MADOPAR Capsule, Rapid dispersible tablet Ref.[50858] Active ingredients: Benserazide Levodopa

General

Hypersensitivity reactions may occur in susceptible individuals.

Regular measurement of intraocular pressure is advisable in patients with open-angle glaucoma, as levodopa theoretically has the potential to raise intraocular pressure.

Depression can be part of the clinical picture in patients with Parkinson’s disease and may also occur in patients treated with Madopar.

If a patient on levodopa requires a general anaesthetic, the normal Madopar regimen should be continued as close to the surgery as possible, except in the case of halothane. In general anaesthesia with halothane, Madopar should be discontinued 12-48 hours before surgical intervention as fluctuations in blood pressure and/or arrhythmias may occur in patients on Madopar therapy. Madopar therapy may be resumed following surgery; the dosage should be increased gradually to the preoperative level. Madopar must not be withdrawn abruptly. Abrupt withdrawal of the preparation may result in a neuroleptic malignant-like syndrome (hyperpyrexia and muscular rigidity, possibly psychological changes and elevated serum creatinine phosphokinase) which may be lifethreatening. Should a combination of such symptoms and signs occur, the patient should be kept under medical surveillance, if necessary, hospitalised and rapid and appropriate symptomatic treatment given. This may include resumption of Madopar therapy after an appropriate evaluation.

Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered (see section 4.7 Effects on ability to drive and use machines).

Use in patients with osteoporosis and osteomalacia

The effects of Madopar on human bone during prolonged administration is not known. It should be remembered that elderly people have a considerable incidence of subclinical osteoporosis and osteomalacia. In animal studies in rats, skeletal abnormalities resulting from disturbance of the growth of the epiphyseal plates, prior to closure, have occurred.

Dopaminergic medicines

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Madopar. Review of treatment is recommended if such symptoms develop. There is no established causal relationship between Madopar, which is not a dopamine agonist, and these events. However, caution is advised as Madopar is a dopaminergic drug.

Potential for Medicine Dependence or Abuse

Dopamine dysregulation syndrome (DDS): a small number of patients suffer from cognitive and behavioural disturbance that can be directly attributed to taking increasing quantities of medication against medical advice and well beyond the doses required to treat their motor disabilities.

Effect on Laboratory Tests

Checks of liver function and blood cell count should be performed during treatment. Patients with diabetes should undergo frequent blood sugar tests, and the dosage of antidiabetic agents should be adjusted to blood sugar levels.

Levodopa may affect the results of laboratory tests for catecholamines, creatinine, uric acid and glucose. False positive urine tests for ketone bodies have been reported.

Coombs' tests may give a false-positive result in patients taking Madopar.

Use in Special Populations

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. Madopar 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

Madopar is contraindicated in patients less than 30 years old (see section 4.3 Contraindications).

Pharmacokinetic interactions

Co-administration of the anticholinergic agent trihexyphenidyl with standard Madopar reduces the rate, but not the extent, of levodopa absorption. Trihexyphenidyl given concomitantly with Madopar HBS does not affect the pharmacokinetics of levodopa. Co-administration of antacids with Madopar HBS reduces the extent of levodopa absorption by 32%.

Ferrous sulphate decreases the maximum plasma concentration and the AUC of levodopa by 30-50%. The pharmacokinetic changes observed during co-treatment with ferrous sulphate appear to be clinically significant in some but not all patients.

Metoclopramide increases the rate of levodopa absorption.

Domperidone may increase the bioavailability of levodopa by stimulation of gastric emptying.

Pharmacodynamic interactions

Neuroleptics, opioids and antihypertensive medications containing reserpine inhibit the action of Madopar.

If Madopar is to be administered to patients receiving irreversible non-selective MAO inhibitors, an interval of at least 2 weeks should be allowed between cessation of the MAO inhibitor and the start of Madopar therapy. Otherwise unwanted effects such as hypertensive crises are likely to occur (see section 4.3 Contraindications). Selective MAO-B inhibitors, such as selegiline and rasagiline and selective MAO-A inhibitors, such as moclobemide, can be prescribed to patients on Madopar therapy; it is recommended to readjust the levodopa dose to the individual patient’s needs, in terms of both efficacy and tolerability. 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 Madopar (see section 4.3 Contraindications).

Madopar should not be administered concomitantly with sympathomimetics (agents such as adrenaline, noradrenaline, isoproterenol or amphetamine which stimulate the sympathetic nervous system) as levodopa may potentiate their effects. Should concomitant administration prove necessary, close surveillance of the cardiovascular system is essential, and the dose of the sympathomimetic agents may need to be reduced.

Combination with other agents such as anticholinergics, amantadine, selegiline, bromocripttine and dopamine agonists is permissible, though both the desired and the undesired effects of treatment may be intensified. It may be necessary to reduce the dosage of Madopar or the other substance. When initiating an adjuvant treatment with a COMT inhibitor, a reduction of the dosage of Madopar may be necessary. Anticholinergics should not be withdrawn abruptly when Madopar therapy is instituted, as levodopa does not begin to take effect for some time.

A diminution of effect is observed when the medicine is taken with a protein-rich meal.

Concomitant administration of antipsychotics with dopamine-receptor blocking properties, particularly D2-receptor antagonists might antagonise the antiparkinsonian effects of levodopa-benserazide. Levodopa may reduce antipsychotic effects of these drugs. These drugs should be co-administered with caution.

General anaesthesia with halothane: Madopar should be discontinued 12-48 hours before surgical intervention requiring general anaesthesia with halothane as fluctuations in blood pressure and/or arrhythmias may occur.

For general anaesthesia with other anaesthetics (see section 4.4 Special warnings and precautions for use – General).

Pregnancy

Category B3.

Madopar is contraindicated during pregnancy and in women of childbearing potential in the absence of adequate contraception. If pregnancy occurs in a woman taking Madopar, the medicine must be discontinued (as advised by the prescribing physician).

Breast-feeding

The safe use of Madopar during lactation has not been established. Since it is not known whether benserazide passes into breast milk, mothers requiring Madopar treatment should not nurse their infants, since the occurrence of skeletal malformations in the infants cannot be excluded.

Fertility

No data available.

Madopar may have a major influence on the ability to drive and use machines.

Patients being treated with levodopa and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see section 4.4 Special warnings and precautions for use – General).

Post marketing experience

The following adverse reactions have been identified from post marketing experience with Madopar (Table 1) based on spontaneous case reports and literature cases.

The corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (these reactions are reported voluntarily from a population of uncertain size, therefore it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure).

Table 1. Adverse Drug Reactions from post marketing experience:

¹ See section 4.4 Special warnings and precautions for use, Effect on Laboratory Tests

Description of selected adverse reactions

Blood and Lymphatic System Disorders

Haemolytic anaemia, transient leucopenia and thrombocytopenia have been reported in any long-term levodopa-containing treatment, blood cell count and liver and kidney function should be monitored periodically.

Psychiatric Disorders

Depression can be part of the clinical picture in patients with Parkinson’s disease and may also occur in patients treated with Madopar. Agitation, anxiety, insomnia, hallucinations, delusions and temporal disorientation may occur particularly in elderly patients and in patients with a history of such disorders.

Central and Peripheral Nervous System Disorders

At later stages of the treatment, dyskinesia (e.g. choreiform or athetotic) may occur. These can usually be eliminated or be made tolerable by a reduction of dosage. With prolonged treatment, fluctuations in therapeutic response may also be encountered. They include freezing episodes, end-of-dose deterioration and the “on-off” effect. These can usually be eliminated or made tolerable by adjusting the dosage and by giving smaller single doses more frequently. An attempt at increasing the dosage again can subsequently be made in order to intensify the therapeutic effect. Madopar is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Musculoskeletal disorders

Muscle cramps, hypotonia

Vascular Disorders

Orthostatic disorders commonly improve following reduction of the Madopar dosage.

Gastrointestinal Disorders

Undesirable gastrointestinal effects, which may occur mainly in the early stages of the treatment, can largely be controlled by taking Madopar with a low protein snack or liquid or by increasing the dose slowly.

Investigations

Urine may be altered in colour, usually acquiring a red tinge which turns dark on standing. Other body fluids or tissues may also be discoloured or stained including saliva, the tongue, teeth or oral mucosa.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

Not applicable.