Document: spc-doc_PL 20395-0111 change

• spc-doc_PL 00142-0094
• spc-doc_PL 17509-0036
• spc-doc_PL 20395-0111
• spc-doc_PL 20416-0406

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methyldopa Tablets BP 500 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 564.0 mg of Methyldopa BP (equivalent to 500mg anhydrous methyldopa)

3 PHARMACEUTICAL FORM

Tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Indications: Hypertension

4.2 Posology and method of administration Posology

Since Methyldopa is largely excreted by the kidneys, patients with impaired renal function may respond to comparatively low doses.

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

Therapy with Methyldopa may be initiated in most patients already on treatment with other antihypertensive agents by terminating these antihypertensive medications gradually if required (see manufacturer’s recommendations on stopping these drugs). Following such previous antihypertensive therapy, Methyldopa should be limited to an initial dose of not more than 500mg daily and increased as required at intervals of not less than two days.

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 methyldopa or adding a thiazide diuretic.

A thiazide may be added at any time during Methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2g of Methyldopa daily.

Methyldopa may also be used concomitantly with the combination of amiloride hydrochloride and hydrochlorothiazide or beta-blocking agents, such as timolol maleate.

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

Substitution of Methyldopa for other antihypertensive therapies:

(i)    Rauwolfia derivatives (reserpine), mebutamate and hydrazine whether used in combination or alone should be discontinued immediately. Methyldopa at a starting dosage of one Methyldopa 250 mg twice a day and increasing as necessary by one methyldopa 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 agent should be reduced by half and Methyldopa added at dosage level of one Methyldopa 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 level while that of Methyldopa should be increased (or decreased) by 1 or 2 Methyldopa 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 Methyldopa further adjusted as found necessary in order to control blood pressure at an optimum level.

(iii)    Discontinue hypotensive agents of the monoamine oxidase inhibitor group immediately and commence therapy with Methyldopa cautiously and commencing with one Methyldopa twice a day. Although the immediate use of Methyldopa is not contraindicated it may be advisable to delay the introduction of Methyldopa until blood pressure starts to rise.

(iv)    Thiazide diuretics may be continued.

Adults and children over 12 years:

Initially 250mg two or three times a day, for two days. Thereafter, it is 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.

An alternative tablet preparation may therefore be required initially for this age group.

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

Children under 12 years:

Initial dosage is based on 10mg/kg of bodyweight daily in 2-4 divided doses increased or decreased as required. The maximum dose is 65mg/kg or 3g daily, whichever is less.

Elderly:

The initial dose should be kept as low as possible, not exceeding 250mg daily. An appropriate starting dose would be 125mg twice daily increasing slowly as required, to a maximum of 2g daily. An alternative tablet preparation may therefore be required initially for this age group.

In the presence of advanced arteriosclerotic vascular disease in older patients, syncopal attacks may result, these being related to an increased sensitivity to the drug. This may be avoided by lower doses.

Method of administration:

For oral administration

4.3 Contraindications

•    Active hepatic disease (such as acute hepatitis and active cirrhosis)

•    Hypersensitivity (including hepatic disorders associated with previous Methyldopa therapy) to Methyldopa or any of the ingredients in the tablets

•    Phaeochromocytoma

•    Depression

•    Therapy with monoamine oxidase inhibitors (MAOIs)

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 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 doserelated, 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 crossmatch, an indirect Coombs test should be performed. If this is negative, transfusion with blood compatible in the major crossmatch may be carried out. If positive, the advisability of transfusion should be determined by a haematologist.

Reversible leukopenia, 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 liverfunction tests. Jaundice, with or without fever, may also 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. Liverfunction tests and a total and differential white bloodcell 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.

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 catecholaminesecreting tumours such as phaeochromocytoma or paraganglioma.

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. Methyldopa is contraindicated for the treatment of patients with a catecholaminesecreting tumour such as phaeochromocytoma or paraganglioma.

Rarely, when urine is exposed to air after voiding, it may darken because of

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol', concomitant use may enhance the hypotensive effect.

Alprostadil: concomitant use may enhance the hypotensive effect.

Anaesthetics: as concomitant use may enhance the hypotensive effect, patients may require reduced doses of anaesthetics when on Methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors. Analgesics: NSAIDs antagonise the hypotensive effect.

Antibacterials: concomitant use with linezolid should be avoided as the hypotensive effect may be enhanced.

Antidepressants: concomitant use may enhance the hypotensive effect. Concomitant use with MAOIs should be avoided.

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

Other classes of drugs: The antihypertensive effect of methyldopa may be diminished by sympathomimetics, phenothiazines, tricyclic antidepressants and MAOI’S (see section 4.3 ‘Contraindications’). In addition, phenothiazines may have additive hypertensive effect.

Antipsychotics: concomitant use can increase the risk of extrapyramidal effects and enhance the hypotensive effect.

Anxiolytics and hypnotics: concomitant use may enhance the hypotensive effect. Beta-blockers: concomitant use may enhance the hypotensive effect. Calcium-channel blockers: concomitant use may enhance the hypotensive effect.

Corticosteroids: concomitant use may antagonise the hypotensive effect. Diuretics: concomitant use may enhance the hypotensive effect.

Dopaminergics: concomitant use may antagonise the antiparkinsonian effect of this type of medicine.

Concomitant use with levodopa or entacapone may enhance the hypotensive effect.

Iron: concomitant use may reduce the hypotensive effect. 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.

Lithium: when Methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity. Neurotoxicity may occur without increased plasma-lithium concentration.

Moxisylyte: concomitant use may enhance the hypotensive effect.

Muscle relaxants: concomitant use with Baclofen and tizanidine may enhance the hypotensive effect.

Nitrates: concomitant use may enhance the hypotensive effect.

Oestrogens and progestogens: Oestrogens and combined oral contraceptives antagonise the hypotensive effect.

Beta ₂ sympathomimetics: acute hypotension has been reported with salbutamol infusion.

Ulcer-healing drugs: Carbenoxolone antagonises the hypotensive effect.

4.6 Fertility, Pregnancy and lactation

Methyldopa crosses the placenta.

No teratogenic effects have been observed. However, the drug should only be used during pregnancy if there are no safe alternatives and if the mother and the foetus are at risk from the degree of hypertension.

Methyldopa is excreted in breast milk and should not be used by nursing mothers.

4.7 Effects on ability to drive and use machines

Methyldopa may induce transient sedation, during the initial period of 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 convention has been utilised for the classification of frequency: Very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (> 1/10,000 and <1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

System Organ Class	Adverse event term	Frequency
Infections and infestations	Sialoadenitis	Not known
Blood and lymphatic system disorders	Haemolytic anaemia, bonemarrow failure, leukopenia, granulocytopenia, thrombocytopenia, eosinophilia	Not known
Endocrine disorders	Hyperprolactinaemia	Not known
Psychiatric disorders	Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido	Not known
Nervous system disorders	Sedation (usually transient), headache, paraesthesia, Parkinsonism, VIIth nerve paralysis, choreoathetosis, mental impairment, carotid sinus syndrome, dizziness, symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure)	Not known
Cardiac disorders	Bradycardia, angina pectoris, myocarditis, pericarditis, atrioventricular block	Not known

4.9 Overdose

Acute overdose may produce acute hypotension with other responses attributable to brain and gastrointestinal 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, but Methyldopa is dialyzable.

Treatment is largely symptomatic but if necessary intravenous infusion may be given to promote urinary excretion and pressor agents given cautiously.

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.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: C02AB01

Methyldopa is an antihypertensive agent, which is considered to exert its effects by interfering with the synthesis and action of noradrenaline. It inhibits the conversion of dopa to dopamine by competing for the enzyme dopa decarboxylase and consequently reduces the amount of noradrenaline formed from dopamine.

It is suggested that a metabolite, alphamethyl noradrenaline, which is much less active than noradrenaline, displaces noradrenaline from its storage sites and acts as a false transmitter.

Methyldopa reduces the concentration of dopamine, noradrenaline and serotonin in the CNS. When administered by mouth its effects appear after about 2 hours and reach a maximum in 6 to 8 hours, some effect is still usually apparent after 24 hours.

5.2 Pharmacokinetic properties

Methyldopa is incompletely and variably absorbed from the GI tract. Only about one half of a dose administered by mouth is absorbed and peak plasma concentrations occur after 3 to 6 hours. In persons with abnormal renal function 80 to 90% of the drug has been reported to be eliminated from the body in 48 hours.

It is partly conjugated, mainly to the O-sulphate, and is excreted by the kidneys. Of the methyldopa eliminated in the urine about 25% is unchanged and the remainder is as metabolites, mainly a Mono-O-Sulphate of Methyldopa. Elimination follows a biphasic pattern with a half life of about 1.7 hours during the initial phase. Plasma protein binding is reported to be minimal. It crosses the placenta and small amounts appear in breast milk.

5.3 Preclinical safety data

There are no preclinical 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

Citric Acid

Disodium Calcium Edetate Ethylcellulose

Guar Gum

Microcrystalline Cellulose PHIOI Avicel Silicon Dioxide Magnesium Stearate Isopropyl Alcohol

Hydroxypropylmethyl Cellulose (2910)

Ethylcellulose

Diethylphthalate

Opaspray K-1-6039 Yellow

Quinoline Yellow Aluminium Lake E104

Methanol

Dichloromethane

6.2 Incompatibilities

None known.

6.3 Shelf life

Unopened container: A shelf life of 36 months

6.4 Special precautions for storage

Store below 25^oC in a dry place. Protect from light.

6.5 Nature and contents of container

Polypropylene securitainers with appropriate bellows or polyeurethane foam wads containing 100 and 500 tablets.

6.6 Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Relonchem Limited,

Cheshire House,

Gorsey Lane,

Widnes,