"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
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 gram 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 lgG (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 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. Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction (see WARNINGS).
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.
A paradoxical pressor response has been reported with intravenous administration of Methyldopate HCl (methyldopate hydrochloride injection, solution) Injection.
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.
Blood count, Coombs test, and liver function tests are recommended before initiating therapy and at periodic intervals (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 chromatic exchanges in Chinese hamster ovary cells. These in vitro 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).
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of methyldopate hydrochloride; nor have evaluations of this ester's mutagenic potential or potential to affect fertility been carried out.
Pregnancy Category C. Animal reproduction studies have not been conducted with Methyldopate HCl (methyldopate hydrochloride injection, solution) . It is also not known whether Methyldopate HCl (methyldopate hydrochloride injection, solution) can affect reproduction capacity or can cause fetal harm when given to a pregnant woman. Methyldopate HCl (methyldopate hydrochloride injection, solution) should be given to a pregnant woman only if clearly needed.
Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.
There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients. (See DOSAGE AND ADMINISTRATION.)This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/11/2008
Additional Methyldopate Hcl Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get tips on handling your hypertension.