SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methyldopa Tablets 250mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains methyldopa BP 250mg.

3    PHARMACEUTICAL FORM

Tablet.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension.

4.2 Posology and method of administration

Initiating therapy:

Adults:

Initial dosage is 250mg two or three times a day, for two days. Thereafter, usually increased at intervals of not less than two days, until an adequate response is achieved. The maximum recommended daily dose should not exceed 3g.

Many patients experience sedation for two or three days when therapy initiated or the dose is increased. Therefore, when increasing the dose of methyldopa it is advisable to increase the evening dosage first.

Children:

Initial dosage is based on 10mg/kg of bodyweight daily in 2-4 oral doses. The daily dosage can be increased or decreased as required until an adequate response is achieved. The maximum recommended daily dose should not exceed 65mg/kg or 3g daily, whichever is less.

Elderly:

Initial dosage should be as low as possible, not exceeding 250mg daily. An appropriate starting dose would be 125mg twice daily, increasing gradually as required, to a maximum of 2g daily.

Because methyldopa is largely excreted in the kidneys, patients with impaired renal function may respond to lower doses.

Requirement for methyldopa may also be reduced if a patient is dosed concurrently with a thiazide diuretic. Downward adjustment of dosage should be made at intervals of 2 days.

When patients are on other hypertensive agents and it is desired to change them to methyldopa, drug interactions must be watched for. In particular, reserpine, hydralazine and mebutamate when used alone or in any combination should be discontinued before methyldopa treatment is started.

Similarly MAO inhibitors should be discontinued before treatment with methyldopa. It should then be used cautiously in case of delayed excretion of the MAO inhibitors.

Ganglion blocking agents and adrenergic blocking agents used alone or in combination should be withdrawn progressively and methyldopa added initially at a dosage of 250mg twice a day. The blocking agent can then be further reduced and dosage of methyldopa adjusted upwards by 250mg to 500mg stages at 2 to 7 day intervals to maintain control of the blood pressure.

For oral administration.

4.3 Contraindications

Methyldopa should not be given in cases of acute hepatitis, active hepatic disease and active cirrhosis.

Or to patients known to be sensitive to methyldopa or any other excipients in this product.

Methyldopa fluoresces at the same wavelength as catecholamines. Care should be taken when methyldopa is used in the treatment of phaeochromocytoma since urine level assays of urine catecholamines may be affected.

Methyldopa is contraindicated in patients with a history of depression.

Methyldopa is contra-indicated in patients on therapy with monoamine oxidase inhibitors (MAOIs).

4.4 Special warnings and precautions for use

Methyldopa reduces both supine and standing blood pressure. Sympotmatic postural hypotension, excessive hypotension and diurnal blood pressure variations rarely occur.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Lithium:

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

Other antihypertensive drugs:

Potentiation of antihypertensive action can occur when methyldopa is used with other antihypertensive agents.

Other classes of drug:

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 hypotensive 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

Methyldopa should not be used with reserpine, hydralazine, mebutamate.

4.6 Fertility, Pregnancy and lactation

Methyldopa is not normally recommended for use during the first trimester of pregnancy.

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.

4.7 Effects on ability to drive and use machines

Methyldopa may cause sedation, usually transient, 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.

4.8 Undesirable effects

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 reactions have been reported:

Central nervous system: Sedation (usually transient), headache, asthenia or weakness, paraesthesiae, Parkinsonism, Bell’s palsy, involuntary choreoathetotic movements.

Psychic disturbances including nightmares, impaired mental acuity and reversible mild psychoses or depression. Dizziness, light-headedness, and symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure).

Cardiovascular: Bradycardia, prolonged carotid sinus hypersensitivity, aggravation of angina pectoris. Orthostatic hypotension (decrease daily dosage). Oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs of heart failure appear.)

Gastro-intestinal: Nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, sore or ‘black’ tongue, pancreatitis, sialadenitis.

Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver-function tests.

Haematological: Positive Coombs test, haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia. Positive tests for antinuclear antibody. LE cells, and rheumatoid factor.

Allergic: Drug-related fever and lupus-like syndrome, myocarditis, pericarditis.

Dermatological: Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis.

Other: Nasal stuffiness, rise in blood urea, breast enlargement, gynaecomastia, hyperprolactinaemia, amenorrhoea, lactation, impotence, decreased libido, failure of ejaculation, mild arthralgia with or without joint swelling, myalgia.

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 at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Acute overdosage may produce acute hypotension with other responses attributable to brain and gastro-intestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distension, flatus, diarrhoea, 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, methyldopa tablets should be discontinued.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

It appears that several mechanisms of action account 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).

5.2 Pharmacokinetic properties

Peak serum levels were observed 2-4 hours after oral administration of 2x 250mg methyldopa tablets.

During the first 24 hours 1% -11% of the oral dose was excreted in the urine as free methyldopa. This corresponds to a toal excretion of 3%-46%, when assuming that free alpha-methyldopa makes up 24%-40% of the urinary alpha-methyldopa metabolites and conjugates. Renal excretion accounts for about two thirds of drug clearance from plasma.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium calciumedetate, citric acid, ethyl cellulose, furcellaran, microcrystalline cellulose, magnesium stearate and lactose. Film coating: hypromellose, povidone, castor oil and FD&C yellow 5.

6.2 Incompatibilities

See Section 4.5, “Interactions with other medicaments and other forms of interaction”.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 25°C. Protect from light.

6.5 Nature and contents of container

Securitainers.

Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112, 250 and 1,000.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0056

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

7 August 1981/ 5 November 1996

10    DATE OF REVISION OF THE TEXT

15/07/2015