Apo-Methyldopa

Apo-Methyldopa

methyldopa

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Methyldopa.
Description
Each tablet contains methyldopa 250 mg.
Gluten- and tartrazine-free.
Action
Pharmacotherapeutic Group: Antihypertensive.
Pharmacology: Methyldopa probably exerts its hypotensive actions through its metabolite, alpha-methylnorepinephrine, which stimulates inhibitory alpha-adrenergic receptors in the CNS and therefore lowers arterial blood pressure.
Reduction in plasma renin activity and inhibition or the decarboxylation of dihydroxyphenylalanine to dopamine and 5-hydroxytryptophane to serotonin may also play a part in methyldopa's hypotensive effect.
Absorption of methyldopa after oral administration is variable and averages about 50%. Plasma levels do not correlate with therapeutic effect. Maximum hypotensive effect occurs in 2 to 3 days after initiation of therapy. Methyldopa is extensively metabolised and its metabolites are excreted in the urine. The elimination is biphasic with a half-life of approximately 1.7 hours and a terminal elimination half-life of 7 to 16 hours.
Indications/Uses
The treatment of arterial hypertension. May be employed in a general treatment program in conjunction with a diuretic and/or other antihypertensive drugs as needed for proper response in patients with hypertension of various severity.
May be employed as the initial agent in the treatment of hypertension in those patients for which treatment should not be started with a diuretic.
Dosage/Direction for Use
Adults: The usual starting dosage is 250 mg 2 or 3 times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than 2 days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. By adjustment of dosage, morning hypotension may be prevented without sacrificing control or afternoon blood pressure.
When methyldopa is given to patients on other antihypertensives, the dose of the agents may need to be adjusted to effect a smooth transition. When methyldopa is added to a thiazide, the dosage of thiazide usually need not be changed. 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 2 g of methyldopa daily. When methyldopa is given with antihypertensives other than thiazides. Its initial dosage should be limited to 500 mg daily in divided doses.
The usual daily maintenance dosage of methyldopa is 500 mg to 2 g in 2 to 4 doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g.
Studies suggest that once optimum dosage is ascertained, the antihypertensive effect can be maintained by giving the same total daily dose once every 24 hours.
Occasionally, tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure.
Smaller doses may be needed in patients with impaired renal function or in older patients with an increased sensitivity or an advanced arteriosclerotic vascular disease (see Precautions).
Children: Initial dosage is based on 10 mg/kg daily in 2 to 4 doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3 g daily, whichever is less.
Overdosage
Symptoms: Acute overdosage may produce acute hypotension with other major responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting).
Potentiation of antihypertensive action may occur in combination therapy with other antihypertensives.
Chronic overdosage may produce hypotension and syncope especially in the presence of advanced arteriosclerosis.
Treatment: Discontinue the drug. If ingestion is recent, gastric lavage or emesis may reduce absorption; when ingestion has been 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 drugs may be indicated.
Contraindications
Active hepatic disease, such as acute hepatitis and active cirrhosis. If previous methyldopa therapy has been associated with liver disorders or hemolytic anemia (see Precautions).
Hypersensitivity to methyldopa.
Special Precautions
With prolonged methyldopa therapy, 10 to 20% or patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is a daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross-matching of blood.
At the start of methyldopa therapy, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
If Coombs positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If hemolytic anemia occurs, the drug should not be reinstituted.
When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the IgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.
Should the need for transfusion arise in a patient receiving methyldopa, both a direct and an indirect Coombs test should be performed on his blood. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
Occasionally, fever has occurred within the first 3 weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin and prothrombin time. Jaundice with or without fever, may occur with onset usually within the first 2 to 3 months of therapy. In some patients the findings are consistent with those of cholestasis.
Rarely, fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determination of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients. Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
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 drug. Rare cases at granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred infrequently.
Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
Methyldopa may interfere with measurement of uric acid by the phosphotungstate method, creatinine by the alkaline picrate method, and SGOT by calorimetric methods. Intereference with spectrophotometric methods for SGOT analysis has not been reported.
Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillymandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.
Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
Patients may require reduced doses of anesthetics when on methyldopa, If hypotension does occur during anesthesia, it usually can 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 drug is removed by this procedure.
Use In Pregnancy & Lactation
Pregnancy: No unusual adverse reactions have been reported in association with the use of methyldopa during pregnancy. Though no obvious teratogenic effects have been reported, the possibility of fetal injury cannot be excluded.
Lactation: Methyldopa is excreted in small amounts in breast milk but is generally tolerated by the nursing infant.
Adverse Reactions
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.
CNS: sedation; headache, asthenia or weakness, dizziness, lightheadedness, symptoms of cerebrovascular insufficiency, paresthesias, parkinsonism, Bell's palsy, decreased mental acuity, involuntary choreoathetotic movements, psychic disturbances including nightmares and reversible mild psychoses or depression, toxic encephalopathy.
Cardiovascular: bradycardia, aggravation of angina pectoris. Orthostatic hypotension (decrease daily dosage). Edema (and weight gain) usually relieved by use of a diuretic, (Discontinue methyldopa if edema progresses or signs of heart failure appear.)
Gastrointestinal: nausea, vomiting, distention, constipation, flatus, diarrhea, mild dryness of mouth, sore or 'black' tongue, pancreatitis. sialadenitis.
Hepatic: abnormal liver function tests, jaundice, liver disorders.
Hematologic: positive Coombs test, hemolytic anemia, leukopenia, granulocytopenia, thrombocytopenia.
Allergic: drug related fever, myocarditis.
Other: nasal stuffiness, rise in BUN, breast enlargement, gynecomastia, lactation, impotence, decreased libido, dermatologic reactions including eczema and lichenoid eruptions, mild arthralgia, myalgia.
Drug Interactions
When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect unusual reactions or manifestations of drug idiosyncrasy. A paradoxical pressor response has been reported with i.v. methyldopa.
Patients receiving methyldopa and phenothiazines or tricyclic antidepressants should be monitored for a possible reduction in hypotensive effect. Adverse psychiatric effects may occur if concomitant therapy with haloperidol is initiated.
Caution For Usage
Incompatibilities: The concurrent use of methyldopa and either alcohol or CNS depressant-producing medications may enhance the CNS depressant effects of either of these drugs or methyldopa.
The use of Coumarin- or indandione-derivative Anticoagulants with Methyldopa may increase the anticoagulant effect of these medications.
The adjustment of anticoagulant dosage based on prothrombin time determinations is recommended.
The use of tricyclic antidepressants may reduce antihypertensive effects of methyldopa. Patients should be monitored to ensure that the proper effect is being obtained.
Antihypertensive effects of methyldopa may be reduced when used concurrent with nonsteroidal Anti-inflammatory analgesics (especially Indomethacin). The patient should be closely monitored to ensure that the desired effect is being achieved.
The use of Appetite suppressants, with the exception of fenfluramine, with methyldopa may decrease the hypotensive effects of methyldopa. Concurrent use of fenfluramine may increase the hypotensive effects of methyldopa.
Concurrent use of Bromocriptine and methyldopa may increase serum prolactin concentrations and interfere with effects of bromocriptine. A dosage adjustment of bromocriptine may be necessary.
It should be noted that estrogen-induced fluid retention tends to increase blood pressure.
Concurrent use of haloperidol with methyldopa may cause unwanted mental effects such as disorientation and slowed or difficult thought processes.
Hypotensive effects may be potentiated when hypotension-producing medications are used concurrently with methyldopa. Although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use.
Concurrent use of levodopa with methyldopa may alter the anti-parkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis.
The use of Monoamine oxidase inhibitors, including furazolidone, pargyline and procarbazine with methyldopa may cause hyperexcitability in patients receiving MAO inhibitors. Headache, severe hypertension and hallucinations have been reported.
The use or Sympathomimetics such as Dobutamine, Dopamine, Ephedrine, Epinephrine, Mephentermine, Metaraminol, Methoxamine, Norepinephrine, Phenylephrine or Phenylpropanolamine concurrent with methyldopa may decrease the hypotensive effect of methyldopa and potentiate the pressor effect of the medications. If concurrent use of norepinephrine or phenylephrine is indicated, caution is required and only very small doses should be administered.
Storage
Store between 15°C and 30°C in a well closed container.
ATC Classification
C02AB01 - methyldopa (levorotatory) ; Belongs to the class of methyldopa, centrally-acting antiadrenergic agents. Used in the treatment of hypertension.
Presentation/Packing
Tab (round, yellow, film-coated) 125 mg x 100's. 250 mg x 100's. 500 mg x 100's, 500's.
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