Actions of Levodopa-Carbi in details
Levodopa-Carbi is a combination of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi), an aromatic amino acid decarboxylase inhibitor, and Levodopa (Levodopa-Carbi), the metabolic precursor of dopamine, in a polymer-based controlled-release tablet formulation, for use in the treatment of Parkinson's disease and syndrome. Levodopa-Carbi is particularly useful to reduce "off" time in patients treated previously with a conventional Levodopa (Levodopa-Carbi)/decarboxylase inhibitor combination who have had predictable peak-dose dyskinesias and unpredictable motor fluctuations.
Patients with Parkinson's disease treated with preparations containing Levodopa (Levodopa-Carbi) 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, it has been demonstrated that they can be attenuated by treatment regimens that produce steady-plasma levels of Levodopa (Levodopa-Carbi).
Levodopa (Levodopa-Carbi) relieves the symptoms of Parkinson's disease by being decarboxylated to dopamine in the brain. Carbidopa (Levodopa (Levodopa-Carbi)-Carbi), which does not cross the blood brain barrier inhibits only the extracerebral decarboxylation of Levodopa (Levodopa-Carbi), making more Levodopa (Levodopa-Carbi) available for transport to the brain and subsequent conversion to dopamine. This normally obviates the necessity for large doses of Levodopa (Levodopa-Carbi) at frequent intervals. The lower dosage reduces or may help eliminate gastrointestinal and cardiovascular side effects, especially those which are attributable to dopamine being formed in extracerebral tissues.
Levodopa-Carbi is designed to release the active ingredients over a 4- to 6-hr period. With this formulation, there is less variation in plasma Levodopa (Levodopa-Carbi) levels and the peak plasma level is 60% lower than with conventional Levodopa-Carbi.
In clinical trials, patients with motor fluctuations experienced reduced "off" time with Levodopa-Carbi when compared with Levodopa-Carbi. Global ratings of improvement and activities of daily living in the "on" and "off" state, as assessed by both patient and physician, were better during therapy with Levodopa-Carbi than with Levodopa-Carbi. Patients considered Levodopa-Carbi to be more helpful for their clinical fluctuations and preferred it over Levodopa-Carbi. In patients without motor fluctuations, Levodopa-Carbi, under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with Levodopa-Carbi.
How should I take Levodopa-Carbi?
Take Levodopa-Carbi exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose.
If you already take Levodopa (Levodopa-Carbi), you must stop taking it at least 12 hours before you start taking Levodopa-Carbi.
Levodopa-Carbi can be taken with or without food. Take your doses at regular intervals to keep a steady amount of the drug in your body at all times. Get your prescription refilled before you run out of medicine completely.
The tablet is sometimes broken in half to give the correct dose. Always swallow a whole or half tablet without chewing or crushing.
It may take up to several weeks of using Levodopa-Carbi before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a few weeks of treatment. Also tell your doctor if the effects of this medication seem to wear off quickly in between doses.
If you use Levodopa-Carbi long-term, you may need frequent medical tests at your doctor's office.
This medicine can affect the results of certain medical tests. Tell any doctor who treats you that you are using Levodopa-Carbi.
Do not stop using Levodopa-Carbi suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using this medicine.
Store at room temperature away from moisture, heat, and light.
Levodopa-Carbi administration
Intestinal suspension (Duopa): Remove one cassette from refrigerator 20 minutes prior to use (failure to use at room temperature may result in inaccurate dosage). Administer as a 16-hour infusion through either a nasojejunal tube (temporary administration) or through a percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube (long-term administration) connected to the CADD-Legacy 1400 pump. At the end of administration, disconnect the tube from the pump at the end of the infusion and flush with room-temperature drinking water with a syringe. Following discontinuation of the daily infusion, patients should administer their routine night-time dosage of oral immediate-release Levodopa-Carbi.
Intestinal gel (Duodopa [Canadian product]): Gel is administered directly to the jejunum via a portable infusion pump (CADD-legacy Duodopa pump). Administer through a temporary nasojejunal tube for a short-term test period to evaluate patient response and for dose optimization. Long-term administration requires placement of PEG-J tube for intestinal infusion. Continuous maintenance dose is infused throughout the day for up to 16 hours if necessary, may administer at night (eg, nocturnal akinesia). Disconnect PEG-J tube from infusion pump at end of infusion and flush with room temperature water to prevent occlusion of tubing. Following discontinuation of the daily infusion, patients should administer their routine night-time dosage of oral Levodopa (Levodopa-Carbi)/Carbidopa (Levodopa (Levodopa-Carbi)-Carbi).
Oral:
ER capsule: Administer with or without food; a high-fat, high-calorie meal may delay the absorption of Levodopa (Levodopa-Carbi) by ~2 hours. Swallow capsules whole; do not chew, divide, or crush capsules. Patients who have difficulty swallowing intact capsules may open the capsule, sprinkle entire contents on a small amount of applesauce (1 to 2 tablespoons) and consume immediately (do not store for future use).
Oral tablet formulations: Space doses evenly over the waking hours. Administer with meals to decrease GI upset. Controlled release product should not be chewed or crushed.
Orally disintegrating tablets do not require water; the tablet should disintegrate on the tongue's surface before swallowing.
Bariatric surgery: Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. Switch to IR formulation (tablet or orally disintegrating tablet) or capsule may be opened and contents sprinkled onto soft food of choice. Patient should be instructed to swallow the mixture without biting down or chewing.
Levodopa-Carbi pharmacology
Mechanism Of Action
Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)
When Levodopa (Levodopa-Carbi) 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. Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) inhibits the decarboxylation of peripheral Levodopa (Levodopa-Carbi), making more Levodopa (Levodopa-Carbi) available for delivery to the brain.
Levodopa (Levodopa-Carbi)
Levodopa (Levodopa-Carbi) is 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 (Levodopa-Carbi) relieves symptoms of Parkinson's disease.
Pharmacodynamics
Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) with Levodopa (Levodopa-Carbi) makes more Levodopa (Levodopa-Carbi) available to the brain. The addition of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) to Levodopa (Levodopa-Carbi) reduces the peripheral effects (nausea, vomiting) due to decarboxylation of Levodopa (Levodopa-Carbi);
however, Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) does not decrease the adverse reactions due to the central effects of Levodopa (Levodopa-Carbi). Patients treated with Levodopa (Levodopa-Carbi) therapy for Parkinson's disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, 'on-off' phenomenon, and akinesia.
Pharmacokinetics
Absorption
Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)
Following oral dosing of Levodopa-Carbi the maximum concentration occurred at approximately 3 hours. The bioavailability of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) from Levodopa-Carbi relative to immediate-release Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) tablets was approximately 50%.
Levodopa (Levodopa-Carbi)
The pharmacokinetics of Levodopa-Carbi were evaluated following single doses in healthy subjects and following single and multiple doses in patients with Parkinson's disease. The bioavailability of Levodopa (Levodopa-Carbi) from Levodopa-Carbi in patients was approximately 70% relative to immediate-release carbidopalevodopa. Following an initial peak at about one hour, plasma concentrations are maintained for about 4 to 5 hours before declining.
Distribution
Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) is approximately 36% bound to plasma proteins. Approximately 10-30% of Levodopa (Levodopa-Carbi) is bound to plasma protein.
Metabolism And Elimination
Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)
The terminal phase elimination half-life of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) is approximately 2 hours.
Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) is metabolized to two main metabolites: α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxy-phenylpropionic acid. These two metabolites are primarily eliminated in the urine unchanged or as a glucuronide. Unchanged Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) accounts for 30% of the total urinary excretion.
Peripheral dopa-decarboxylase may be saturated by Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) in other Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) products at 70 to 100 mg per day, which produces equivalent exposure to 140 to 200 mg of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) provided by Levodopa-Carbi.
Levodopa (Levodopa-Carbi)
The terminal phase elimination half-life of Levodopa (Levodopa-Carbi), the active moiety of antiparkinsonian activity, is approximately 2 hours in the presence of Carbidopa (Levodopa (Levodopa-Carbi)-Carbi).
Levodopa (Levodopa-Carbi) is extensively metabolized to various metabolites. The two major metabolic pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).
Dose Proportionality
Levodopa-Carbi shows approximately dose proportional pharmacokinetics for both Levodopa-Carbi over the Levodopa (Levodopa-Carbi) dosage strength range of 95 mg to 245 mg.
Effect Of Food
In healthy adults, oral administration of Levodopa-Carbi after a high-fat, high-calorie meal reduced C approximately 13% for Levodopa (Levodopa-Carbi) compared to administration in the fasted state. There may be a delay by 2 hours in the absorption of Levodopa (Levodopa-Carbi) when Levodopa-Carbi is taken with a high-fat, high-calorie meal. In addition, absorption of Levodopa (Levodopa-Carbi) may be decreased by a high protein meal.
Specific Populations
Elderly
In pharmacokinetics studies following a single dose of Levodopa-Carbi, the peak concentrations of Levodopa-Carbi are generally similar between younger (45-60 years) and older (60-75 years) subjects.
Gender
In pharmacokinetics studies following a single dose of Levodopa-Carbi:
- Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)
At comparable doses females are reported to have higher Carbidopa (Levodopa (Levodopa-Carbi)-Carbi) peak concentrations and systemic exposure (approximately 33%) compared to males. Median time to peak concentration and terminal half-life are comparable between males and females.
- Levodopa (Levodopa-Carbi)
At comparable doses females are reported to have higher Levodopa (Levodopa-Carbi) peak concentrations (approximately 23% to 33%) and systemic exposure (approximately 33% to 37%) compared to males. Median time to peak concentration and terminal half-life are comparable between males and females.
Clinical Studies
Patients With Early Parkinson's Disease
The effectiveness of Levodopa-Carbi in patients with early Parkinson's disease was established in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group, 30-week clinical trial (Study 1). Patients enrolled in Study 1 (n=381) were Hoehn and Yahr Stage I–III with a median disease duration of 1 year, and had limited or no prior exposure to Levodopa (Levodopa-Carbi) and dopamine agonists. Patients continued taking concomitant selective monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics provided the doses were stable for at least 4 weeks before screening. Eligible patients were randomized (1:1:1:1) to placebo or one of three fixed doses of Levodopa-Carbi (Levodopa-Carbi doses of 36.25 mg / 145 mg, 61.25 mg / 245 mg, or 97.5 mg / 390 mg, three times a day). Patients were not allowed to receive supplemental Levodopa (Levodopa-Carbi) or catechol-O-methyl transferase (COMT) inhibitors. Patients receiving Levodopa-Carbi initiated treatment at 23.75 mg / 95 mg three times daily (TID). The dose was increased on Day 4 and the maximum study dose (97.5 mg / 390 mg TID) was achieved by Day 22.
The clinical outcome measure in Study 1 was the mean change from baseline in the sum of the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (activities of daily living) score, and UPDRS Part III (motor score) for Levodopa-Carbi, compared to placebo at Week 30 (or early termination). The mean score decrease (i.e., improvement) from baseline to Week 30 for each of the three Levodopa-Carbi dosage groups was significantly greater than for placebo. The results of Study 1 are shown in Table 4.
Table 4: Study 1: Change from Bas eline in UPDRS Part II plus Part III Score at Week 30 (or at early termination) in Levodopa (Levodopa-Carbi)-Naïve Patients with Early Parkins on's Dis eas e
| Treatment | Mean UPDRS (Part II and Part III) Score* | ||
| Baseline† | Week 30 Change from Bas eline at Week 30‡ | ||
| Placebo | 36.5 | 35.9 | –0.6 |
| Levodopa-Carbi 36.25 mg / 145 mg TID | 36.1 | 24.4 | –11.7§ |
| Levodopa-Carbi 61.25 / 245 mg TID | 38.2 | 25.3 | –12.9§ |
| Levodopa-Carbi 97.5 mg / 390 mg TID | 36.3 | 21.4 | –14.9§ |
| *For the UPDRS, higher scores indicate greater severity of impairment †All values based on 361 patients who had valid End-of-Study values ‡Negative numbers indicate improvement as compared with the baseline value §P-value is less than 0.05 |
Patients With Advanced Parkinson's Disease
Study 2 was a 22-week trial consisting of a 3-week dose adjustment of current Levodopa (Levodopa-Carbi) treatment prior to a 6-week conversion to Levodopa-Carbi, which was followed by a 13-week, randomized, multicenter, double-blind, Levodopa (Levodopa-Carbi)-containing active control, double-dummy, parallel group trial. The study enrolled 471 (393 randomized) patients (Hoehn & Yahr Stages I-IV) who had been maintained on a stable regimen of at least 400 mg per day of Levodopa (Levodopa-Carbi) prior to entry into the trial. Patients were continued on concomitant dopamine agonists, selective monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics provided the doses were stable for at least 4 weeks prior to screening. Patients were randomized to receive either Levodopa-Carbi or immediate-release Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) at the dose determined during the adjustment or conversion phases. Patients were not allowed to receive supplemental Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) or catechol-O-methyl transferase (COMT) inhibitor products during the trial.
In Study 2, approximately 60% of patients required further up titration and approximately 16% of patients required down titration compared to the recommended starting dose of Levodopa-Carbi. The final total daily dose of Levodopa (Levodopa-Carbi) from Levodopa-Carbi was approximately double that of the final total daily dose of Levodopa (Levodopa-Carbi) from immediate-release tablets. The majority (88%) of patients in Study 2 received less than 2400 mg; the median dose was 1365 mg.
The clinical outcome measure in Study 2 was the percentage of "off" time during waking hours at Week 22 (or at early termination), as assessed by the patient's Parkinson's Disease Diary. The "off" time was significantly improved in Levodopa-Carbi-treated patients compared to immediate-release carbidopalevodopa- treated patients (Table 5). The decrease in "off" time observed with Levodopa-Carbi occurred with a concomitant increase in "on time" without troublesome dyskinesia.
Table 5: Study 2: Parkinson's Disease Diary Measures in Patients with Advanced Parkinson's Disease
| Baseline | Week 22 (or early termination) | |
| Percentage of waking hours spent in "Off" | ||
| Levodopa-Carbi | 36.9% | 23.8%* |
| Immediate-release Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) | 36.0% | 29.8% |
| "Off" Time (hours ) | ||
| Levodopa-Carbi | 6.1 hours | 3.9 hours* |
| Immediate-release Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) | 5.9 hours | 4.9 hours |
| "On" Time with no or non-troublesome dyskinesia (hours) | ||
| Levodopa-Carbi | 10.0 hours | 11.8 hours* |
| Immediate-release Carbidopa (Levodopa (Levodopa-Carbi)-Carbi)-Levodopa (Levodopa-Carbi) | 10.1 hours | 10.9 hours |
| *P-value is less than 0.05 |
References
- DailyMed. "CARBIDOPA; ENTACAPONE; LEVODOPA: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Carbidopa Anhydrous: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- NCIt. "Levodopa: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Levodopa-Carbi are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Levodopa-Carbi. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
