TABLETS
ALDORIL ^®
(METHYLDOPA-HYDROCHLOROTHIAZIDE)

This fixed combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static, but must be re-evaluated as conditions in each patient warrant.

ALDORIL Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1986 All rights reserved (Methyldopa-Hydrochlorothiazide) combines two antihypertensives: methyldopa and hydrochlorothiazide.

Methyldopa is an antihypertensive and is the L-isomer of alphamethyldopa. It is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine. Its empirical formula is C₁₀H₁₃NO₄, with a molecular weight of 211.22, and its structural formula is:

Methyldopa is a white to yellowish white, odorless fine powder, and is soluble in water.

Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂ and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

ALDORIL is supplied as tablets in four strengths for oral use:

ALDORIL 15, contains 250 mg of methyldopa and 15 mg of hydrochlorothiazide.

ALDORIL 25, contains 250 mg of methyldopa and 25 mg of hydrochlorothiazide.

ALDORIL D30, contains 500 mg of methyldopa and 30 mg of hydrochlorothiazide.

ALDORIL D50, contains 500 mg of methyldopa and 50 mg of hydrochlorothiazide.

Each tablet contains the following inactive ingredients: calcium disodium edetate, calcium phosphate, cellulose, citric acid, colloidal silicon dioxide, ethylcellulose, guar gum, hydroxypropyl methylcellulose, magnesium stearate, propylene glycol, talc, and titanium dioxide. ALDORIL 15 and ALDORIL D30 also contain iron oxide.

Methyldopa 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-methylnorepinephrine, 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.

Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.

Methyldopa has no direct effect on cardiac function and 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. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.

Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Hypertension (see box warning).

ALDORIL is contraindicated in patients:

• with active hepatic disease, such as acute hepatitis and active cirrhosis
• with liver disorders previously associated with methyldopa therapy (see WARNINGS)
• with anuria
• with hypersensitivity to methyldopa, or to hydrochlorothiazide or other sulfonamide-derived drugs
• on therapy with monoamine oxidase (MAO) inhibitors.

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 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at 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.

Before treatment is started 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 the hemolytic anemia is related to methyldopa, 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. 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 three 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 two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.

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.

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.

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

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.

Thiazides may add to or potentiate the action of other antihypertensive drugs.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

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

Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions).

Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of the combination.

Use of diuretics during normal pregnancy is inappropriate 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.

Methyldopa and thiazides appear in breast milk. Therefore, because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Clinical studies of ALDORIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Safety and effectiveness of ALDORIL in pediatric patients have not been established.

The following adverse reactions have been reported and, within each category, are uled in order of decreasing severity.

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. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.

Cardiovascular: Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, orthostatic hypotension (decrease daily dosage), edema or weight gain, bradycardia.

Digestive: Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or “black” tongue, nausea, constipation, distention, flatus, dryness of mouth.

Endocrine: Hyperprolactinemia.

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

Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver function tests (see WARNINGS).

Hypersensitivity: Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.

Nervous System/Psychiatric: Parkinsonism, Bell's palsy, decreased mental acuity, involuntary choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, lightheadedness, paresthesias.

Metabolic: Rise in BUN.

Musculoskeletal: Arthralgia, with or without joint swelling; myalgia.

Respiratory: Nasal stuffiness.

Skin: Toxic epidermal necrolysis, rash.

Urogenital: Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.

Body as a Whole: Weakness.

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis. (See WARNINGS.)

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

Special Senses: Transient blurred vision, xanthopsia.

Urogenital: Impotence.

Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, distention, flatus, diarrhea, nausea, vomiting).

In the event of overdosage, symptomatic and supportive measures should be employed. When 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 special attention to cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.

Sympathomimetic drugs [e.g., levarterenol, epinephrine, ARAMINE (Metaraminol Bitartrate)] may be indicated. Methyldopa is dialyzable. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

The oral LD₅₀ of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat.

DOSAGE MUST BE INDIVIDUALIZED, AS DETERMINED BY TITRATION OF THE INDIVIDUAL COMPONENTS (see box warning). Once the patient has been successfully titrated, ALDORIL may be substituted if the previously determined titrated doses are the same as in the combination. The usual starting dosage is one tablet of ALDORIL 15 two or three times a day or one tablet of ALDORIL 25 two times a day. Alternatively, one tablet of ALDORIL D30 or ALDORIL D50 once daily may be used. Hydrochlorothiazide doses greater than 50 mg daily should be avoided.

Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The usual daily dosage of methyldopa is 500 mg to 2 g. To minimize the sedation associated with methyldopa, start dosage increases in the evening. The maximum recommended daily dose of methyldopa is 3 g.

Occasionally tolerance to methyldopa may occur, usually between the second and third month of therapy. Additional separate doses of methyldopa or replacement of ALDORIL with single entity agents is necessary until the new effective dose ratio is re-established by titration. If ALDORIL does not adequately control blood pressure, additional doses of other agents may be given. When ALDORIL is given with antihypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses and the dose of these other agents may need to be adjusted to effect a smooth transition.

Since both components of ALDORIL have a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.

Since methyldopa is largely excreted by the kidney, 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. (See PRECAUTIONS, Geriatric Use.)

No. 3294 — Tablets ALDORIL 15 are salmon, round, film coated tablets, coded MSD 423 on one side and ALDORIL on the other. Each tablet contains 250 mg of methyldopa and 15 mg of hydrochlorothiazide. They are supplied as follows:

NDC 0006-0423-68 bottles of 100.

No. 3295 — Tablets ALDORIL 25 are white, round, film coated tablets, coded MSD 456 on one side and ALDORIL on the other. Each tablet contains 250 mg of methyldopa and 25 mg of hydrochlorothiazide. They are supplied as follows:

NDC 0006-0456-68 bottles of 100

NDC 0006-0456-82 bottles of 1000.

No. 3362 — Tablets ALDORIL D30 are salmon, oval, film coated tablets, coded MSD 694 on one side and ALDORIL on the other. Each tablet contains 500 mg of methyldopa and 30 mg of hydrochlorothiazide. They are supplied as follows:

NDC 0006-0694-68 bottles of 100.

No. 3363 — Tablets ALDORIL D50 are white, oval, film coated tablets, coded MSD 935 on one side and ALDORIL on the other. Each tablet contains 500 mg of methyldopa and 50 mg of hydrochlorothiazide. They are supplied as follows:

NDC 0006-0935-68 bottles of 100.

Keep container tightly closed. Protect from light, moisture, freezing, –20°C (–4°F) and store at controlled room temperature, 15-30°C (59-86°F).

MERCK& CO., Inc., Whitehouse Station, NJ 08889, USA

Issued February 2004

Printed in USA

7843556