SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Methyldopa 125 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 125 mg of methyldopa (anhydrous).

3    PHARMACEUTICAL FORM

Film coated tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of all grades of hypertension.

4.2    Posology and method of administration

For oral administration.

Adults

Initial dose of usually 250 mg two or three times a day for two days.

It is usually adjusted at intervals of two days or more, until an adequate response is obtained.

The maximum recommended dosage is 3 g.

Patients may experience sedation for the first two or three days of therapy or when the dose is increased. It is advisable to increase the evening dose first if the dosage of methyldopa is to be increased.

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

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 on treatment with other hypertensive agents.

Methyldopa therapy may be initiated in most patients already on treatment by terminating the other antihypertensive medications gradually if required. Following previous antihypertensive therapy methyldopa 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.

*    Addition of a thiazide

A thiazide may be added during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if blood pressure control cannot be maintained on 2.0 g methyldopa daily.

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

Children

An initial dose based on 10 mg/kg body weight daily in 2-4 oral doses. The daily dose is then increased or decreased until an adequate response is obtained. The maximum dosage is 3.0 g or 65 mg/kg daily, whichever is less.

Elderly

The initial dose should be as low as possible, not more than 250 mg/day. An appropriate starting dose is 125 mg b.d. increasing slowly as required, but not to exceed 2 g/day.

4.3 Contraindications

Depression, active hepatic disease such as acute hepatitis and active cirrhosis, hypersensitivity (including hepatic disorders associated with previous methyldopa therapy) to methyldopa and any of the other ingredients in the tablets, therapy with monoamine oxidase inhibitors (MAOIs).

Methyldopa 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 haemotocrit determinations should be made. If anaemia is confirmed, tests should be done for haemolysis. If haemolysis 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%. 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 crossmatch 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 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 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 anaesthetics, 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.

Methyldopa 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

When methyldopa is used with other antihypertensive drugs or alcohol, the anti-hypertensive action may be enhanced Similarly, the antihypertensive effect may be modified by concurrent administration of tricyclic antidepressants, sympathomimetics, phenothiazines and MAOIs. Interactions with lithium have been reported

Several studies have demonstrated 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 has been used under close medical supervision for the treatment of hypertension during pregnancy. There was no clinical evidence that methyldopa caused foetal abnormalities or affected the neonate.

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 nursing their new-born infants 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

Significant side effects are infrequent, methyldopa is usually well tolerated. The following reactions have been reported:-

Central Nervous System : 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. Parasthesiae, Bell’s Palsy, Parkinsonism, involuntary choreothetotic movements. Psychic disturbances (e.g. 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, aggravation of angina pectoris, prolonged carotid sinus hypersensivity. 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).

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

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

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

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

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

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

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 dialyzable. 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 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. Methyldopa is thought to exert its hypotensive effect within the central nervous system (CNS) by virtue of its conversion to a-methylnorepinephrine, a potent a₂-adrenergic agonist which lowers arterial pressure by stimulating a₂-adrenergic receptors.

Pharmacokinetic properties

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.

5.3 Preclinical safety data

No information submitted.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Anhydrous citric acid, povidone, sodium starch glycollate, stearic acid, magnesium stearate, microcrystalline cellulose, hydroxypropylmethylcellulose and opaspray M-1F-6047B solids.

6.2    Incompatibilities

None known.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

HDPE Container: Do not store above 25°C and store in the original container. Polypropylene Securitainer: Protect from light, store in a dry place below

20°C.

6.5 Nature and contents of container

Polypropylene containers containing 21, 100, 250, 500, 1000 tablets or HDPE containers containing 56 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Waymade plc Trading as Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex.

SSl4 3FR United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 06464/1432

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23 January 2002

10 DATE OF REVISION OF THE TEXT

26/02/2004