Hardal

Parkinsonism - idiopathic post-encephalitic.

Previous neurosurgery is not a contra-indication to Hardal.

Dosage and administration are variable and no more than a guide can be given.

Adults

Patients not previously treated with levodopa

The recommended initial dose is one capsule or dispersible tablet of Hardal 50 mg/12.5 mg three or four times daily. If the disease is at an advanced stage, the starting dose should be one capsule or dispersible tablet of Hardal 100 mg/25 mg three times daily.

The daily dosage should then be increased by one capsule or dispersible tablet of Hardal 100 mg/25 mg, or their equivalent, once or twice weekly until a full therapeutic effect is obtained, or side-effects supervene.

In some elderly patients, it may suffice to initiate treatment with one capsule or dispersible tablet of Hardal 50 mg/12.5 mg once or twice daily, increasing by one capsule or dispersible tablet every third or fourth day.

The effective dose usually lies within the range of four to eight capsules or dispersible tablets of Hardal 100 mg/25 mg (two to four capsules of Hardal 200 mg/50 mg) daily in divided doses, most patients requiring no more than six capsules or dispersible tablets of Hardal 100 mg/25 mg daily.

Optimal improvement is usually seen in one to three weeks but the full therapeutic effect of Hardal may not be apparent for some time. It is advisable, therefore, to allow several weeks to elapse before contemplating dosage increments above the average dose range. If satisfactory improvement is still not achieved, the dose of Hardal may be increased but with caution. It is rarely necessary to give more than ten capsules or dispersible tablets of Hardal 100 mg /25 mg (five capsules of Hardal 200 mg/50 mg) per day.

Treatment should be continued for at least six months before failure is concluded from the absence of a clinical response.

Hardal 50 mg/12.5 mg capsules or dispersible tablets may be used to facilitate adjustment of dosage to the needs of the individual patient. Patients who experience fluctuations in response may be helped by dividing the dosage into smaller, more frequent doses with the aid of Hardal 50 mg/12.5 mg capsules or dispersible tablets without, however, altering the total daily dose.

Hardal 200 mg/50 mg capsules are only for maintenance therapy once the optimal dosage has been determined using Hardal 100 mg/25 mg capsules or dispersible tablets.

Patients previously treated with levodopa

The following procedure is recommended: Levodopa alone should be discontinued and Hardal started on the following day. The patient should be initiated on a total of one less Hardal 100 mg/25 mg capsule or dispersible tablet daily than the total number of 500 mg levodopa tablets or capsules previously taken (for example, if the patient had previously taken 2g levodopa daily, then he should start on three capsules or dispersible tablets Hardal 100 mg/25 mg daily on the following day). Observe the patient for one week and then, if necessary, increase the dosage in the manner described for new patients.

Patients previously treated with other levodopa/decarboxylase inhibitor combinations

Previous therapy should be withdrawn for 12 hours. In order to minimise the potential for any effects of levodopa withdrawal, it may be beneficial to discontinue previous therapy at night and institute Hardal therapy the following morning. The initial Hardal dose should be one capsule or dispersible tablet of Hardal 50 mg/12.5 mg three or four times daily. This dose may then be increased in the manner described for patients not previously treated with levodopa.

Other anti-Parkinsonian drugs may be given with Hardal. Existing treatment with other anti-Parkinsonian drugs, e.g. anticholinergics or amantadine, should be continued during initiation of Hardal therapy. However, as treatment with Hardal proceeds and the therapeutic effect becomes apparent, the dosage of the other drugs may need to be reduced or the drugs gradually withdrawn.

Elderly

Although there may be an age-related decrease in tolerance to levodopa in the elderly, Hardal appears to be well-tolerated and side-effects are generally not troublesome.

Children

Not to be given to patients under 25 years of age: therefore, no dosage recommendations are made for the administration of Hardal to children.

Hardal capsules are for oral administration. They should be taken with, or immediately after, meals.

Hardal must not be given to patients with known hypersensitivity to levodopa or benserazide or any of the excipients.

Hardal must not be given in conjunction with non-selective monoamine oxidase (MAO) inhibitors. 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 Hardal.

Hardal must not be given to patients with decompensated endocrine (e.g. phaeochromocytoma, hyperthyroidism, Cushing syndrome), renal (except RLS patients on dialysis) or hepatic function, cardiac disorders (e.g. severe cardiac arrhythmias and cardiac failure), psychiatric diseases with a psychotic component or closed angle glaucoma (it may be used in wide-angle glaucoma provided that the intra-ocular pressure remains under control).

Hardal must not be given to patients less than 25 years old (skeletal development must be complete).

Hardal must not be given to pregnant women or to women of childbearing potential in the absence of adequate contraception. If pregnancy occurs in a woman taking Hardal, the drug must be discontinued (as advised by the prescribing physician).

Suspicion has arisen that levodopa may activate a malignant melanoma. Therefore, Hardal should not be used in persons who have a history of, or who may be suffering from, a malignant melanoma.

Close monitoring of patients with risk factors for (e.g. elderly patients, concomitant antihypertensives or other medication with orthostatic potential) or a history of orthostatic hypotension is recommended especially at the beginning of treatment or at dose increases.

Hardal has been reported to induce decreases in blood count (e.g. haemolytic anaemia, thrombocytopenia and leukopenia). In a few instances agranulocytosis and pancytopenia have been reported in which the association with Hardal could neither be established, nor be completely ruled out. Therefore, periodical evaluation of blood count should be performed during treatment.

Depression can be part of the clinical picture in patients with Parkinson's disease and RLS and may also occur in patients treated with Hardal. All patients should be carefully monitored for psychological changes and depression with or without suicidal ideation.

Hardal may induce dopamine dysregulation syndrome resulting in excessive use of the product. A small subgroup of PD 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.

If a patient requires a general anaesthetic, the normal Hardal regimen should be continued as close to the surgery as possible, except in the case of halothane. In general anaesthesia with halothane Hardal should be discontinued 12 - 48 hours before surgical intervention as fluctuations in blood pressure and/or arrhythmias may occur in patients on Hardal therapy. Hardal therapy may be resumed following surgery; the dosage should be increased gradually to the preoperative level.

If a patient has to undergo emergency surgery, when Hardal has not been withdrawn, anaesthesia with halothane should be avoided.

Hardal 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, additional signs in severe cases may include myoglobinuria, rhabdomyolysis - and acute renal failure) which may be life-threatening. Should a combination of such symptoms and signs occur, the patient should be kept under medical surveillance, if necessary, hospitalized and rapid and appropriate symptomatic treatment given. This may include resumption of Hardal therapy after an appropriate evaluation.

Pyridoxine (vitamin B₆) may be given with Hardal since the presence of a decarboxylase inhibitor protects against the peripheral levodopa transformation facilitated by pyridoxine.

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.

Impulse control disorders

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 Hardal. Review of treatment is recommended if such symptoms develop.

Laboratory tests

Periodical evaluation of hepatic, haemopoietic, renal and cardiovascular function and blood count should be performed during treatment.

Patients with diabetes should undergo frequent blood sugar tests and the dosage of anti-diabetic agents should be adjusted to blood sugar levels.

Patients who improve on Hardal therapy should be advised to resume normal activities gradually as rapid mobilisation may increase the risk of injury.

Malignant melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population (approximately 2-6 fold higher). It is unclear whether the increased risk observed was due to Parkinson's disease, or other factors such as levodopa used to treat Parkinson's disease. Therefore patients and providers are advised to monitor for melanomas on a regular basis when using Hardal for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

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.

The following undesirable effects have been reported (frequency not known, cannot be estimated from the available data) to occur when levodopa- benserazide is administered:

Frequency categories are as follows:

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 (cannot be estimated from the available data)

*These events may occur particularly in elderly patients and in patients with a history of such disorders.

Impulse Control Disorders:

- 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 Hardal..

Nervous System Disorder:

Psychiatric disturbances are common in Parkinsonian patients, including those treated with levodopa, including mild elation, anxiety, agitation, insomnia, drowsiness, depression, aggression, delusions, hallucinations, temporal disorientation and “unmasking” of psychoses.

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. Levodopa-benserazide is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Gastrointestinal disorders:

- Undesirable gastrointestinal effects, which may occur mainly in the early stages of the treatment, can largely be controlled by taking Hardal with some food or liquid or by increasing the dose slowly.

- Gastro-intestinal bleeding has been reported with levodopa therapy.

- Isolated cases of loss or alterations of taste.

Vascular Disorders:

Orthostatic disorders commonly improve following reduction of the Hardal dosage.

Musculoskeletal and connective tissue disorders:

Restless Legs Syndrome: The development of augmentation (time shift of symptoms from the evening/night into the early afternoon and evening before taking the next nightly dose, is the most common adverse effect of dopaminergic long-term treatment.

Others:

Flushing and sweating have been reported with levodopa.

Investigations:

Urine may be altered in colour; usually acquiring a red-tinge which turns dark on standing. These changes are due to metabolites and are no cause for concern.

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 medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.

Symptoms and signs

Symptoms and signs of overdosage are qualitatively similar to the side-effects of Hardal in therapeutic doses but may be of greater severity.

Overdose may lead to cardiovascular side effects (e.g. cardiac arrhythmias), psychiatric disturbances (e.g. confusion and insomnia), gastro-intestinal effects (e.g. nausea and vomiting) and abnormal involuntary movements

Treatment

Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular patients may require symptomatic treatment for cardiovascular effects (e.g. antiarrhythmics) or central nervous system effects (e.g. respiratory stimulants, neuroleptics).

Hardal is an anti-Parkinsonian agent. Levodopa is the metabolic precursor of dopamine. The latter is severely depleted in the striatum, pallidum and substantia nigra of Parkinsonian patients and it is considered that administration of levodopa raises the level of available dopamine in these centres. However, conversion of levodopa into dopamine by the enzyme dopa decarboxylase also takes place in extracerebral tissues. As a consequence the full therapeutic effect may not be obtained and side-effects occur.

Administration of a peripheral decarboxylase inhibitor, which blocks the extracerebral decarboxylation of levodopa, in conjunction with levodopa has significant advantages; these include reduced gastro-intestinal side-effects, a more rapid response at the initiation of therapy and a simpler dosage regimen. Hardal is a combination of levodopa and benserazide in the ratio 4:1 which in clinical trials has been shown to be the most satisfactory.

Like every replacement therapy, chronic treatment with Hardal will be necessary.

Absorption

Low levels of endogenous levodopa are detectable in pre-dose blood samples. After oral administration of Hardal, levodopa and benserazide are rapidly absorbed, mainly in the upper regions of the small intestine and absorption there is independent of the site. Interaction studies indicate that a higher proportion of levodopa is absorbed when administered in combination with benserazide, compared with levodopa administered alone. Maximum plasma concentrations of levodopa are reached approximately one hour after ingestion of Hardal. The absolute bioavailability of levodopa from standard Hardal is approximately 98%.

The maximum plasma concentration of levodopa and the extent of absorption (AUC) increase proportionally with dose (50 - 200 mg levodopa). The peak levodopa plasma concentration is 30% lower and occurs later when Hardal is administered after a standard meal. Food intake generally reduces the extent of levodopa absorption by 15% but this can be variable.

Distribution

Levodopa crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins. Benserazide does not cross the blood-brain barrier at therapeutic doses. Benserazide is concentrated mainly in the kidneys, lungs, small intestine and liver.

Metabolism

The 2 major routes of metabolism of levodopa are decarboxylation to form dopamine, which in turn is converted to a minor degree to norepinephrine and to a greater extent, to inactive metabolites, and O-methylation, forming 3-O-methyldopa, which has an elimination half-life of approximately 15 hours and accumulates in patients receiving therapeutic doses of Hardal. Decreased peripheral decarboxylation of levodopa when it is administered with benserazide is reflected in higher plasma levels of levodopa and 3-O-methyldopa.

Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.

Elimination

In the presence of the peripheral decarboxylase inhibitor, benserazide, the elimination half-life of levodopa is approximately 1.5 hours. In elderly patients the elimination half-life is slightly (25%) longer. Clearance of levodopa is 430ml/min.

Benserazide is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a small extent in faeces (24%).

See section 4.6 Pregnancy and lactation.

None known

No special requirements.