Document: spc-doc_PL 33414-0060 change

• spc-doc_PL 06464-1433
• spc-doc_PL 11311-0360
• spc-doc_PL 17907-0350
• spc-doc_PL 33414-0060

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

MEDOMET 250 mg Tablets Methyldopa 250 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methyldopa BP 282 mg

3 PHARMACEUTICAL FORM

Film-coated tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension

4.2 Posology and method of administration

Adults:

The normal dose range is 500 mg - 2 g per day in divided doses. Therapy is usually started with one 250 mg tablet Methyldopa twice a day for two days and thereafter adjusted upwards by amounts of 1 - 2 tablets or downwards by 1 x 250 mg, and it is important that an interval of not less than two days should elapse before such adjustment which should be made 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 Medomet and may be used either initially or at any stage

during therapy. It is not advisable to increase the daily dose beyond 3 grammes of Methyldopa. Patients with impaired renal function may respond to smaller doses of the drug as Methyldopa is largely excreted by the kidneys. In the presence of advanced arterio-sclerotic vascular disease in older patients syncopal attacks may result, these being related to an increased sensitivity to the drug. These may be avoided by reducing the dosage of Medomet. 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 Medomet or adding a thiazide diuretic.

Substitution of Medomet for other Antihypertensive Therapies:

i.	Rauwolfia derivatives (reserpine), Mebutamate and Hydralazine whether used in combination or alone should be discontinued immediately. Medomet at a starting dosage of one Medomet 250 mg twice a day and increasing as necessary by one Medomet 250 mg 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agents either used alone or in combination with those agents listed above should be progressively and cautiously withdrawn.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 Medomet added at dosage level of one Medomet 250 mg 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 Medomet should be increased (or decreased) by 1 or 2 Medomet 250 mg 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 Medomet further adjusted as found necessary in order to control blood pressure at an optimum level.
iii.	Discontinus hypotensive agents of the monoamine oxidase inhibitor group immediately and commence therapy with Medomet cautiously with one Medomet twice a day. Although the immediate use of Medomet is not contra-indicated it may be advisable to delay the introduction of Medomet until blood pressure starts to rise.
iv.	Thiazide diuretics may be continued.

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.

Elderly:

The initial dose for elderly patients should be kept as low as possible and not exceed

250 mg daily. Maximum daily dose of 2 g should not be exceeded.

Method of administration: Oral.

4.3 Contraindications

•    Hypersensitivity to the drug or to any component of Methyldopa Tablets 250mg

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

•    Depression

•    On therapy with monoamine oxidase inhibitors (MAOIs)

•    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, MEDOMET 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. 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 crossmatch, 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 (see section 4.3 - Contra-indications).

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 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

Potentiaton of the antihypertensive action of MEDOMET 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 MEDOMET 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.

Patients should be monitored for symptoms of lithium toxicity if MEDOMET and lithium are given concurrently. Neurotoxicity may occur without increased concentration of lithium.

4.6 Pregnancy and lactation

Although there are no clinical evidence that Methyldopa caused foetal abnormalities or effected the neonate and although no teratonegic effects have been reported, foetal damage cannot be excluded and the use of MEDOMET in women who are, or who may become, pregnant or who are nursing their new born infant demands that dosage benefits be weighed against the possible risks.

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

4.7 Effects on ability to drive and use machines

Drowsiness may affect performance at skilled tasks such as driving or operating machinery. The effects of alcohol may be enhanced.

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 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, 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

Overdose may produce acute hypotension manifested through excessive sedation, weakness, dizziness, light-headedness, bradycardia, distension, constipation, nausea and vomiting. Gastric lavage should be performed. There is no specific antidote. Treatment is symptomatic. Infusions may be helpful to promote urinary excretion. Careful attention should be paid to cardiac rate and output, electrolyte balance, blood volume, urinary function, cerebral activity and paralytic ileus. 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 properties

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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric Acid

Sodium Calcium Edetate Microcrystalline Cellulose Magnesium Stearate Ethylcellulose Colloidal Anhydrous Silica Guar Gum

In the coating:

Opaspray K-1-6039 (titanium dioxide E171, talc, iron oxide yellow E172, hydroxypropyl cellulose)

Hypromellose

Ethylcellulose

Diethyl phthalate

Dispersed Yellow 14650 (E104)

6.2 Incompatibilities

None Stated

6.3 Shelf life

36 months all sizes

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 polythene lids and polyurethane or polythene inserts.

Pack sizes: 56, 100 and 500

6.6    Special precautions for disposal

No special instructions

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

Boumpoulinas 11, 3 ^rd Floor

NICOSIA

CYPRUS

PC. 1060