Most prominent clinical symptoms of an overdose with levodopa/carbidopa are dystonia and dyskinesia. Blepharospasms can be an early sign of overdose.
The treatment of an acute overdose of Duodopa is in general the same as that of an acute overdose of levodopa: However, pyridoxine has no effect on the reversal of the action of Duodopa. Electrocardiographic monitoring should be used and the patient observed carefully for the development of cardiac arrhythmias; if necessary an appropriate antiarrhythmic therapy should be given. The possibility that the patient took other medicinal products together with Duodopa should be taken into consideration. To date experiences with dialysis have not been reported, therefore its value in the treatment of overdose is unknown.
Unopened: 15 weeks.
Once opened: Use immediately. The product is to be used for up to 16 hours once it is out of the refrigerator. Discard any unused portion.
Not applicable.
Carmellose sodium
Purified water
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In reproductive toxicity studies both levodopa and the combination of carbidopa/levodopa have caused visceral and skeletal malformations in rabbits.
Hydrazine is a degradation product of Carbidopa.).
Pharmacotherapeutic group: Anti-Parkinson drugs, levodopa and decarboxylase inhibitor
ATC code: N04BA02.
Mechanism of Action:
Duodopa is a combination of levodopa and carbidopa (ratio 4:1) in a gel for continuous intestinal infusion in advanced Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia. Levodopa is a metabolic precursor of dopamine that relieves symptoms of Parkinson's disease following decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the extracerebral decarboxylation of levodopa, which means that a larger amount of levodopa becomes available for transportation to the brain and transformation into dopamine. Without the simultaneous administration of carbidopa much larger amounts of levodopa would be required to achieve the desired effect. Intestinal infusion of individualized doses of Duodopa maintains plasma concentrations of levodopa at steady levels within the individual therapeutic windows.
Pharmacodynamic Effects:
Intestinal therapy with Duodopa reduces the motor fluctuations and decreases the “Off†time for patients with advanced Parkinson's disease who have received tablet treatment with levodopa/decarboxylase inhibitor for many years. The motor fluctuations and hyper-/dyskinesias are reduced due to less variable plasma concentrations than oral carbidopa/levodopa which allows treatment in a narrow therapeutic window. Therapeutic effects on motor fluctuations and hyper-/dyskinesias are often achieved during the first treatment day.
Clinical Efficacy and Safety:
The efficacy of Duodopa was confirmed in two identically-designed Phase 3, 12-week, randomized, double-blind, double-dummy, active-controlled, parallel group, multicenter studies to evaluate the efficacy, safety, and tolerability of Duodopa against levodopa/carbidopa 100/25 mg tablets. The studies were conducted with patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations despite optimized treatment with oral levodopa carbidopa and other available anti-Parkinson's disease medications and enrolled a total of 71 patients. The results of the two studies were combined and a single analysis was conducted.
The primary efficacy endpoint, change in normalized "Off" time (baseline to endpoint) based on Parkinson's Disease Diary© data using last observation carried forward demonstrated a statistically significant least square (LS) mean difference in favor of the Duodopa treatment group (Table 3).
The primary end point results were supported by a Mixed Model Repeated Measures (MMRM) analysis which examined the change from baseline to each post-baseline study visit. This analysis of “Off†time demonstrated a statistically significant greater improvement of the Duodopa group over the LC-oral group at Week 4, and that improvement was shown to be statistically significant at Weeks 8, 10, and 12.
This change in “Off†time was associated with a statistically significant LS mean difference from baseline in the average daily normalized "On" time without troublesome dyskinesia between the Duodopa treatment group and the active control group based on Parkinson's Disease Diary© data. The baseline values were collected three days prior to randomization and after 28 days of oral therapy standardization.
Table 3 Change from Baseline to Endpoint in "Off" Time and in "On" Time Without Troublesome Dyskinesia
|
Treatment Group |
N |
Baseline Mean (SD) (hours) |
Endpoint (SD) (hours) |
LS Mean (SE) of Change (hours) |
LS Mean (SE) of Difference (hours) |
P value |
|
Primary Measure | ||||||
|
"Off" time Active Controla |
31 |
6.90 (2.06) |
4.95 (2.04) |
-2.14 (0.66) | ||
|
Duodopa |
35 |
6.32 (1.72) |
3.05 (2.52) |
-4.04 (0.65) |
-1.91 (0.57) |
0.0015 |
|
Secondary Measure | ||||||
|
"On" time without troublesome dyskinesia Active Control |
31 |
8.04 (2.09) |
9.92 (2.62 |
2.24 (0.76) | ||
|
Duodopa |
35 |
8.70 (2.01) |
11.95 (2.67) |
4.11 (0.75) |
1.86 (0.65) |
0.0059 |
SD = standard deviation; SE = standard error
a. Active control, oral levodopa/carbidopa 100/25 mg tablets
Analyses of other secondary efficacy endpoints, in order of the hierarchical testing procedure, demonstrated statistically significant results for Duodopa compared to oral levodopa/-carbidopa for the Parkinson's Disease Questionnaire (PDQ-39) Summary Index (an index Parkinson's disease-related quality of life), Clinical Global Impression (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (Activities of Daily Living (ADL)). The PDQ-39 Summary Index showed a decrease from baseline of 10.9 points at week 12. Other secondary endpoints, UPDRS Part III score, EQ-5D Summary Index, and ZBI total score, did not meet statistical significance based on the hierarchical testing procedure.
A Phase 3, open-label, single-arm, multicenter study was conducted to assess the long-term safety and tolerability of Duodopa over 12 months in 354 patients. The target population was levodopa-responsive patients with advanced Parkinson's disease and motor fluctuations despite optimized treatment with available Parkinson's disease medications. The average daily normalized "Off" time changed by - 4.44 hours from Baseline to Endpoint (6.77 hours at Baseline and 2.32 hours at Endpoint) with a corresponding 4.8 hour increase in “On†time without dyskinesia.
Pediatric population
The safety of Duodopa in patients under 18 years of age has not been established and its use in patients below the age of 18 is not recommended.
Absorption
Duodopa is administered via an inserted tube directly into the duodenum or jejunum. Levodopa is absorbed quickly and effectively from the intestine through a high capacity transport system for amino acids. The absolute bioavailability of levodopa from oral levodopa/carbidopa immediate release tablets is reported to be 84-99%. A cross-study population pharmacokinetic analysis suggested that Duodopa has comparable levodopa bioavailability to the oral levodopa/carbidopa (100/25 mg) tablets.
In a Phase 1 study, intrajejunal administration of Duodopa rapidly achieved therapeutic plasma levels of levodopa and maintained consistent levodopa levels over the course of infusion. Following termination of infusion, levodopa levels declined rapidly (Figure 1). The intra-subject variability in levodopa plasma concentrations starting from hour 2 to hour 16 following initiation of infusion was low (13%).
Figure 1. Plasma Concentrations (mean ± standard deviation) versus Time Profile of Levodopa with Duodopa 16-Hour Infusion
In a Duodopa double-blind, active-controlled, Phase 3 Study, the intra-subject variability in levodopa plasma concentrations was lower for patients treated with Duodopa (21%) than in patients treated with oral levodopa/carbidopa 100/25 mg over-encapsulated tablets (67%).
Distribution
Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Clearance and volume of distribution for levodopa is 0.3 l/hour/kg and 0.9-1.6 l/kg, respectively, when given together with a decarboxylase inhibitor. The partitioning ratio for levodopa between erythrocytes and plasma is approximately 1. The protein binding of levodopa in plasma is negligible (about 10%-30%). Levodopa is transported into the brain by the carrier mechanism for large neutral amino acids.
Carbidopa is approximately 36% bound to plasma protein. Carbidopa does not cross the blood-brain barrier.
Biotransformation and elimination
When administered with carbidopa, the elimination half-life for levodopa is approximately 1.5 hours. Levodopa is eliminated completely through metabolism and the metabolites formed are excreted mainly in the urine. Four metabolic pathways are known, but levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol-O-methyl-transferase (COMT) enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. When levodopa is co-administered with carbidopa, the decarboxylase enzyme is inhibited, so that metabolism via catechol-O-methyl-transferase (COMT) becomes the dominant metabolic pathway. O-methylation of levodopa by COMT forms 3-O-methyldopa.
Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.
Pharmacokinetic-pharmacodynamic relationship
The reduced fluctuations in the plasma concentration of levodopa reduce fluctuations in the treatment response. The levodopa dose needed varies considerably in advanced Parkinson's disease and it is important that the dose is individually adjusted based on the clinical response. Development of tolerance over time has not been observed with Duodopa.
29 November 2017
AbbVie Ltd
Maidenhead
SL6 4UB, UK
Store and transport refrigerated (2°C-8°C).
Keep the cassette in the outer carton in order to protect from light.
Total amount of 100 ml in PVC bag inside a hard plastic cassette for protection, carton with 7 cassettes.
PL 41042/0001
Cassettes are for single use only.
Do not re-use an opened cassette.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Empty/used cassettes should be returned to the pharmacy for destruction.
Date of first authorisation: 21 January 2004
Date of last renewal: 21 January 2009
