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