Product Information
Registration Status: ActiveMADOPAR 125 CAPSULE 125mg is approved to be sold in Singapore with effective from 1991-05-17. It is marketed by ROCHE SINGAPORE PTE LTD, with the registration number of SIN06121P.
This product contains Benserazide 28.5mg, and Levodopa 100mg in the form of CAPSULE. It is approved for ORAL use.
This product is manufactured by Roche S.p.A. in ITALY.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
When levodopa is used by itself as a therapy for treating Parkinson's disease, its ubiquitous metabolism into dopamine is responsible for a resultant increase in the levels of circulating dopamine in the blood and to various extracerebral tissues. This can result in a number of side effects like nausea, vomiting, or even cardiac arrhythmias that may diminish patient adherence [F2, L2553]. A decarboxylase inhibitor like benserazide is consequently an effective compound to combine with levadopa as it is incapable of crossing the blood-brain barrier itself but acts to prevent the formation of dopamine from levadopa in extracerebral tissues - thereby acting to minimize the occurrence of extracerebral side effects [F2, L2553]. Levodopa/benserazide combination products are used commonly worldwide for the management of Parkinson's disease. In particular, although the specific levodopa/benserazide combination is formally approved for use in Canada and much of Europe, the FDA has approved another similar levodopa/dopa decarboxylase inhibitor combination in the form of levodopa and carbidopa. Moreover, the European Medcines Agency has conferred an orphan designation upon benseraside since 2015 for its potential to be used as a therapy for beta thalassaemia as well [F3].
Indication
The primary therapeutic use for which benserazide is currently indicated for is as a combination therapy with levadopa for the treatment of Parkinson's disease in adults > 25 years of age, with the exception of drug-induced parkinsonism [F2, L2553]. At certain doses, the combination product of levodopa and benserazide may also be used to treat restless legs syndrome, which is sometimes associated with Parkinson's disease [L2553, T181]. There have also been some studies that have prompted the European Medicines Agency to confer orphan designation upon benserazide hydrochloride as a potential therapy for beta thalassaemia [F3]. Although studies are ongoing, no evidence has been formally elucidated as of yet [F3].
Mechanism of Action
The combination of levodopa and benserazide is an anti-Parkinsonian agent [F2, L2553]. Levodopa itself is the metabolic precursor of dopamine. In Parkinson's disease, dopamine is depleted to a large degree in the striatum, pallidum, and substantia nigra in the central nervous system (CNS) [F2, L2553]. The administration of levodopa to treat the disease is subsequently proposed to facilitate raises in the levels of available dopamine in these areas [F2, L2553]. The metabolism of levodopa to dopamine occurs via the enzyme dopa decarboxylase, although unfortunately, this metabolism can also occur in extracerebral tissues [F2, L2553]. As a result, the full therapeutic effect of an administered dose of levodopa may not be obtained if portions of it are catabolized outside of the CNS and various patient adherence diminishing extracerebral side effects due to the extracerebral presence of dopamine like nausea, vomiting, or even cardiac arrhythmias can also happen [F2, L2553]. Subsequently, a peripheral decarboxylase inhibitor like benserazide, which blocks the extracerebral decarboxylation of levodopa, when administered in combination with levodopa has obvious and significant advantages. Such benefits include reduced gastrointestinal side effects, a more rapid and complete response at the initiation of therapy, and a simpler dosing regimen [F2, L2553]. It is important to note, however, that benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver [F2, L2553], and that as a potent inhibitor of the aromatic amino acid decarboxylase [F2, L2553, T181], it is this trihydroxybenzylhydrazine metabolite of benserazide that mainly protects levodopa against decarboxylation to dopamine in the gut and also around the rest of the body outside of the blood-brain barrier [T181]. Regardless, because Parkinson's disease progresses even with the therapy of levodopa and benserazide, this kind of combined therapy is only ever indicated if it is capable of improving the quality of life and adverse effect profile of using such drugs for Parkinson's patients and there is little to be gained by switching to or starting this combination therapy if patients are already being managed with stable, effective, and well-tolerated levadopa-only therapy [F2, L2553]. Finally, it is also proposed that benserazide hydrochloride may be able to treat beta thalassaemia by maintaining the active expression of the gene for fetal hemoglobin so that constant production of fetal hemoglobin may replace the missing adult hemoglobin variation that is characteristic of patients with the condition, thereby decreasing the need for blood transfusion therapy [F3].
Pharmacokinetics
- Absorption
- In a study, three patients were administered 50 mg of radiolabelled 14C-benserazide by both intravenous and oral routes [F2, L2553]. Three additional patients received oral doses of 50 mg 14C-benserazide alone [F2, L2553]. Comparison of the time-plasma concentration curves of total radioactivity in the patients receiving oral and intravenous 14C-benserazide indicated that between 66% and 74% of the administered dose was absorbed from the gastrointestinal tract [F2, L2553]. Peak plasma concentrations of radioactivity were detected one hour after oral administration in five of the six patients [F2, L2553].
- Distribution
- Readily accessible data regarding the volume of distribution of benserazide is not available [T181].
- Metabolism
- Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver [F2, L2553]. Trihydroxybenzylhydrazine is a potent inhibitor of the aromatic acid decarboxylase [F2, L2553], and it is believed that the levodopa in a levodopa/benserazide combination product is largely protected against decarboxylation mainly by way of this benserazide metabolite [T181].
- Elimination
Clearance
Readily accessible data regarding the clearance of benserazide is not available.
Toxicity
Overdosage may lead to cardiovascular side effects like cardiac arrhythmias, psychiatric disturbances like confusion and insomnia, gastrointestinal effects like nausea and vomiting, and abnormal involuntary movements [F2, L2553]. Various LD50 values have been established for the rat model, including an oral LD50 of 5300 mg/kg in rats [MSDS].
Active Ingredient/Synonyms
benserazida | benserazidum | Benserazide |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.
Indication
For the treatment of idiopathic Parkinson's disease (Paralysis Agitans), postencephalitic parkinsonism, symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication, and manganese intoxication.
Mechanism of Action
Striatal dopamine levels in symptomatic Parkinson's disease are decreased by 60 to 80%, striatal dopaminergic neurotransmission may be enhanced by exogenous supplementation of dopamine through administration of dopamine's precursor, levodopa. A small percentage of each levodopa dose crosses the blood-brain barrier and is decarboxylated to dopamine. This newly formed dopamine then is available to stimulate dopaminergic receptors, thus compensating for the depleted supply of endogenous dopamine.
Pharmacokinetics
- Absorption
- Levodopa is rapidly absorbed from the proximal small intestine by the large neutral amino acid (LNAA) transport carrier system.
- Distribution
- Metabolism
- 95% of an administered oral dose of levodopa is pre-systemically decarboxylated to dopamine by the L-aromatic amino acid decarboxylase (AAAD) enzyme in the stomach, lumen of the intestine, kidney, and liver. Levodopa also may be methoxylated by the hepatic catechol-O-methyltransferase (COMT) enzyme system to 3-O-methyldopa (3-OMD), which cannot be converted to central dopamine.
- Elimination
Toxicity
Oral, mouse: LD50 = 2363 mg/kg; Oral, rabbit: LD50 = 609 mg/kg; Oral, rat: LD50 = 1780 mg/kg.
Active Ingredient/Synonyms
(−)-3-(3,4-dihydroxyphenyl)-L-alanine | (−)-dopa | 3-Hydroxy-L-tyrosine | 3,4-Dihydroxy-L-phenylalanine | Dihydroxy-L-phenylalanine | L-3,4-dihydroxyphenylalanine | L-beta-(3,4-Dihydroxyphenyl)alanine | L-DOPA | Levodopum | β-(3,4-dihydroxyphenyl)-L-alanine | β-(3,4-dihydroxyphenyl)alanine | Levodopa |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.