INFORMATION FOR HEALTH PROFESSIONALS
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Methyldopa USP in:
125mg tablet: Circular, yellow, biconvex film-coated tablet of 8mm diameter engraved novo on one side and 125 on the reverse.
250mg tablet: Circular, yellow, biconvex film-coated tablet of 10mm diameter engraved novo on one side and 250 on the reverse.
500mg tablet: Circular, yellow, biconvex film-coated tablet of 13mm diameter engraved novo on one side and 500 on the reverse.
Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in man. It lowers arterial blood pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. A net reduction in the tissue concentration of serotonin, dopamine, adrenaline and noradrenaline has been noted.
Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow or filtration fraction.
Cardiac output is usually maintained with cardiac acceleration although occasionally cardiac slowing is noted.
Methyldopa reduces both supine and standing blood pressure.
Methyldopa is incompletely absorbed from the gastrointestinal tract achieving peak plasma concentrations (approx. 3.3 µg/mL) about two to three hours after administration of a 500mg dose. Plasma protein binding is minimal and the methyldopa appears to distribute extravascularly. Methyldopa crosses the placenta and small amounts appear in breast milk mostly in the conjugated form.
Elimination involves partial conjugation to the O-Sulphate with excretion of this conjugate and unchanged medicine in the urine. It follows a biphasic pattern with the µ-phase half-life ranging from 0.74-1.10h and the b-phase half-life ranging from 8.0-65.0h.
Sustained moderate to severe hypertension.
Therapy is initiated with 250mg two to three times daily during the first 48 hours. Dosage is then adjusted at intervals of not less than two days until an adequate response has been achieved.
Once the effective dose range is attained, a smooth reduction in the blood pressure response occurs in most patients in 12 to 14 hours.
The recommended daily dosage range of methyldopa is 500mg to 2.0g in divided doses. Although occasional patients have responded to higher dosages it is not recommended.
The 125mg tablet is useful when small increments of methyldopa are required for adjustment of the antihypertensive response. The 500mg tablet is intended for use in stabilised patients requiring two 250mg tablets for any given dose. These two strengths are not designed for use as initial therapy in previously untreated patients.
If, at a daily intake of 2.0g of methyldopa, effective control of the blood pressure cannot be maintained, it is recommended that a thiazide diuretic is added in small increments or the dose of methyldopa is reduced by 50% as soon as the thiazide is added. Whatever the case, constant blood pressure monitoring is essential.
Methyldopa is largely excreted by the kidney, therefore, patients with impaired kidney function may respond to smaller doses. Many patients may experience sedation for two or three days when methyldopa therapy is initiated or when the dose is increased.
Tolerance may occur occasionally, and usually between the second and third month after initiation of treatment. Also, methyldopa has a short duration of action. Withdrawal is followed by a gradual return to previous blood pressure levels, usually within 48 hours.
Children: Initial dosage is 10mg/kg of body weight daily in two to four doses. The daily dosage is then increased or decreased until an adequate response is achieved. The maximum daily dose is 65mg/kg or 3.0g, whichever is less.
Active hepatic disease, such as acute hepatitis or active cirrhosis or history of liver disease or dysfunction. Hypersensitivity.
See also usage in pregnancy.
Acquired haemolytic anaemia has occurred rarely in association with therapy with methyldopa. Should clinical symptoms indicate the possibility of anaemia, haemoglobin and/or haematocrit determinations should be performed. If anaemia is present, appropriate laboratory studies should be done to determine if haemolysis is present.
Evidence of haemolytic anaemia is an indication for discontinuation of the medicine. Discontinuation of methyldopa alone or in the initiation of adrenocortical steroids usually results in a prompt remission of anaemia. Rarely, however, fatalities have occurred.
Some patients on continued therapy with methyldopa develop a positive direct Coombs test. The exact mechanism and significance of this phenomenon has not been established. The incidence of positive Coombs test as reported by different investigators has averaged between 10-20%.
If a positive test is to develop, it usually does within twelve months following start of therapy with methyldopa. This phenomenon is also dose-related with the lowest incidence occurring in patients receiving 1g of methydopa or less per day. Reversal of the positive Coombs occurs within weeks to months after discontinuation of the medicine.
Should the need for transfusion arise, prior knowledge of a positive Coombs reaction will aid in evaluation of the cross match. Patients with a positive Coombs test at the time of cross match may exhibit an incompatible minor cross match. When this occurs, an indirect Coombs test should be performed. If negative, transfusion with such blood which is otherwise compatible in the major cross match may be carried out. However, if positive, the advisability of transfusion with blood compatible in the major cross match should be determined by a haematologist or expert in transfusion problems.
Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the medicine. Rare cases of clinical agranulocytosis have been reported. In each instance the white cell count returned to normal upon discontinuing the medicine.
Occasionally, fever has occurred within the first three weeks of administration of methyldopa. In some cases this fever has been associated with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, cephalin cholesterol, flocculation, prothrombin time, and bromsulphthalein retention.
Jaundice, with or without fever, may occur also, with onset usually within the first two or three months of therapy. 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 medicine hypersensitivity. These changes have also been seen with other antihypertensive therapy in the absence of methyldopa and the significance is not established. A determination of hepatic function and a white cell and differential blood count should be done at intervals during the first six to twelve weeks of therapy, or whenever an unexplained fever may occur.
If fever, abnormalities in liver function tests, or jaundice appear, therapy with methyldopa should be stopped. If related to methyldopa the temperature and abnormalities in liver function have usually reverted to normal when the medicine was discontinued.
Since methyldopa will cause fluorescence in urine samples at the same wave lengths as catecholamines, spuriously high concentrations of urinary catecholamines may be reported. This will interfere with the diagnosis of phaeochromatocytoma. Methyldopa will not serve as a diagnostic test for phaeochromcytoma.
It is important to recognise this phenomenon before a patient with possible phaeochromocytoma is subjected to surgery. Methyldopa does not interfere with the measurement of vanillyl mandelic acid (VMA), a test for phaeochromotyoma, by those methods which convert VMA to vanillin.
Involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease in rare instances. Should such movements occur, stop therapy. Patients may require reduced doses of anaesthetics while on methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
Hypertension has recurred occasionally after dialysis in patients given methyldopa because the medicine is removed by this procedure.
Use in pregnancy: Because, at this time, clinical experience and follow-up studies in pregnancy have been limited, methyldopa is not recommended for use in pregnant patients. Therefore, the usage of this medicine when pregnancy is present or suspected requires that the benefits be weighed against the possible hazards to the foetus.
Reproduction studies with methyldopa including three successive generations in mice and two successive litters in rats, and teratogenic studies in rabbits, did not reveal adverse effects.
The most common side effect of methyldopa is drowsiness. Other common side effects include depression, psychic effects, impaired mental acuity, nightmares, nausea, dryness of the mouth, nasal stuffiness, weakness, dizziness, light-headedness, headache, oedema, and disorders of sexual function.
More rarely, black or sore tongue, breast enlargement, lactation, hyperprolactinaemia, pancreatitis, salivary gland inflammation, paraesthesia, Bell's palsy, parkinsonism, gastrointestinal upsets, diarrhoea, constipation, fever, mild arthralgia, myalgia, uraemia, myocarditis, and aggravation of angina pectoris may occur.
There may be bradycardia and postural hypotension.
Involuntary choreathetotic movements have occurred in patients with severe bilateral cerebrovascular disease. Eczematous rashes and lichenoid and granulomatous skin eruptions have occurred.
Thrombocytopenia, leucopenia, granulocytopenia, and haemolytic anaemia have also been reported. A positive response to the direct Coombs test may occur in 10 to 20% of patients on prolonged therapy, usually without evidence of haemolysis. Fever may occur within the first few weeks of therapy and may be accompanied by eosinophila and abnormal liver function tests. Jaundice with or without fever may occur. Liver damage may also develop after long-term administration and, rarely, fatal hepatic necrosis has been reported. A condition resembling systemic lupus erythematosus has been reported.
Methyldopa may occasionally cause urine to darken on exposure to the air because of the breakdown of the medicine or its metabolites.
Methyldopa will potentiate the antihypertensive effects of other antihypertensive agents. Methyldopa can interfere with some laboratory tests (see Warnings and Precautions).
Acute overdosage may produce acute hypotension with other major responses attributable to brain and gastrointestinal malfunction. Chronic overdosage may produce hypotension and syncope, especially in the presence of advanced arteriosclerosis. There is no specific antidote. If ingestion is recent, gastric lavage or emesis may reduce absorption.
If ingestion was earlier, infusions may be helpful to promote urinary excretion. Otherwise, management includes symptomatic treatment with special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function, and cerebral activity. Administration of sympathomimetic medicines may be indicated.
Protect from light and moisture. Store below 30°C. Keep out of reach of children.
Prescription Medicine.
125mg, 250mg and 500mg tablets: 100s.
Methyldopa is levo-3-(3,4-dihydroxy-phenyl)-2-methylalanine. Its molecular formula and weight are C10H13NO4,11/2H2O and 283.24 respectively.
Toxicity: Subacute oral toxicity studies in dogs indicated no pertinent histopathologic changes when methyldopa was administered in dosages up to 2000mg/kg/day for four weeks, although inanition was observed at the maximal dosage.
Chronic oral toxicity studies conducted for long periods at dosages up to and including 1800mg/kg/day for rats, 1350mg/kg/day for dogs and 1000mg/kg/day for monkeys elicited no histopathologic or chemical changes of clinical significance.
The mechanism of the development of a positive Coombs test has been under study in several species of animals including primates.
The results indicate that a positive direct Coombs test of unknown etiology has been observed occasionally in dogs and rats at high doses of methyldopa. Further, in one dog, anaemia and arrest of erythropoietic maturation at the prorubricyterubricyte level occurred during two periods of treatment with methyldopa at doses of 1000mg/kg/day and one period of treatment at doses of 20mg/kg/day.
On each occasion, withdrawal of the medicine was followed by a return of the haemoglobin to pretest levels.
Other ingredients of the tablets are: Starch, Microcrystalline cellulose, Magnesium stearate, Povidone, Carboxymethyl-starch, Ethyl cellulose, Hydroxypropyl methyl-cellulose, distilled acetylated monoglycerides, Opacoat yellow NA-2124 and Opaspray K-1-2013.
Douglas Pharmaceuticals Ltd
P O Box 45-027
AUCKLAND
Ph: (09) 835-0660
Fax: (09) 835-0665
18 March 1999