aldomet supsension

DESCRIPTION
ALDOMET * (Methyldopa) is an antihypertensive drug aldomet supsension.

Methyldopa, the L -isomer of alpha-methyldopa is levo-3-(3,4 - dihydroxyphenyl)-2-methylalanine aldomet supsension. Its empirical formula is C 10 H 13 NO 4 , with a molecularweight of 211.22, and its structural formula is:

Methyldopa is a white to yellowish white, odorless fine powder, and is solublein water aldomet supsension.

ALDOMET is supplied as tablets, for oral use, in three strengths: 125 mg, 250mg, or 500 mg of methyldopa per tablet aldomet supsension. Inactive ingredients in the tabletsare: calcium disodium edetate, cellulose, citric acid, colloidal silicon dioxide,D&C Yellow 10, ethylcellulose, guar gum, hydroxypropyl methylcellulose,iron oxide, magnesium stearate, propylene glycol, talc, and titanium dioxide aldomet supsension.

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*Registered trademark of MERCK & CO., INC aldomet supsension.

CLINICAL PHARMACOLOGY

ALDOMET is an aromatic-amino-acid decarboxylase inhibitor in animals and inman aldomet supsension. Although the mechanism of action has yet to be conclusively demonstrated,the antihypertensive effect of methyldopa probably is due to its metabolismto alpha-methylnorepinephrine, which then lowers arterial pressure by stimulationof central inhibitory alpha-adrenergic receptors, false neurotransmission, and/orreduction of plasma renin activity aldomet supsension. Methyldopa has been shown to cause a netreduction in the tissue concentration of serotonin, dopamine, norepinephrine,and epinephrine aldomet supsension.

Only methyldopa, the L -isomer of alpha-methyldopa, has the ability to inhibitdopa decarboxylase and to deplete animal tissues of norepinephrine aldomet supsension. In man theantihypertensive activity appears to be due solely to the L -isomer aldomet supsension. About twicethe dose of the racemate ( DL -alpha-methyldopa) is required for equal antihypertensiveeffect aldomet supsension.

Methyldopa has no direct effect on cardiac function and usually does not reduceglomerular filtration rate, renal blood flow, or filtration fraction aldomet supsension. Cardiacoutput usually is maintained without cardiac acceleration aldomet supsension. In some patientsthe heart rate is slowed aldomet supsension.

Normal or elevated plasma renin activity may decrease in the course of methyldopatherapy aldomet supsension.

ALDOMET reduces both supine and standing blood pressure aldomet supsension. Methyldopa usuallyproduces highly effective lowering of the supine pressure with infrequent symptomaticpostural hypotension aldomet supsension. Exercise hypotension and diurnal blood pressure variationsrarely occur aldomet supsension.

Pharmacokinetics and Metabolism

The maximum decrease in blood pressure occurs four to six hours after oraldosage aldomet supsension. Once an effective dosage level is attained, a smooth blood pressureresponse occurs in most patients in 12 to 24 hours aldomet supsension. After withdrawal, bloodpressure usually returns to pretreatment levels within 24-48 hours aldomet supsension.

Methyldopa is extensively metabolized aldomet supsension. The known urinary metabolites are: (alpha)-methyldopamono-0-sulfate; 3-0-methyl-(alpha)-methyldopa; 3,4-dihydroxyphenylacetone; (alpha)-methyldopamine;3-0-methyl-(alpha)-methyldopamine and their conjugates aldomet supsension.

Approximately 70% of the drug which is absorbed is excreted in the urine asmethyldopa and its mono-0-sulfate conjugate aldomet supsension. The renal clearance is about 130mL/min in normal subjects and is diminished in renal insufficiency aldomet supsension. The plasmahalf-life of methyldopa is 105 minutes aldomet supsension. After oral doses, excretion is essentiallycomplete in 36 hours aldomet supsension.

Methyldopa crosses the placental barrier, appears in cord blood, and appearsin breast milk aldomet supsension.

INDICATION AND USAGE
Hypertension aldomet supsension.

CONTRAINDICATIONS
ALDOMET 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 hypersensitivity to any component of these products
on therapy with monoamine oxidase (MAO) inhibitors aldomet supsension.

WARNINGS
It is important to recognize that a positive Coombs test, hemolytic anemia,and liver disorders may occur with methyldopa therapy aldomet supsension. The rare occurrencesof hemolytic anemia or liver disorders could lead to potentially fatal complicationsunless properly recognized and managed aldomet supsension. Read this section carefully to understandthese reactions aldomet supsension.
With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positivedirect Coombs test which usually occurs between 6 and 12 months of methyldopatherapy aldomet supsension. Lowest incidence is at daily dosage of 1 g or less aldomet supsension. This on rare occasionsmay be associated with hemolytic anemia, which could lead to potentially fatalcomplications aldomet supsension. One cannot predict which patients with a positive direct Coombstest may develop hemolytic anemia aldomet supsension.

Prior existence or development of a positive direct Coombs test is not in itselfa contraindication to use of methyldopa aldomet supsension. If a positive Coombs test developsduring methyldopa therapy, the physician should determine whether hemolyticanemia exists and whether the positive Coombs test may be a problem aldomet supsension. For example,in addition to a positive direct Coombs test there is less often a positiveindirect Coombs test which may interfere with cross matching of blood aldomet supsension.

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 thereis anemia aldomet supsension. Periodic blood counts should be done during therapy to detect hemolyticanemia aldomet supsension. It may be useful to do a direct Coombs test before therapy and at 6and 12 months after the start of therapy aldomet supsension.

If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa andthe drug should be discontinued aldomet supsension. Usually the anemia remits promptly aldomet supsension. If not,corticosteroids may be given and other causes of anemia should be considered aldomet supsension. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted aldomet supsension.

When methyldopa causes Coombs positivity alone or with hemolytic anemia, thered cell is usually coated with gamma globulin of the IgG (gamma G) class only aldomet supsension. The positive Coombs test may not revert to normal until weeks to months aftermethyldopa is stopped aldomet supsension.

Should the need for transfusion arise in a patient receiving methyldopa, botha direct and an indirect Coombs test should be performed aldomet supsension. In the absence ofhemolytic anemia, usually only the direct Coombs test will be positive aldomet supsension. A positivedirect Coombs test alone will not interfere with typing or cross matching aldomet supsension. Ifthe indirect Coombs test is also positive, problems may arise in the major crossmatch and the assistance of a hematologist or transfusion expert will be needed aldomet supsension.

Occasionally, fever has occurred within the first 3 weeks of methyldopa therapy,associated in some cases with eosinophilia or abnormalities in one or more liverfunction tests, such as serum alkaline phosphatase, serum transaminases (SGOT,SGPT), bilirubin, and prothrombin time aldomet supsension. Jaundice, with or without fever, mayoccur with onset usually within the first 2 to 3 months of therapy aldomet supsension. In somepatients the findings are consistent with those of cholestasis aldomet supsension. In others thefindings are consistent with hepatitis and hepatocellular injury aldomet supsension.

Rarely, fatal hepatic necrosis has been reported after use of methyldopa aldomet supsension. Thesehepatic changes may represent hypersensitivity reactions aldomet supsension. Periodic determinationsof hepatic function should be done particularly during the first 6 to 12 weeksof therapy or whenever an unexplained fever occurs aldomet supsension. If fever, abnormalitiesin liver function tests, or jaundice appear, stop therapy with methyldopa aldomet supsension. Ifcaused by methyldopa, the temperature and abnormalities in liver function characteristicallyhave reverted to normal when the drug was discontinued aldomet supsension. Methyldopa should notbe reinstituted in such patients aldomet supsension.

Rarely, a reversible reduction of the white blood cell count with a primaryeffect on the granulocytes has been seen aldomet supsension. The granulocyte count returned promptlyto normal on discontinuance of the drug aldomet supsension. Rare cases of granulocytopenia havebeen reported aldomet supsension. In each instance, upon stopping the drug, the white cell countreturned to normal aldomet supsension. Reversible thrombocytopenia has occurred rarely aldomet supsension.

PRECAUTIONS
General

Methyldopa should be used with caution in patients with a history of previousliver disease or dysfunction (see WARNINGS ) aldomet supsension.

Some patients taking methyldopa experience clinical edema or weight gain whichmay be controlled by use of a diuretic aldomet supsension. Methyldopa should not be continued ifedema progresses or signs of heart failure appear aldomet supsension.

Hypertension has recurred occasionally after dialysis in patients given methyldopabecause the drug is removed by this procedure aldomet supsension.

Rarely involuntary choreoathetotic movements have been observed during therapywith methyldopa in patients with severe bilateral cerebrovascular disease aldomet supsension. Shouldthese movements occur, stop therapy aldomet supsension.

Laboratory Tests

Blood count, Coombs test, and liver function tests are recommended before initiatingtherapy and at periodic intervals (see WARNINGS ) aldomet supsension.

Drug Interactions

When methyldopa is used with other antihypertensive drugs, potentiation ofantihypertensive effect may occur aldomet supsension. Patients should be followed carefully todetect side reactions or unusual manifestations of drug idiosyncrasy aldomet supsension.

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

When methyldopa and lithium are given concomitantly the patient should be carefullymonitored for symptoms of lithium toxicity aldomet supsension. Read the circular for lithium preparations aldomet supsension.

Several studies demonstrate a decrease in the bioavailability of methyldopawhen it is ingested with ferrous sulfate or ferrous gluconate aldomet supsension. This may adverselyaffect blood pressure control in patients treated with methyldopa aldomet supsension. Coadministrationof methyldopa with ferrous sulfate or ferrous gluconate is not recommended aldomet supsension.

Monoamine oxidase (MAO) inhibitors: see CONTRAINDICATIONS aldomet supsension.

Drug/Laboratory Test Interactions

Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstatemethod, serum creatinine by the alkaline picrate method, and SGOT by colorimetricmethods aldomet supsension. Interference with spectrophotometric methods for SGOT analysis hasnot been reported aldomet supsension.

Since methyldopa causes fluorescence in urine samples at the same wave lengthsas catecholamines, falsely high levels of urinary catecholamines may be reported aldomet supsension. This will interfere with the diagnosis of pheochromocytoma aldomet supsension. It is importantto recognize this phenomenon before a patient with a possible pheochromocytomais subjected to surgery aldomet supsension. Methyldopa does not interfere with measurement of VMA(vanillylmandelic acid), a test for pheochromocytoma, by those methods whichconvert VMA to vanillin aldomet supsension. Methyldopa is not recommended for the treatment ofpatients with pheochromocytoma aldomet supsension. Rarely, when urine is exposed to air after voiding,it may darken because of breakdown of methyldopa or its metabolites aldomet supsension.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was seen when methyldopa was given fortwo years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats,respectively, when compared on the basis of body weight; 2.5 and 0.6 times themaximum recommended human dose in mice and rats, respectively, when comparedon the basis of body surface area; calculations assume a patient weight of 50kg) aldomet supsension.

Methyldopa was not mutagenic in the Ames Test and did not increase chromosomalaberration or sister chromatid exchanges in Chinese hamster ovary cells aldomet supsension. Thesein vitro studies were carried out both with and without exogenous metabolicactivation aldomet supsension.

Fertility was unaffected when methyldopa was given to male and female ratsat 100 mg/kg/day (1.7 times the maximum daily human dose when compared on thebasis of body weight; 0.2 times the maximum daily human dose when compared onthe basis of body surface area) aldomet supsension. Methyldopa decreased sperm count, sperm motility,the number of late spermatids and the male fertility index when given to malerats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dosewhen compared on the basis of body weight; 0.5 and 1 times the maximum dailyhuman dose when compared on the basis of body surface area) aldomet supsension.

Pregnancy

Pregnancy Category B aldomet supsension. Reproduction studies performed with methyldopa at oraldoses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealedno evidence of harm to the fetus aldomet supsension. These doses are 16.6 times, 3.3 times and1.7 times, respectively, the maximum daily human dose when compared on the basisof body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when comparedon the basis of body surface area; calculations assume a patient weight of 50kg aldomet supsension. There are, however, no adequate and well-controlled studies in pregnantwomen in the first trimester of pregnancy aldomet supsension. Because animal reproduction studiesare not always predictive of human response, ALDOMET should be used during pregnancyonly if clearly needed aldomet supsension.

Published reports of the use of methyldopa during all trimesters indicate thatif this drug is used during pregnancy the possibility of fetal harm appearsremote aldomet supsension. In five studies, three of which were controlled, involving 332 pregnanthypertensive women, treatment with ALDOMET was associated with an improved fetaloutcome aldomet supsension. The majority of these women were in the third trimester when methyldopatherapy was begun aldomet supsension.

In one study, women who had begun methyldopa treatment between weeks 16 and20 of pregnancy gave birth to infants whose average head circumference was reducedby a small amount (34.2 ± 1.7 cm vs aldomet supsension. 34.6 ± 1.3 cm [mean ±1 S.D.]) aldomet supsension. Long-term follow up of 195 (97.5%) of the children born to methyldopa-treatedpregnant women (including those who began treatment between weeks 16 and 20)failed to uncover any significant adverse effect on the children aldomet supsension. At four yearsof age, the developmental delay commonly seen in children born to hypertensivemothers was less evident in those whose mothers were treated with methyldopaduring pregnancy than those whose mothers were untreated aldomet supsension. The children of thetreated group scored consistently higher than the children of the untreatedgroup on five major indices of intellectual and motor development aldomet supsension. At age sevenand one-half developmental scores and intelligence indices showed no significantdifferences in children of treated or untreated hypertensive women aldomet supsension.

Nursing Mothers

Methyldopa appears in breast milk aldomet supsension. Therefore, caution should be exercised whenmethyldopa is given to a nursing woman aldomet supsension.

Pediatric Use

There are no well-controlled clinical trials in pediatric patients aldomet supsension. Informationon dosing in pediatric patients is supported by evidence from published literatureregarding the treatment of hypertension in pediatric patients aldomet supsension. (See DOSAGE ANDADMINISTRATION .)

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