SUPRES®
Merck Frosst
Methyldopa-Chlorothiazide
Antihypertensive
Action and Clinical
Methyldopa: Methyldopa, an antihypertensive agent, is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine and epinephrine.
In man the antihypertensive activity appears to be due solely to the L-isomer.
Methyldopa usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension.
Exercise hypotension and diurnal blood pressure variations rarely occur.
Since methyldopa has a relatively short duration of action, withdrawal is followed by a gradual return to previous blood pressure levels, usually within 48Â hours. This is not complicated by an overshoot of blood pressure.
Chlorothiazide: Chlorothiazide, when given orally is an effective diuretic and antihypertensive agent. Chlorothiazide interferes with the renal tubular mechanism of electrolyte reabsorption. This compound increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
While this compound is predominantly a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.
Chlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs.
Chlorothiazide does not affect normal blood pressure. The mechanism of its antihypertensive action is not known. Lowering of the sodium content of arteriolar smooth muscle cells and diminished response to norepinephrine have been postulated.
Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.
Indications And Clinical Uses:
For maintenance therapy of patients with essential hypertension.
Fixed-dose combination drugs are not indicated for initial therapy. Patients should be titrated on the individual drugs. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. If during maintenance therapy dosage adjustment is necessary it is advisable to use the individual drugs.
Contra-Indications:
Active hepatic disease, such as acute hepatitis and active cirrhosis. If previous methyldopa therapy has been associated with liver disorders or hemolytic anemia (see Warnings).:
Because of the diuretic action of chlorothiazide, Supres is contraindicated in anuria. See also usage in Pregnancy and Lactation under Warnings.
This product is contraindicated in persons known to be sensitive to chlorothiazide or methyldopa.
Warnings in Clinical States:
Methyldopa: A positive Coombs’ test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed.
With prolonged methyldopa therapy, 10 to 20% of patients develop a positive direct Coombs’ test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at 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’ positively 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 [AST, ALT], bilirubin, cephalin cholesterol flocculation, prothrombin time, and bromsulphalein retention. 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 of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.
When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. A paradoxical pressor response has been reported with i.v. methyldopate HCI.
Chlorothiazide: Azotemia may be precipitated or increased by chlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, the diuretic should be discontinued.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
Chlorothiazide may add to or potentiate the action of other antihypertensive drugs.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Non-specific small bowel lesions consisting of stenosis with or without ulceration may occur in association with the administration of enteric-coated potassium salts alone or with oral diuretics. These small bowel lesions have caused obstruction, hemorrhage and perforation. Surgery was frequently required and deaths have occurred. Available information tends to implicate enteric-coated potassium salts, although lesions of this type also occur spontaneously. Such preparations should be used only when adequate dietary supplementation is not practical, and should be discontinued immediately if abdominal pain, distension, nausea, vomiting or gastrointestinal bleeding occur.
Pregnancy: Use of any drug in women who are or may become pregnant requires that anticipated benefits be weighed against possible risks. Methyldopa crosses the placental barrier and appears in cord blood. 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.
Thiazides cross the placental barrier and appear in cord blood. When chlorothiazide is used in pregnancy or in women of child-bearing age, the potential benefits of the drug should be weighed against the possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
Lactation: Methyldopa and chlorothiazide appear in breast milk. Patients taking Supres should stop nursing.
Warnings in Clinical States:
PrecautionsMethyldopa: Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction (see Warnings).
Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and AST by colorimetric methods. Interference with spectrophotometric methods for AST 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 (vanillylmandelic 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.
Chlorothiazide: Careful check should be kept for signs of fluid and electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, hypokalemia and hypomagnesemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances.
Hypokalemia may develop with chlorothiazide, as with any other potent diuretic, especially with brisk diuresis, when severe cirrhosis is present, during concomitant steroid or ACTH administration, or after prolonged therapy. Interference with adequate electrolyte intake will contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effect of digitalis (e.g., increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Thiazide drugs may increase the responsiveness to tubocurarine.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. Chlorothiazide may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.
Insulin requirements in diabetic patients may be increased, decreased or unchanged. Diabetes mellitus which has been latent may become manifest during thiazide administration.
Lithium should generally not be given to patients receiving diuretics, since the risk of lithium toxicity is very high in such patients.
Adverse Reactions:
Methyldopa: 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, prolonged carotid sinus hypersensitivity, 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, colitis, mild dryness of mouth, sore or “black” tongue, pancreatitis, sialadenitis.
Hepatic: abnormal liver function tests, jaundice, hepatocellular damage.
Hematologic: positive Coombs’ test, hemolytic anemia, bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia. Positive tests for antinuclear antibody, LEÂ cells, and rheumatoid factor.
Allergic: drug-related fever, lupus-like syndrome, myocarditis.
Dermatologic: rash as in eczema or lichenoid eruption, toxic epidermal necrolysis.
Others: nasal stuffiness, rise in BUN, breast enlargement, gynecomastia, lactation, hyperprolactinemia, amenorrhea, impotence, decreased libido, mild arthralgia, myalgia.
Chlorothiazide: Gastrointestinal: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis.
CNS: dizziness, vertigo, paresthesias, headache, xanthopsia.
Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.
Cardiovascular: orthostatic hypotension (may be aggravated by alcohol, barbiturates or narcotics).
Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.
Others: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, transient blurred vision.
Whenever adverse reactions are moderate or severe, dosage should be reduced or therapy withdrawn.
Symptoms And Treatment Of Overdose:
OverdoseSymptoms: Methyldopa: 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 presence of advanced arteriosclerosis.
Chlorothiazide: Overdosage may lead to excessive diuresis with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration.
Signs are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, gastrointestinal disturbances, mental confusion, delirium, convulsions, shock, coma.
If digitalis has also been administered, hypokalemia may accentuate myocardial abnormalities (e.g. cardiac arrhythmias).
Chlorothiazide may precipitate hepatic coma in cirrhotics, potentiate other antihypertensive agents, and decrease responsiveness to norepinephrine.
Treatment: There is no specific antidote.
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, dehydration, paralytic ileus, urinary function, hepatic coma, and cerebral activity. Administration of sympathomimetic drugs (e.g. norepinephrine, epinephrine) may be indicated. Administer oxygen or artificial respiration for respiratory impairment. When chronic overdosage is suspected, the drug should be discontinued.
Dosage And Administration:
Therapy is usually begun by administering 1 tablet twice daily during the first 48 hours. Thereafter, the daily dosage may be adjusted by the deletion of 1 or addition of 1 or 2 tablets, preferably at intervals of not less than two days, until an adequate response has been achieved. Once the effective dosage range has been attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. Although occasional patients have responded to higher doses, the maximal recommended daily dose is 3 g of methyldopa and 1 to 2 g of chlorothiazide. Where maximum doses have provided inadequate blood pressure control, it is suggested that additional methyldopa be given as the single drug to obtain the maximal blood pressure response.
Transfer from other Antihypertensive Agents: Supres may be introduced into the antihypertensive regimen of patients on treatment with thiazides by stopping the thiazides.
Therapy with Supres may be initiated in patients on ganglion-blocking agents or guanethidine by initially decreasing their dosage by 50% and by subsequent gradual withdrawal as Supres is gradually added. The gradual addition of Supres will provide a smooth transition with optimal control of blood pressure.
Therapy with Supres may be initiated in most other patients already on treatment with other antihypertensive agents (e.g., reserpine, other rauwolfia derivatives, hydralazine and antihypertensive agents of the monoamine oxidase inhibitor group) by terminating these antihypertensive medications. Following such previous antihypertensive therapy, Supres should be limited to an initial dose of one tablet daily and increased as required at intervals of not less than 2 days.
General Treatment Considerations: Methyldopa is largely excreted by the kidney. Therefore, patients with impaired kidney function may respond to smaller doses of the drug than patients with normal kidney function. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease; this may be avoided by lower doses of Supres.
Many patients experience sedation for 2 or 3 days when therapy with Supres is started or when the dose is increased. The sedation can be expected to disappear after an effective maintenance dosage has been achieved. When increasing the dosage, it may be desirable to start with the evening dose to minimize the sedative effect without exaggerating morning postural hypotension.
Tolerance to Supres may occur occasionally as either an early or late event in treatment, but it is more likely to occur between the second and third month after initiation of therapy. Increasing the dosage of Supres or either methyldopa or chlorothiazide independently frequently will restore effective blood pressure control.
Since methyldopa and chlorothiazide have a relatively short duration of antihypertensive effect, withdrawal of Supres is followed by a gradual return to pretreatment blood pressure levels, usually within 48Â hours. This is not complicated by an overshoot of blood pressure.
Availability And Storage:
Supres-150: Each oval, biconvex shaped, beige film-coated tablet, with a phi mark on one side, contains: methyldopa 250 mg and chlorothiazide 150 mg. Gluten-, lactose- and tartrazine-free. Bottles of 100.
Supres-250: Each oval, biconvex shaped, green film-coated tablet, with a phi mark on one side, contains: methyldopa 250 mg and chlorothiazide 250 mg. Gluten-, lactose- and tartrazine-free. Bottles of 100.
SUPRES® Merck Frosst Methyldopa-Chlorothiazide Antihypertensive
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