa and levodopa extended-release tablets USP are designed in a drug delivery system that controls the release of carbidopa and levodopa as it slowly erodes. The 25 mg/100 mg carbidopa and levodopa extended-release tablets USP is available to facilitate titration and as an alternative to the half-tablet of 50 mg/200 mg carbidopa and levodopa extended-release tablets USP.
Carbidopa and levodopa extended-release tablets USP meet USP Dissolution Test 5.
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.
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.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain.
Patients treated with levodopa therapy for Parkinson’s disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, in some patients they may be attenuated by treatment regimens that produce steady plasma levels of levodopa.
Each tablet contains either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa in a extended-release dosage form designed to release these ingredients over a 4- to 6-hour period. With carbidopa and levodopa extended-release there is less variation in plasma levodopa levels than with carbidopa levodopa immediate release tablets, the conventional formulation. However, carbidopa and levodopa extended-release is less systemically bioavailable than carbidopa and levodopa and may require increased daily doses to achieve the same level of symptomatic relief as provided by carbidopa and levodopa.
In clinical trials, patients with moderate to severe motor fluctuations who received carbidopa and levodopa extended-release did not experience quantitatively significant reductions in ‘off’ time when compared to carbidopa and levodopa. However, global ratings of improvement as assessed by both patient and physician were better during therapy with carbidopa and levodopa extended-release than with carbidopa and levodopa. In patients without motor fluctuations, carbidopa and levodopa extended-release, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared to carbidopa and levodopa.
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.
Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following carbidopa and levodopa extended-release, the apparent half-life of levodopa may be prolonged because of continuous absorption.
In healthy elderly subjects (56 to 67 years old) the mean time-to-peak concentration of levodopa after a single dose of 50 mg/200 mg carbidopa and levodopa extended-release was about 2 hours as compared to 0.5 hours after standard carbidopa and levodopa. The maximum concentration of levodopa after a single dose of carbidopa and levodopa extended-release was about 35% of the standard carbidopa and levodopa (1151 vs. 3256 ng/mL). The extent of availability of levodopa from carbidopa and levodopa extended-release was about 70 to 75% relative to intravenous levodopa or standard carbidopa and levodopa in the elderly. The absolute bioavailability of levodopa from carbidopa and levodopa extended-release (relative to I.V.) in young subjects was shown to be only about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the elderly after a single dose and at steady state after t.i.d. administration of 50 mg/200 mg carbidopa and levodopa extended-release. In elderly subjects, the average trough levels of levodopa at steady state after the extended-release tablet were about 2 fold higher than after the standard carbidopa and levodopa (163 vs. 74 ng/mL).
In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with carbidopa and levodopa extended-release fluctuated in a narrower range than with carbidopa and levodopa. Because the bioavailability of levodopa from carbidopa and levodopa extended-release relative to carbidopa and levodopa is approximately 70 to 75%, the daily dosage of levodopa necessary to produce a given clinical response with the extended-release formulation will usually be higher.
The extent of availability and peak concentrations of levodopa after a single dose of 50 mg/200 mg carbidopa and levodopa extended-release increased by about 50% and 25%, respectively, when administered with food.
At steady state, the bioavailability of carbidopa from carbidopa and levodopa tablet is approximately 99% relative to the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability from 50 mg/200 mg carbidopa and levodopa extended-release is approximately 58% relative to that from carbidopa and levodopa .
Pyridoxine hydrochloride (vitamin B6 ), 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.
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 (≥ 65 yr) compared to young patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (≥ 65 yr) compared to young patients (< 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.
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