MEDOMET

Posology Adults:

Initial dosage: Usually 250 mg tablet Methyldopa twice or thrice a day for two days.

Adjustment:

Usually adjusted at an interval of not less than two days until an adequate response is obtained. It is recommended that a thiazide diuretic be introduced to the regime if effective control cannot be maintained on 8 x 250 mg Methyldopa daily.

The use of thiazide diuretics complements the effectiveness of Methyldopa and may be used either initially or at any stage during therapy. The maximum recommended daily dose is 3 grammes of Methyldopa. Many patients experience sedation for two or three days when therapy with methyldopa is started or when the dose is increased.

When increasing the dosage, therefore, it may be desirable to increase the evening dose first. Withdrawal of Methyldopa is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.

Patients with renal impairment:

Patients with impaired renal function may respond to smaller doses of the drug as Methyldopa is largely excreted by the kidneys. Tolerance if it occurs is most likely to be seen in the second and third months after the commencement of therapy, and this may be overcome by increasing the dosage of Methyldopa or adding a thiazide diuretic.

Substitution of Methyldopa for other Antihypertensive Therapies: i Rauwolfia derivatives (reserpine), Mebutamate and Hydralazine whether used in combination or alone should be discontinued immediately. A starting dosage of one Methyldopa 250 mg tablet twice a day and increasing as necessary by one Methyldopa 250 mg tablet at weekly intervals.

ii Adrenergic and ganglion blocking agents either used alone or in combination with those agents listed above should be progressively and cautiously withdrawn. In the first week of transfer for example the dosage of the blocking may be reduced by half and Methyldopa added at dosage level of one Methyldopa 250 mg tablet twice a day.

In the second and third weeks the dosage of the blocking agent may be reduced to one quarter of its original while that of Methyldopa should be increased (or decreased) by 1 or 2 Methyldopa 250 mg tablet at three to seven day intervals in order that optimum control of blood pressure may be maintained.

The blocking agent may thereafter be discontinued and the dosage of Methyldopa further adjusted as found necessary in order to control blood pressure at an optimum level. iii Discontinue hypotensive agents of the monoamine oxidase inhibitor group immediately and commence therapy with Methyldopa cautiously with one Methyldopa tablet twice a day.

Although the immediate use of Methyldopa is not contra-indicated it may be advisable to delay the introduction of Methyldopa tablets until blood pressure starts to rise. iv Thiazide diuretics may be continued. When 500 mg of Methyldopa is added to 50 mg of hydrochlorothiazide, the two agents may be given together once daily.

Paediatric population:

Initial dosage is based on 10 mg/kg of bodyweight daily in 2-4 oral doses. The daily dosage then is increased or decreased until an adequate response is achieved. 0 g daily, whichever is less. d. increasing slowly as required, but not to exceed a maximum daily dosage of 2 g.

Syncope in older patients may be related to an increased sensitivity and advanced arterioclerotic vascular disease. This may be avoided by lower doses.

Method of administration:

Oral

Sedation usually transient, may occur during the initial period of therapy or whenever the dose is increased. If affected, patients should not attempt to drive, or operate machinery. Headache, asthenia or weakness may be noted as early and transient symptoms.

The following convention has been utilised for the classification of frequency:

Very common (≥1/10),common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). System Organ Class Adverse event term Frequency Infections and infestations Sialoadenitis Not known Blood and lymphatic system disorders Haemolytic anaemia, bone- marrow failure, leukopenia, granulocytopenia, thrombocytopenia, eosinophilia Not known Endocrine disorders Hyperprolactinaemia Not known Psychiatric disorders Psychiatric disturbances including nightmares, reversible mild psychoses or depression, decreased libido Not known Nervous system disorders Sedation (usually transient), headache, paraesthesia, parkinsonism, VIIth nerve paralysis, choreoathetosis, mental impairment, carotid sinus syndrome, dizziness, symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure) Not known Cardiac disorders Bradycardia, angina pectoris, myocarditis, pericarditis, atrioventricular block Not known Vascular disorders Orthostatic hypotension (decrease daily dosage) Not known Respiratory, thoracic and mediastinal disorders Nasal congestion Not known Gastrointestinal disorders Nausea, vomiting, abdominal distension, constipation, flatulence, diarrhoea, colitis, dry mouth, glossodynia, tongue discolouration, pancreatitis Not known Hepatobiliary disorders Liver disorders including hepatitis, jaundice Not known Skin and subcutaneous tissue disorders Rash (eczema, lichenoid eruption), toxic epidermal necrolysis, angioedema, urticaria Not known Musculoskeletal and connective tissue disorders Lupus-like syndrome, mild arthralgia with or without joint swelling, myalgia Not known Reproductive system and breast disorders Breast enlargement, gynaecomastia, amenorrhoea, lactation disorder, erectile dysfunction, ejaculation failure Not known General disorder and administrative site conditions Asthenia, oedema (and weight gain) usually relieved by use of a diuretic.

(Discontinue methyldopa if oedema progresses or signs of heart failure appear). Pyrexia. Not known Investigations Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, increased blood urea Not known 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Acquired haemolytic anaemia has occurred rarely. Should symptoms suggest anaemia, haemoglobin and/or haematocrit determinations should be made. If anaemia is confirmed, tests should be done for haemolysis. If haemolytic anaemia is present, methyldopa should be discontinued.

Stopping therapy, with or without giving a corticosteroid, has usually brought prompt remission. Rarely, however, deaths have occurred. Some patients on continued therapy with methyldopa develop a positive Coombs test. From the reports of different investigators, the incidence averages between 10% and 20% of patients.

A positive Coombs test rarely develops in the first six months of therapy, and if it has not developed within 12 months, it is unlikely to do so later on continuing therapy. Development is also dose-related, the lowest incidence occurring in patients receiving 1 g or less of methyldopa per day.

The test becomes negative usually within weeks or months of stopping methyldopa. Prior knowledge of a positive Coombs reaction will aid in evaluating a cross-match for transfusion. If a patient with a positive Coombs reaction shows an incompatible minor cross-match, an indirect Coombs test should be performed.

If this is negative, transfusion with blood compatible in the major cross-match may be carried out. If positive, the advisability of transfusion should be determined by a haematologist. Reversible leucopenia, with primary effect on granulocytes has been reported rarely.

The granulocyte count returned to normal on discontinuing therapy. Reversible thrombocytopenia has occurred rarely. Occasionally, fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in liver-function tests.

Jaundice, with or without fever, also may occur. Its onset is usually within the first two or three months of therapy. In some patients the findings are consistent with those of cholestasis. Rare cases of fatal hepatic necrosis have been reported.

Liver biopsy, performed in several patients with liver dysfunction, showed a microscopic focal necrosis compatible with drug hypersensitivity. Liver function tests and a total and differential white blood count are advisable at intervals during the first six weeks to twelve weeks of therapy, or whenever an unexplained fever occurs.

Should fever, abnormality in liver function or jaundice occur, therapy should be withdrawn. If related to Methyldopa, the temperature and abnormalities in liver function will then return to normal. Methyldopa should not be used again in these patients.

Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction. Patients may require reduced doses of anaesthetics when on methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors.

The adrenergic receptors remain sensitive during treatment with methyldopa. Dialysis removes methyldopa; therefore, hypertension may recur after this procedure. Rarely, involuntary choreoathetotic movements have been observed during therapy with Methyldopa in patients with severe bilateral cerebrovascular disease.

Should these movements occur, therapy should be discontinued.

Interference with laboratory tests:

Methyldopa may interfere with the measurement of urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and AST (SGOT) by colorimetric method. Interference with spectrophotometric methods for AST (SGOT) analysis has not been reported.

As methyldopa fluoresces at the same wavelengths as catecholamines, spuriously high amounts of urinary catecholamines may be reported interfering with a diagnosis of phaeochromocytoma or paraganglioma. It is important to recognise this phenomenon before a patient with a possible phaeochromocytoma is subjected to surgery.

Methyldopa does not interfere with measurements of VMA (vanillylmandelic acid) by those methods which convert VMA to vanillin. Methyldopa is contraindicated for the treatment of patients with a catecholamine-secreting tumour such as phaeochromocytoma or paraganglioma.

Rarely, when urine is exposed to air after voiding, it may darken because of the breakdown of methyldopa or its metabolites.

1. • Active liver disease, such as acute hepatitis and active cirrhosis • Depression • On therapy with monoamine oxidase inhibitors (MAOIs) • A catecholamine-secreting tumour such as phaeochromocytoma or paraganglioma • Porphyria