Methyldopa Tablets Bp 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Methyldopa Tablets BP 500mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active: Per Tablet:
Methyldopa Ph.Eur 563.920 mg equivalent to methyldopa anhydrous
500mg
For the full list of excipients, see Section 6.1.
3 PHARMACEUTICAL FORM
Round, yellow film coated biconvex tablet having ‘M500’ debossed on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe hypertension.
4.2 Posology and method of administration
ADULTS:
250mg 2-3 times daily for 2 days, adjusted at intervals of 2 days until adequate response is obtained. Maximum dose 3g daily (increase evening dose first). Usual effective dose 500mg to 2g daily.
ELDERLY:
Initial dose should be kept as low as possible not exceeding 250mg daily. An appropriate starting dose would be 125mg twice daily, increased slowly as required but not exceeding a maximum daily dosage of 2g.
CHILDREN: 10mg/kg bodyweight daily in 2-4 divided doses. The dosage is increased or decreased until adequate response is achieved. Maximum recommended daily dose is 65mg/kg bodyweight or 3g whichever is less.
4.3 Contraindications
Methyldopa tablets are contraindicated in patients with:
•Hypersensitivity to methyldopa or to any of the excipients listed in section 6 (including hepatic disorders associated with previous methyldopa therapy)
•A history of depression
•Acute hepatic disease such as acute hepatitis and active cirrhosis •On therapy with monoamine oxidase inhibitors (MAOIs)
•Porphyria
•Methyldopa Tablets are not recommended for the treatment of phaeochromocytoma (see 4.4 'Special warnings and precautions for use').
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 tablets 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 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 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 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.
Methyldopa Tablets 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 carefully monitored for symptoms of lithium toxicity.
Other antihypertensive drugs:
When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive action may occur. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy. Concurrent use of verapamil and methyldopa can intensify sinus bradycardia.
Other classes of drugs:
The antihypertensive effect of methyldopa may be diminished by sympathomimetics, tricyclic antidepressants, phenothiazine derivatives and monoamine oxidase inhibitors (MAOIs), when administered concomitantly with these drugs (see 4.3 'Contra-indications'). In addition, phenothiazines may have additive hypotensive effects.
Concomitant administration of methyldopa with thiazide diuretics and other antihypertensive agents, general anaesthetics and levodopa enhances the antihypertensive effect.
The toxicity of haloperidol may be increased by concurrent use. Monoamine oxidase inhibitors should be discontinued before treatment with methyldopa.
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.
4.6 Fertility, pregnancy and lactation
Methyldopa has been used under medical supervision for the treatment of hypertension during pregnancy. There is no clinical evidence of foetal abnormalities or effect on the neonate.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of foetal harm appears remote.
Methyldopa crosses the placental barrier and is present in cord blood and in 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
Caution should be observed when driving or operating machinery, as methyldopa therapy may result in drowsiness, dizziness, light headedness, involuntary choreoathetotic movements in patients with severe cerebrovascular disease. The patient should be advised accordingly on initiation of therapy and/or increase in dosage.
4.8 Undesirable effects
The following reactions have been reported
|
Cardiac disorders |
Bradycardia, aggravation of angia pectoris, myocarditis, pericarditis. |
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Blood and lymphatic system disorders |
Haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia |
|
Nervous system disorders |
Sedation (usually transient), headache, paraesthesia, Parkinsonism, Bell's palsy, involuntary choreoathetotic movements. Impaired mental acuity, prolonged carotid sinus hypersensitivity. Dizziness, light-headedness, and symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure) |
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Respiratory, thoracic and mediastinal disorders |
Nasal Stuffiness |
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Gastrointestinal disorders |
Nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, sore or 'black' tongue, pancreatitis |
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Skin and subcutaneous tissue disorders |
Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis |
|
Musculoskeletal and connective tissue disorders |
Lupus-like syndrome, mild arthralgia with or without joint swelling, myalgia |
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Endocrine |
Hyp erprol actinaemi a |
|
disorders | |
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Infections and Infestations |
Sialadentis |
|
Vascular disorders |
Orthostatic hypotension (decrease daily dosage) |
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General disorders and administrative site conditions |
Asthenia or weakness, oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs or heart failure appear.), drug-related fever |
|
Hepatobiliary disorders |
Liver disorders including hepatitis, jaundice |
|
Reproductive system and breast disorders |
Breast enlargement, gynaecomastia, amenorrhoea, lactation, impotence, failure of ejaculation |
|
Psychiatric disorders |
Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido |
|
Investigations |
Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, rise in blood urea |
Reporting of suspected adverse reactions
Reporting of 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 suspected adverse reactions via Yellow Card Scheme, Tel: Freephone 0808 100 3352, Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms of overdose may include acute hypotension, sedation, weakness, bradycardia, dizziness, gastrointestinal disturbances, light-headedness, constipation, distension, flatus, diarrhoea, nausea and vomiting.
Stomach emptied by aspiration, lavage and emesis may be induced if ingestion is recent. There is no specific antidote. Methyldopa is dialyzable. Treatment is symptomatic. Intravenous infusion may be given to promote urinary excretion and pressor agents such as metaraminol or noradrenaline given. Special care is needed with cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Methyldopa is an antihypertensive agent acting centrally by stimulating alpha adrenergic receptors. It inhibits the decarboxylation of dopa to dopamine but this action is not responsible for the hypotensive effect. It is suggested that a metabolite, alpha methylnoradrenaline may act as a false transmitter in the CNS. It reduces tissue concentration of dopamine noradrenaline, adrenaline and serotonin.
5.2 Pharmacokinetic properties
Methyldopa is incompletely absorbed from the gastrointestinal tract. Methyldopa is extensively metabolised through pathways common to the catecholamines utilising dopa decarboxylates and dopamine B-hydroxylase.
Decarboxylation is stereospecific. The bioavailability of an oral dose averages 25%(± 16%) and peak plasma levels occur 2 to 3 hours later. Elimination is biphasic. It is partly conjugated mainly to the o-sulphate and is excreted by the kidneys.
The elimination half-life is 1.8 ± 0.2 hours, methyldopa has been shown to cross the placental barrier and is found in the lungs, heart and muscles after 24 hours, detectable quantities are present in the liver and kidneys.
5.3 Preclinical safety data
None.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
lactose monohydrate , maize starch , citric acid , talc , magnesium stearate , stearic acid , silica colloidal anhydrous , hypromellose, macrogol 400, titanium dioxide (E171), iron oxide yellow (E172).
6.2 Incompatibilities
None known.
6.3 Shelf life
30 months in Blister strips
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from light.
Nature and contents of container
6.5
Aluminium / PVC (opaque) blister strips of 14 tablets in cartons containing 28 or 56 tablets.
6.6 Special precautions for disposal
No special instruction necessary.
7 MARKETING AUTHORISATION HOLDER
Intrapharm Laboratories Limited,
The Courtyard Barns,
Choke Lane,
Cookham Dean,
Maidenhead,
Berkshire,
SL6 6PT
8 MARKETING AUTHORISATION NUMBER(S)
PL 17509/0036
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/04/2011
10 DATE OF REVISION OF THE TEXT
07/11/2016