Actions of Levodopa comp TAD in details
Levodopa comp TAD is a combination of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD), an aromatic amino acid decarboxylase inhibitor, and Levodopa (Levodopa comp TAD), 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 comp TAD is particularly useful to reduce "off" time in patients treated previously with a conventional Levodopa (Levodopa comp TAD)/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 comp TAD) 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 comp TAD).
Levodopa (Levodopa comp TAD) relieves the symptoms of Parkinson's disease by being decarboxylated to dopamine in the brain. Carbidopa (Levodopa (Levodopa comp TAD) comp TAD), which does not cross the blood brain barrier inhibits only the extracerebral decarboxylation of Levodopa (Levodopa comp TAD), making more Levodopa (Levodopa comp TAD) available for transport to the brain and subsequent conversion to dopamine. This normally obviates the necessity for large doses of Levodopa (Levodopa comp TAD) 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 comp TAD 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 comp TAD) levels and the peak plasma level is 60% lower than with conventional Levodopa comp TAD.
In clinical trials, patients with motor fluctuations experienced reduced "off" time with Levodopa comp TAD when compared with Levodopa comp TAD. 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 comp TAD than with Levodopa comp TAD. Patients considered Levodopa comp TAD to be more helpful for their clinical fluctuations and preferred it over Levodopa comp TAD. In patients without motor fluctuations, Levodopa comp TAD, under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with Levodopa comp TAD.
How should I take Levodopa comp TAD?
Take Levodopa comp TAD 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 comp TAD), you must stop taking it at least 12 hours before you start taking Levodopa comp TAD.
Levodopa comp TAD 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 comp TAD 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 comp TAD 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 comp TAD.
Do not stop using Levodopa comp TAD 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 comp TAD 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 comp TAD.
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 comp TAD)/Carbidopa (Levodopa (Levodopa comp TAD) comp TAD).
Oral:
ER capsule: Administer with or without food; a high-fat, high-calorie meal may delay the absorption of Levodopa (Levodopa comp TAD) 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 comp TAD pharmacology
Mechanism Of Action
Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)
When Levodopa (Levodopa comp TAD) 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 comp TAD) comp TAD) inhibits the decarboxylation of peripheral Levodopa (Levodopa comp TAD), making more Levodopa (Levodopa comp TAD) available for delivery to the brain.
Levodopa (Levodopa comp TAD)
Levodopa (Levodopa comp TAD) 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 comp TAD) relieves symptoms of Parkinson's disease.
Pharmacodynamics
Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) with Levodopa (Levodopa comp TAD) makes more Levodopa (Levodopa comp TAD) available to the brain. The addition of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) to Levodopa (Levodopa comp TAD) reduces the peripheral effects (nausea, vomiting) due to decarboxylation of Levodopa (Levodopa comp TAD);
however, Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) does not decrease the adverse reactions due to the central effects of Levodopa (Levodopa comp TAD). Patients treated with Levodopa (Levodopa comp TAD) 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 comp TAD) comp TAD)
Following oral dosing of Levodopa comp TAD the maximum concentration occurred at approximately 3 hours. The bioavailability of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) from Levodopa comp TAD relative to immediate-release Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) tablets was approximately 50%.
Levodopa (Levodopa comp TAD)
The pharmacokinetics of Levodopa comp TAD 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 comp TAD) from Levodopa comp TAD 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 comp TAD) comp TAD) is approximately 36% bound to plasma proteins. Approximately 10-30% of Levodopa (Levodopa comp TAD) is bound to plasma protein.
Metabolism And Elimination
Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)
The terminal phase elimination half-life of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) is approximately 2 hours.
Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) 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 comp TAD) comp TAD) accounts for 30% of the total urinary excretion.
Peripheral dopa-decarboxylase may be saturated by Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) in other Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) products at 70 to 100 mg per day, which produces equivalent exposure to 140 to 200 mg of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) provided by Levodopa comp TAD.
Levodopa (Levodopa comp TAD)
The terminal phase elimination half-life of Levodopa (Levodopa comp TAD), the active moiety of antiparkinsonian activity, is approximately 2 hours in the presence of Carbidopa (Levodopa (Levodopa comp TAD) comp TAD).
Levodopa (Levodopa comp TAD) 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 comp TAD shows approximately dose proportional pharmacokinetics for both Levodopa comp TAD over the Levodopa (Levodopa comp TAD) dosage strength range of 95 mg to 245 mg.
Effect Of Food
In healthy adults, oral administration of Levodopa comp TAD after a high-fat, high-calorie meal reduced C approximately 13% for Levodopa (Levodopa comp TAD) compared to administration in the fasted state. There may be a delay by 2 hours in the absorption of Levodopa (Levodopa comp TAD) when Levodopa comp TAD is taken with a high-fat, high-calorie meal. In addition, absorption of Levodopa (Levodopa comp TAD) may be decreased by a high protein meal.
Specific Populations
Elderly
In pharmacokinetics studies following a single dose of Levodopa comp TAD, the peak concentrations of Levodopa comp TAD are generally similar between younger (45-60 years) and older (60-75 years) subjects.
Gender
In pharmacokinetics studies following a single dose of Levodopa comp TAD:
- Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)
At comparable doses females are reported to have higher Carbidopa (Levodopa (Levodopa comp TAD) comp TAD) 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 comp TAD)
At comparable doses females are reported to have higher Levodopa (Levodopa comp TAD) 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 comp TAD 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 comp TAD) 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 comp TAD (Levodopa comp TAD 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 comp TAD) or catechol-O-methyl transferase (COMT) inhibitors. Patients receiving Levodopa comp TAD 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 comp TAD, 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 comp TAD 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 comp TAD)-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 comp TAD 36.25 mg / 145 mg TID | 36.1 | 24.4 | –11.7§ |
| Levodopa comp TAD 61.25 / 245 mg TID | 38.2 | 25.3 | –12.9§ |
| Levodopa comp TAD 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 comp TAD) treatment prior to a 6-week conversion to Levodopa comp TAD, which was followed by a 13-week, randomized, multicenter, double-blind, Levodopa (Levodopa comp TAD)-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 comp TAD) 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 comp TAD or immediate-release Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) at the dose determined during the adjustment or conversion phases. Patients were not allowed to receive supplemental Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) 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 comp TAD. The final total daily dose of Levodopa (Levodopa comp TAD) from Levodopa comp TAD was approximately double that of the final total daily dose of Levodopa (Levodopa comp TAD) 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 comp TAD-treated patients compared to immediate-release carbidopalevodopa- treated patients (Table 5). The decrease in "off" time observed with Levodopa comp TAD 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 comp TAD | 36.9% | 23.8%* |
| Immediate-release Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) | 36.0% | 29.8% |
| "Off" Time (hours ) | ||
| Levodopa comp TAD | 6.1 hours | 3.9 hours* |
| Immediate-release Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) | 5.9 hours | 4.9 hours |
| "On" Time with no or non-troublesome dyskinesia (hours) | ||
| Levodopa comp TAD | 10.0 hours | 11.8 hours* |
| Immediate-release Carbidopa (Levodopa (Levodopa comp TAD) comp TAD)-Levodopa (Levodopa comp TAD) | 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
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Information checked by Dr. Sachin Kumar, MD Pharmacology
