DESCRIPTION

Methyldopate HCl Injection, USP, is an antihypertensive agent for intravenous use. Sterile, nonpyrogenic.

Methyldopate hydrochloride [levo-3-(3,4-dihydroxyphenyl)-2-methylalanine, ethyl ester hydrochloride] is the ethyl ester of methyldopa, supplied as the hydrochloride salt with a molecular weight of 275.73. Methyldopate hydrochloride is more soluble and stable in solution than methyldopa and is the preferred form for intravenous use.

The molecular formula for Methyldopate hydrochloride is C12H17NO4·HCl and the structural formula is:

Each mL contains:

Methyldopate Hydrochloride ......... 50 mg
Citric Acid (Anhydrous) ................. 5 mg
Edetate Disodium ......................... 0.5 mg
Monothioglycerol ...........................  2 mg
Water for Injection ................q.s. to 1 mL

Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.

CLINICAL PHARMACOLOGY

Methyldopate, an antihypertensive agent, 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-methyl-norepinephrine, 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.

INDICATIONS AND USAGE

Hypertension, when parenteral medication is indicated. The treatment of hypertensive crises may be initiated with Methyldopate HCl Injection.

CONTRAINDICATIONS

Methyldopate hydrochloride 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 this product, including sulfites (see WARNINGS).

-     on therapy with monoamine oxidase (MAO) inhibitors.

WARNINGS

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.

PRECAUTIONS

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.

Cardiovascular: Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, paradoxical pressor response with intravenous use, orthostatic hypotension (decrease daily dosage), edema and weight gain, bradycardia.

Digestive: Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or ``black′′ tongue, nausea, constipation, distension, 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 tests.

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

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

Nervous System/Psychiatric: Parkinsonism, Bell's palsy, decreased mental acuity, 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.

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. 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, MSD)] may be indicated.

The acute intravenous LD50 of Methyldopate HCl in the mouse is 321 mg/kg.

DOSAGE AND ADMINISTRATION

Methyldopate HCl Injection when given intravenously in effective doses, causes a decline in blood pressure that may begin in four to six hours and last 10 to 16 hours after injection.

Add the desired dose of Methyldopate HCl Injection to 100 mL of Dextrose Injection 5%, USP. Alternatively the desired dose may be given in 5% dextrose in water in a concentration of 100 mg/10 mL. Give this intravenous infusion slowly over a period of 30 to 60 minutes.

HOW SUPPLIED

Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL).

NDC 0517-8905-10   5 mL Single Dose Vial   Boxes of 10

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).

Rx Only

IN8905
Rev. 11/05
MG #7604

AMERICAN
REGENT, INC.
SHIRLEY, NY  11967

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - Container

NDC 0517-8905-10

METHYLDOPATE HCl
INJECTION, USP

250 mg/5 mL (50 mg/mL)

5 mL SINGLE DOSE VIAL

FOR IV USE AFTER DILUTION

Rx Only

AMERICAN REGENT, INC.
SHIRLEY, NY  11967

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - Carton

PRINCIPAL DISPLAY PANEL – Carton

METHYLDOPATE HCl
INJECTION, USP

250 mg/5 mL (50 mg/mL)

NDC 0517-8905-10

10 x 5 mL
SINGLE DOSE VIALS

FOR INTRAVENOUS USE AFTER DILUTION

Rx Only

Each mL contains: Methyldopate HCl 50 mg, Citric Acid (Anhydrous) 5 mg, Edetate Disodium 0.5 mg, Monothioglycerol 2 mg, Water for Injection q.s. Methylparaben 1.5 mg and Propylparaben 0.2 mg added as preservatives, Sodium Bisulfite 3.2 mg added as an antioxidant. pH adjusted with Sodium Hydroxide and/or Hydrochloric Acid.
DISCARD UNUSED PORTION.
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).
Directions for Use: See Package Insert.

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967

Rev. 11/05