Methyldopa Information
Methyldopa () Description
Methyldopa () is an antihypertensive drug.
Methyldopa () is the L-isomer of alpha-Methyldopa () . Its chemical name is levo-3-(3,4-dihydroxyphenyl)- 2-methylalanine sesquihydrate. Its structural formula is:
CHNO • 1 1/2 HO M.W. 238.24
Methyldopa () is a white to yellowish white, odorless fine powder, and is soluble in water.
Each tablet, for oral administration, contains 250 mg or 500 mg of Methyldopa () . Potency is calculated in the anhydrous basis. Inactive ingredients: citric acid, colloidal silicon dioxide, edetate disodium, ethylcellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. In addition, the 250 mg tablet contains calcium sulfate, hydroxypropyl cellulose, and talc, and the 500 mg tablet contains polysorbate 80.
Methyldopa () Clinical Pharmacology
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 (-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. Methyldopa () usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
Methyldopa () Indications And Usage
Methyldopa () Contraindications
Methyldopa () is contraindicated in patients:
- with active hepatic disease, such as acute hepatitis and active cirrhosis.
- with liver disorders previously associated with Methyldopa () therapy (see ).
- with hypersensitivity to any component of this product.
- on therapy with monoamine oxidase (MAO) inhibitors.
Methyldopa () Warnings
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 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 (SGOT, SGPT), bilirubin and prothrombin time. Jaundice, with or without fever, may occur with onset, usually within the first 2 or 3 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 determinations 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.
Methyldopa () Precautions
Methyldopa () should be used with caution in patients with a history of previous liver disease or dysfunction (See ).
Some patients taking Methyldopa () experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa () should not be continued if edema progresses or signs of heart failure appear.
Hypertension has recurred occasionally after dialysis in patients given Methyldopa () because the drug is removed by this procedure.
Rarely involuntary choreoathetotic movements have been observed during therapy with Methyldopa () in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
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.
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 () .
When Methyldopa () and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.
Several studies demonstrate a decrease in the bioavailability of Methyldopa () when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with Methyldopa () . Coadministration of Methyldopa () with ferrous sulfate or ferrous gluconate is not recommended.
Monoamine oxidase (MAO) inhibitors: see .
Methyldopa () may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported.
Since Methyldopa () causes fluorescence in urine samples at the same wavelengths 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.
No evidence of a tumorigenic effect was seen when Methyldopa () was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/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 the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).
Methyldopa () was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatid exchanges in Chinese hamster ovary cells. These studies were carried out both with and without exogenous metabolic activation.
Fertility was unaffected when Methyldopa () was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa () decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day. (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).
Of the total number of subjects (1685) in clinical studies of Methyldopa () , 223 patients were 65 years of age and over while 33 patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. (See .)
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.
Methyldopa () Adverse Reactions
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.
The following adverse reactions have been reported, and within each category, are listed in order of decreasing severity.
Methyldopa () Overdosage
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 imbalance, paralytic ileus, urinary function and cerebral activity.
Sympathomimetic drugs [e.g., levarterenol, epinephrine, metaraminol bitartrate] may be indicated.
Methyldopa () is dialyzable.
The oral LD of Methyldopa () is greater than 1.5 g/kg in both the mouse and the rat.
Methyldopa () How Supplied
Methyldopa () tablets USP are available as round, white, film-coated tablets, debossed Z2931, containing 250 mg of Methyldopa () USP, packaged in bottles of 60 (NDC 21695-879-60) and 90 tablets (NDC 21695-879-90) and as round, white, film-coated tablets, debossed Z2932, containing 500 mg of Methyldopa () USP, packaged in bottles of 60 (NDC 21695-880-60).
PHARMACIST: Dispense in a well-closed container as defined in the USP. Use child-resistant closure.
Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].
Manufactured by:
IVAX PHARMACEUTICALS, INC.
Miami, FL 33137
Manufactured for:
TEVA PHARMACEUTICALS, USA
Sellersville, PA 18960
0172
08/06
B17
Repackaged by:
Rebel Distributors Corp
Thousand Oaks, CA 91320
Methyldopa () Prindipal Display Panel
Methyldopa () Principal Display Panel
