aldomet fever

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

Methyldopa, the L -isomer of alpha-methyldopa is levo-3-(3,4 - dihydroxyphenyl)-2-methylalanine aldomet fever. 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 fever.

ALDOMET is supplied as tablets, for oral use, in three strengths: 125 mg, 250mg, or 500 mg of methyldopa per tablet aldomet fever. 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 fever.

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

CLINICAL PHARMACOLOGY

ALDOMET is an aromatic-amino-acid decarboxylase inhibitor in animals and inman aldomet fever. 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 fever. Methyldopa has been shown to cause a netreduction in the tissue concentration of serotonin, dopamine, norepinephrine,and epinephrine aldomet fever.

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

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

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

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

Pharmacokinetics and Metabolism

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

Methyldopa is extensively metabolized aldomet fever. 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 fever.

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

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

INDICATION AND USAGE
Hypertension aldomet fever.

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 fever.

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

Prior existence or development of a positive direct Coombs test is not in itselfa contraindication to use of methyldopa aldomet fever. 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 fever. 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 fever.

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

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

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 fever. The positive Coombs test may not revert to normal until weeks to months aftermethyldopa is stopped aldomet fever.

Should the need for transfusion arise in a patient receiving methyldopa, botha direct and an indirect Coombs test should be performed aldomet fever. In the absence ofhemolytic anemia, usually only the direct Coombs test will be positive aldomet fever. A positivedirect Coombs test alone will not interfere with typing or cross matching aldomet fever. 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 fever.

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 fever. Jaundice, with or without fever, mayoccur with onset usually within the first 2 to 3 months of therapy aldomet fever. In somepatients the findings are consistent with those of cholestasis aldomet fever. In others thefindings are consistent with hepatitis and hepatocellular injury aldomet fever.

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

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

PRECAUTIONS
General

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

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

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

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

Laboratory Tests

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

Drug Interactions

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

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

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

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

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

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 fever. Interference with spectrophotometric methods for SGOT analysis hasnot been reported aldomet fever.

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

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 fever.

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

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 fever. 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 fever.

Pregnancy

Pregnancy Category B aldomet fever. 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 fever. 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 fever. There are, however, no adequate and well-controlled studies in pregnantwomen in the first trimester of pregnancy aldomet fever. Because animal reproduction studiesare not always predictive of human response, ALDOMET should be used during pregnancyonly if clearly needed aldomet fever.

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 fever. In five studies, three of which were controlled, involving 332 pregnanthypertensive women, treatment with ALDOMET was associated with an improved fetaloutcome aldomet fever. The majority of these women were in the third trimester when methyldopatherapy was begun aldomet fever.

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 fever. 34.6 ± 1.3 cm [mean ±1 S.D.]) aldomet fever. 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 fever. 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 fever. The children of thetreated group scored consistently higher than the children of the untreatedgroup on five major indices of intellectual and motor development aldomet fever. At age sevenand one-half developmental scores and intelligence indices showed no significantdifferences in children of treated or untreated hypertensive women aldomet fever.

Nursing Mothers

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

Pediatric Use

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

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