ALDOMET® Tablets 500 mg

'Aldomet' Tablets 500 mg, contain methyldopa equivalent to 500mg anhydrous methyldopa.

Yellow film-coated tablets

'Aldomet' Tablets 500mg are marked 'ALDOMET' on one side and '500' on the other side.

In the treatment of hypertension.

General considerations: Methyldopa is largely excreted by the kidney, and patients with impaired renal function may respond to smaller doses.

Withdrawal of 'Aldomet' is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.

Therapy with 'Aldomet' may be initiated in most patients already on treatment with other antihypertensive agents by terminating these antihypertensive medications gradually, as required. Following such previous antihypertensive therapy, 'Aldomet' should be limited to an initial dose of not more than 500 mg daily and increased as required at intervals of not less than two days.

When methyldopa is given to patients on other antihypertensives the dose of these agents may need to be adjusted to effect a smooth transition.

When 500mg of 'Aldomet' is added to 50mg or hydrochlorothiazide, the two agents may be given together once daily.

Many patients experience sedation for two or three days when therapy with 'Aldomet' is started or when the dose is increased. When increasing the dosage, therefore, it may be desirable to increase the evening dose first.

Oral therapy – Adults: Initial dosage: Usually 250mg two or three times a day for two days.

Adjustment: Usually adjusted at intervals of not less than two days, until an adequate response is obtained. The maximum recommended dosage is 3g.

Oral therapy – Children: initial dose is based on 10mg/kg of bodyweight daily in 2-4 oral doses. The daily dosage is then increased or decreased until adequate response is achieved. The maximum dosage is 65mg/kg or 3.0g daily, whichever is less.

Use in the elderly: The initial dose in elderly patients should be kept as low as possible, not exceeding 250mg daily, an appropriate starting dose in the elderly would be 125mg b.d increasing slowly as required, but not to exceed a maximum daily dosage of 2g. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.

'Aldomet' is contra-indicated in patients with:

• Active hepatic disease, such as acute hepatitis and active cirrhosis

• Hypersensitivity (including hepatic disorders associated with previous methyldopa therapy) to any component of these products

• Depression

• On therapy with monoamine oxidase inhibitors (MAOIs).

'Aldomet' is not recommended for the treatment of phaeochromocytoma (see 4.4 'Special warnings and precautions for use').

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, 'Aldomet' 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%. 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-cell count are advisable before therapy and 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.

'Aldomet' should be used with extreme caution in patients, or in near relatives of patients, with hepatic porphyria.

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.

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.

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

Lithium:

When methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity.

Other hypertensive drugs:

When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive action may occur. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy.

Other classes of drugs:

The antihypertensive effect of 'Aldomet' may be diminished by sympathomimetics, phenothiazines, tricyclic antidepressants and MAOIs (see 4.3 'Contra-indications'). In addition, phenothiazines may have additive hypertensive effects.

Iron:

Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulphate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa.

'Aldomet' has been used under close medical supervision for the treatment of hypertension during pregnancy. There was no clinical evidence that 'Aldomet' caused foetal abnormalities or affected the neonate.

Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of foetal harm appears remote.

Methyldopa crosses the placental barrier and appears in cord blood and breast milk.

Although no obvious teratogenic effects have been reported, the possibility of foetal injury cannot be excluded and the use of the drug in women who are, or may become, pregnant or who are breast-feeding their newborn infant requires that anticipated benefits be weighed against possible risks.

'Aldomet' may cause sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. If affected, patients should not carry out activities where alertness is necessary, such as driving a car or operating machinery.

The following reactions have been reported:

Cardiac disorders: Bradycardia, aggravation of angia pectoris, myocarditis, pericarditis.

Blood and lymphatic system disorders: Haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia,

Nervous system disorders: Sedation (usually transient), headache, paraesthesiae, Parkinsonism, Bell's palsy, involuntary choreoathetotic movements. Impaired mental acuity, prolonged carotid sinus hypersensitivity. Dizziness, light-headedness, and symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure).

Respiratory, thoracic and mediastinal disorders: Nasal Stuffiness.

Gastrointestinal disorders: Nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, sore or 'black' tongue, pancreatitis, sialadenitis.

Skin and subcutaneous tissue disorders: Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: Lupus-like syndrome, mild arthralgia with or without joint swelling, myalgia.

Endocrine disorders: Hyperprolactinaemia.

Infectious and Infestations: Sialadentis.

Vascular disorders: Orthostatic hypotension (decrease daily dosage).

General disorders and administrative site conditions: Asthenia or weakness, oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs or heart failure appear.), drug-related fever.

Hepatobiliary disorders: Liver disorders including hepatitis, jaundice.

Reproductive system and breast disorders: Breast enlargement, gynaecomastia, amenorrhoea, lactation, impotence, failure of ejaculation.

Psychiatric disorders: Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido.

Investigations: Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, rise in blood urea.

Acute overdosage may produce acute hypotension with other responses attribute to brain and gastro-intestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distension, flatus, diarrhea, nausea, and vomiting).

If ingestion is recent, emesis may be induced or gastric lavage performed. There is no specific antidote. Methyldopa is dialysable. Treatment is symptomatic. Infusions may be helpful to promote urinary excretion. Special attention should be directed towards cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity. Administration of sympathomimetic agents may be indicated. When chronic overdosage is suspected, 'Aldomet' should be discontinued.

It appears that several mechanisms of action for the clinically useful effects of methyldopa and the current generally accepted view is that its principal action is on the central nervous system.

The antihypertensive effect of methyldopa is probably due to its metabolism to alpha-methylnoradrenaline, which lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline).

Absorption of oral methyldopa is variable and incomplete. Bioavailability after oral administration averages 25%. Peak concentrations in plasma occur at two to three hours, and elimination of the drug is biphasic regardless of the route of administration. Plasma half-life is 1.8 ± 0.2 hours. Renal excretion accounts for about two thirds of drug clearance from plasma.

No relevant information.

Tablet-core: cellulose powder, anhydrous citric acid; collodial silicon dioxide; ethylcellulose; guar gum; magnesium stearate; sodium calcium edetate;

Tablet-coating: propylene glycol; anhydrous citric acid; hypromellose; quinoline yellow aluminium lake E104; red iron oxide E172; talc; titanium dioxide, carnauba wax.

None known.

36 months

Keep containers well closed and store below 25˚C, protected from light.

White polyethylene bottle of 100 and 500 tablets with turquoise polyethylene closure, or PVC aluminium blister packs of 30 tablets.

None

Aspen Europe Gmbh

Industriestrasse 32-36

D-23843 Bad Oldesloe

Germany

PL 34568/0013

Licence first granted: 21 February 1974

Licence last renewed: 05 September 2001

26/10/2010