Aparkin

Uses

Levodopa & benserazide is used for the treatment of all forms of Parkinson's syndrome with the exception of medicine-induced parkinsonism. Levodopa & benserazide dispersible is a formulation which is suitable for patients with dysphagia (difficulties in swallowing) or who require a formulation with a more rapid onset of action, e.g. patients suffering from early morning and afternoon akinesia, or who exhibit "delayed on" or "wearing off" phenomena. Levodopa & benserazide HBS is used for patients presenting with all types of fluctuations in response, especially those related to fluctuations in plasma levels (i.e. "peak dose dyskinesia" and "end of dose deterioration") and for better control of nocturnal symptoms. Further experience is required to determine whether it is also advantageous to use Levodopa & benserazide HBS in new Parkinson patients.
Renal impairment: Levodopa and benserazide are both extensively metabolised and less than 10% of levodopa is excreted unchanged through the kidneys. No dose reduction is therefore necessary in case of mild or moderate renal insufficiency. Pharmacokinetic data with levodopa in renal impaired patients are not available. This combination is well tolerated by uraemic patients undergoing haemodialysis.

Hepatic impairment: Levodopa is mainly metabolised by the aromatic amino acid decarboxylase that is abundantly present in the intestinal tract, in the kidney and heart in addition to the liver. Pharmacokinetic data with levodopa in hepatic impaired patients are not available.

Paediatric use: This combination is contraused for patients less than 30 years old

Aparkin is also used to associated treatment for these conditions: Parkinson's Disease (PD)Paralysis agitans, Parkinson's Disease (PD), Parkinsonism, Postencephalitic parkinsonism, Restless Legs Syndrome (RLS), Advanced Motor fluctuations

How Aparkin works

The combination of levodopa and benserazide is an anti-Parkinsonian agent . 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) . The administration of levodopa to treat the disease is subsequently proposed to facilitate raises in the levels of available dopamine in these areas . The metabolism of levodopa to dopamine occurs via the enzyme dopa decarboxylase, although unfortunately, this metabolism can also occur in extracerebral tissues . 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 .

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 .

It is important to note, however, that benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver , and that as a potent inhibitor of the aromatic amino acid decarboxylase , 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 .

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 .

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 .

Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors.

Dosage

Aparkin dosage

Standard dosage: Treatment with this combination should be introduced gradually; dosage should be assessed individually and titrated for optimal effect. The following dosage instructions should therefore be regarded as guidelines.

Initial therapy: In the early stages of Parkinson’s disease, it is advisable to start treatment with one capsule of this combination 62.5 three to four times daily. As soon as tolerability of the initial dosing schedule is confirmed, the dosage should be increased slowly in accordance with the patient’s  response. An optimal effect is generally achieved with a daily dosage of this combination corresponding to 300-800 mg of levodopa 75-200 mg benserazide, to be divided into 3 or more doses. Between 4 and 6 weeks may be needed to achieve the optimal effect. If it proves necessary to further, increase the daily dosage, this should be done on a monthly basis.

Maintenance therapy: The average maintenance dosage is 1 capsule of this combination 125 three to six times daily. The number of individual doses (not less than 3) and their distribution throughout the day must be titrated for optimal effect. this combination HBS and this combination dispersible may substitute standard this combination to achieve an optimal effect.

When taking standard this combination capsules or this combination HBS, patients must always ensure that they swallow the whole capsule without chewing it. this combination dispersible tablets are to be dispersed in a quarter of a glass of water (approx. 25-50 ml). The tablets disintegrate completely, producing a milky-white dispersion within a few minutes. Because of rapid sedimentation, it is advisable to stir the dispersion before drinking. this combination dispersible tablets should be taken within half an hour of preparing the dispersion.

Where possible, this combination should be taken at least 30 minutes before or 1 hour after meals, so that the competitive effect of dietary protein on levodopa uptake can be avoided and to facilitate a more rapid onset of action. Undesirable gastrointestinal effects, which may occur mainly in the early stages of the treatment, can largely be controlled by taking this combination with a low protein snack (e.g. biscuits) or liquid or by increasing the dose slowly.

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 .

Various LD50 values have been established for the rat model, including an oral LD50 of 5300 mg/kg in rats .

There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment.

Volume of Distribution

Readily accessible data regarding the volume of distribution of benserazide is not available .

168L for orally inhaled levodopa.

Elimination Route

In a study, three patients were administered 50 mg of radiolabelled 14C-benserazide by both intravenous and oral routes . Three additional patients received oral doses of 50 mg 14C-benserazide alone . 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 . Peak plasma concentrations of radioactivity were detected one hour after oral administration in five of the six patients .

Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.

Half Life

The half-life of benserazide is documented as 1.5 hours .

2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours.

Clearance

Readily accessible data regarding the clearance of benserazide is not available.

Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.

Elimination Route

Benserazide is rapidly excreted in the urine in the form of metabolites, mostly within the first 6 hours of administration, 85% of urinary excretion occurs within 12 hours .

Elimination of radiolabelled 14C-benserazide was primarily by urinary excretion with 86% to 90% of an intravenous dose recovered in the urine while 53% to 64% of an oral dose was detected in the urine . The majority of the 14C-benserazide was ultimately accounted for in the urine within 48 hours after administration . Fecal recovery studies conducted over five to eight days accounted for the majority (about 30%) of the remainder of the administered 14C-benserazide .

Ultimately, benserazide is almost entirely eliminated by metabolism . These metabolites are mainly excreted in the urine (64%) and to a smaller extent in the feces (24%) .

After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine

Pregnancy & Breastfeeding use

Pregnancy Category B3. This combination is contraindicated during pregnancy and in women of childbearing potential in the absence of adequate contraception. If pregnancy occurs in a woman taking this combination, the medicine must be discontinued (as advised by the prescribing physician). The safe use of this combination during lactation has not been established. Since it is not known whether benserazide passes into breast milk, mothers requiring this combination treatment should not nurse their infants, since the occurrence of skeletal malformations in the infants cannot be excluded.

Contraindication

This combination is contraindicated in:

• Patients with known hypersensitivity to levodopa or benserazide or any of the excipients.
• Patients receiving non-selective monoamine oxidase (MAO) inhibitors due to the risk of hypertensive crisis. However, selective MAO-B inhibitors, such as selegiline and rasagiline, or selective MAO-A inhibitors, such as moclobemide, are not contraindicated. Combination of MAO-A and MAO-B inhibitors is equivalent to non-selective MAO inhibition, and hence this combination should not be given concomitantly with this combination.
• Patients with decompensated endocrine, renal or hepatic function, cardiac disorders, psychiatric diseases with a psychotic component or closed angle glaucoma. Because levodopa may activate a malignant melanoma, this combination should not be used in patients with suspicious, undiagnosed lesions or a history of melanoma.
• The management of patients with intention tremor and Huntington’s chorea.
• Patients less than 30 years old (skeletal development must be complete).

Storage Condition

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Innovators Monograph

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