Aldoril (Methyldopa – Hydrochlorothiazide)



Methyldopa – Hydrochlorothiazide


Action And Clinical Pharmacology: In Aldoril, 2 antihypertensive agents with complementary properties are combined for the treatment of hypertension.

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.

Hydrochlorothiazide: Hydrochlorothiazide, when given orally, is an effective diuretic and antihypertensive. Hydrochlorothiazide interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.

Aldoril: The concomitant use of methyldopa and hydrochlorothiazide, as provided in Aldoril, frequently produces a more pronounced antihypertensive response than when either compound is the sole therapeutic agent. In those cases of hypertensive vascular disease where sodium and water retention is a problem, the hydrochlorothiazide component of Aldoril will help control the fluid imbalance.

Indications And Clinical Uses: 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.

Aldoril is recommended for maintenance therapy of patients with essential hypertension.

Contra-Indications: Active hepatic disease, such as acute hepatitis and active cirrhosis, is a contraindication for use of methyldopa.

Because of the diuretic action of hydrochlorothiazide, Aldoril is contraindicated in anuria. See also Warnings, Pregnancy and Lactation.

This product is also contraindicated in the presence of hypersensitivity to any component of the produce (see Supplied), including hepatic disorders or hemolytic anemia associated with previous methyldopa therapy or sulfonamide-derived drugs.

Manufacturers’ Warnings In Clinical States: Methyldopa: It is important to recognize that 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. Read this section carefully to understand these reactions. 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’ 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. 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. Liver biopsy, performed in several patients with liver dysfunction, showed a microscopic focal necrosis compatible with drug hypersensitivity. 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.

Hydrochlorothiazide: Azotemia may be precipitated or increased by hydrochlorothiazide. 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.

Hydrochlorothiazide adds to or potentiates the action of other antihypertensive drugs. Therefore, the dosage of these agents, especially ganglionic or peripheral adrenergic blocking drugs, must be reduced by at least 50% as soon as hydrochlorothiazide is added to the regimen.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported for sulfonamide derivatives, including thiazides.

Pregnancy and Lactation: The routine use of diuretics in otherwise healthy pregnant women with or without mild edema is not indicated and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Use of any drug in women who are or may become pregnant requires that anticipated benefits be weighed against possible risks. Methyldopa and thiazides cross the placental barrier and appear in cord blood. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Lactation: Methyldopa and thiazides appear in breast milk. If use of Aldoril is deemed essential, the patient should stop nursing.

Precautions: Methyldopa: 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.

Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.

Drug Interactions: When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side effects or unusual manifestations of drug idiosyncrasy. A paradoxical pressor response has been reported with i.v. methyldopate HCl.

The adrenergic receptors remain sensitive during treatment with methyldopa. Dialysis removes methyldopa; therefore, hypertension may recur after this procedure.

Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, usually it can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.

Hydrochlorothiazide: When creatinine clearance falls below 30 mL/min, thiazide diuretics are ineffective.

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of renal disease, the diuretic should be discontinued.

Careful check should be kept for signs of fluid 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, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop with hydrochlorothiazide as with any other potent diuretic, especially with brisk diuresis, after prolonged therapy or when severe cirrhosis is present. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hepatic Disease: 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.

Hypokalemia may be avoided or treated by use of potassium chloride or giving foods with a high potassium content. Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease).

Diuretic induced hyponatremia is usually mild and asymptomatic. In a few patients hyponatremia may become severe and symptomatic. Such patients require immediate attention and appropriate treatment.

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.

Pathological changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen.

Hyperuricemia may occur or gout may be precipitated in certain patients receiving thiazide therapy.

Thiazide therapy may impair glucose tolerance.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Increases in cholesterol and triglyceride levels may be associated with thiazide therapy.

Drug Interactions: When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs: additive effect. Diuretic theapy should be discontinued for 2 to 3 days prior to initiation of therapy with an ACE-inhibitor to reduce the likelihood of first dose hypotension.

Corticosteroids, ACTH: intensified electrolyte depletin, particularly hypokalemia.

Pressor Amines (e.g., epinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine): possible increased responsiveness to the muscle relaxant.

Lithium: generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Nonsteroidal Anti-inflammatory Drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

Drug/Laboratory Test Interactions : Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see Precautions).

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: liver disorders including hepatitis, abnormal liver function tests, jaundice.

Hematologic: positive Coombs’ test, hemolytic anemia, bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia. Positive tests for antinuclear antibody, LE cells, and rheumatoid factor.

Allergic: drug-related fever and lupus-like syndrome, myocarditis, pericarditis.

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, with or without joint swelling, myalgia.

Hydrochlorothiazide: 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.

Metabolic: hyperglycemia, glycosuria, hyperuricemia, electrolyte imbalance.

Renal: renal dysfunction, interstitial nephritis, renal failure.

Others: muscle spasm, weakness, restlessness, transient blurred vision.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

In the event of overdosage, symptomatic and supportive measures should be employed. If ingestion is recent, emesis should be induced or gastric lavage performed. Dehydration, electrolyte imbalance, hepatic coma and hypotension should be corrected by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.

Dosage And Administration: Dosage must be determined for individual patients by titration of each component separately. Where the fixed combination in Aldoril provides the dosage so determined Aldoril may be used for maintenance therapy. If during maintenance therapy dosage adjustment is necessary, it is advisable to use the individual drugs.

The usual maintenance dose is 1 to 4 tablets twice daily.

Although occasional patients have responded to higher doses, the maximal recommended daily dose is 3 g of methyldopa and 100 to 200 mg of hydrochlorothiazide. Where maximum dosage has provided inadequate blood pressure control, it is suggested that additional methyldopa be given as the single drug to obtain the maximal blood pressure response.

When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid excessive reduction in blood pressure.

Patients with impaired kidney function may respond to smaller doses of the drug since methyldopa is excreted primarily by the kidney. Lower doses may also be required in elderly patients.

Tolerance 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. Patients may require titration on individual drugs to restore effective blood pressure control.

Availability And Storage: Aldoril-15: Each biconvex-shaped, salmon-colored, film-coated tablet, engraved MSD 423 on one side and Aldoril on the other, contains: methyldopa 250 mg and hydrochlorothiazide 15 mg. Nonmedicinal ingredients: carnauba wax, citric acid, colloidal silicon dioxide, dibasic calcium phosphate, edetate calcium disodium, ethylcellulose, guar gum, hydroxypropyl methylcellulose, magnesium stearate, powdered cellulose, propylene glycol, red ferric oxide, talc and titanium dioxide. Bottles of 100.

Aldoril-25: Each biconvex-shaped, white, film-coated tablet, engraved MSD 456 on one side and Aldoril on the other, contains: methyldopa 250 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: carnauba wax, citric acid, colloidal silicon dioxide, dibasic calcium phosphate, edetate calcium disodium, ethylcellulose, guar gum, hydroxypropyl methylcellulose, magnesium stearate, powdered cellulose, propylene glycol, talc and titanium dioxide. Bottles of 100.

Store at 15 to 30°C. Protect from light.

ALDORIL®-15 ALDORIL®-25 MSD Methyldopa – Hydrochlorothiazide Antihypertensive

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