SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-Caps Methyldopa 250 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Methyldopa (equivalent to Anhydrous Methyldopa) BP 250 mg For excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Anti-hypertensive

4.2 Posology and method of administration

Adults:    250-500 mg six hourly. In severe cases, up to 1 g six-hourly.

Elderly:    The initial dose in elderly patients should be kept as low as possible, not

exceeding 250 mg daily. Maximum daily dosage of 2 g.

Children:    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, the maximum dosage is 65 mg/kg or 3.0 g daily, whichever is less

Method of administration: Oral

4.3    Contraindications

Active liver disease, such as acute hepatitis and active cirrhosis. Hypersensitivity to the drug or to any component of Methyldopa 250mg. Depression. Phaeochromocytoma. Porphyria.

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, 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 direct Coombs test. Which may affect blood cross-matching. From the reports of different investigators, the incidence averages up to 20% of patients. A positive Coombs test rarely develops in the first six months of therapy.

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.

Caution is required in patients with renal impairment (start with small dose as there may be increased sensitivity to hypotensive and sedative effect).

Methyldopa should be given with caution in patients with history of depression.

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, hypotension may recur after this procedure.

Rarely, involuntary choreo-athetotic 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 calorimetric 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. Methydopa 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 the breakdown of methyldopa or its metabolites.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction with lithium may cause neurotoxicity without increased plasma concentrations.

Potentiaton of the antihypertensive action of methyldopa may occur when this drug is used with other hypertensive agents, alcohol, alprostadil, anaesthetics, antidepressants (concomitant use with MAOIs should be avoided), antipsychotics, anxiolytics and hypnotics, beta-blockers, calcium-channel blockers, diuretics, moxisylyte, the muscle relaxants baclofen and tizanidine, nitrates, ACE inhibitors, adrenergic neurone blockers, alpha-blockers, angiotensin-II receptor antagonists, aldesleukin, levodopa and possibly entacapone. Acute hypotension has been reported with salbutamol infusion.

The hypotensive effect of methyldopa is antagonised by NSAIDs, corticosteroids, iron, oestrogens and combined oral contraceptives.

Methyldopa antagonises the antiparkinsonian effect of dopaminergics. There is an increased risk of extrapyramidal side effects when methyldopa is given with amantadine.

4.6 Pregnancy and lactation

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 newborn infant requires that anticipated benefits be weighed against possible risks.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

Sedation usually transient may occur during the initial period of therapy or whenever the dose is increased. 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 caroteid 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, stomatitis, pancreatitis, sialadenitis.

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

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

Allergic: Drug-related fever and abnormal liver function tests with jaundice and hepatocellular damage, lupus erythematous-like syndrome, myocarditis and 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, failure of ejaculation, impotence, decreased libido, mild arthralgia with or without joint swelling, myalgia.

4.9 Overdose

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.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Methyldopa acts centrally by stimulating alpha-adrenergic receptors. It inhibits the decarboxylation of dopa to dopamine but this action does not appear to be responsible for its hypotensive effect. It is suggested that a metabolite, alpha-methylnoradrenaline, may act as a false transmitter in the central nervous system. Methyldopa reduces the tissue concentrations of dopamine, noradrenaline, adrenaline, and serotonin.

When administered by mouth its effects may appear after about two hours and reach a maximum in 6 to 8 hours, although the maximum hypotensive effect may not occur until the second day of treatment; some effect is still usually apparent until 48 hours after a dose.

5.2    Pharmacokinetic particulars

Methyldopa is completely absorbed from the gastro-intestinal tract. It is partly conjugated, mainly to the O-sulphate, and is excreted by the kidneys. Elimination follows a biphasic pattern. Plasma protein binding is reported to be minimal. It crosses the placenta and small amounts appear in breast milk.

5.3    Preclinical safety data

Not applicable

6.1 List of excipients

Starch 1500

Sodium Starch Glycollate Magnesium Stearate Gelatin

Titanium Dioxide (E171) Tartrazine (E102)

6.2 Incompatibilities

None stated

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store below 25°C in a dry place. Protect from light. Keep container well closed.

6.5 Nature and contents of container

High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polythene or polyurethane inserts

Pack sizes: 100 and 500

Special precautions for disposal

No special instructions

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

Boumpoulinas 11, 3 ^rd Floor

NICOSIA

CYPRUS

PC. 1060

CYPRUS

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0062

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/11/1987    09/02/1998

10    DATE OF REVISION OF THE TEXT

26/08/1997