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Methyldopa

Pronunciation

Class: Central alpha-Agonists
Note: This monograph also contains information on methyldopate hydrochloride
VA Class: CV490
CAS Number: 41372-08-1
Brands: Aldoril

Warning(s)

  • Methyldopa in Fixed Combination with Hydrochlorothiazide
  • Should not use initially for the treatment of hypertension.b d

  • Adjust dosage initially by administering each drug separately.d

  • Fixed combination may be used if it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation.d

  • Reevaluate dosage as conditions in the patient warrant.d

Introduction

Hypotensive agent; centrally acting α2-adrenergic agonist.b c d e f h

Uses for Methyldopa

Hypertension

Used alone or in combination with other classes of antihypertensive agents in the management of hypertension.c d e f

Thiazide diuretics are considered the preferred initial monotherapy for uncomplicated hypertension by JNC 7.144

May be more effective when used with a diuretic.122 126 127

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Use of a diuretic may prevent tolerance to methyldopa and permit reduction of methyldopa dosage.122 126 127

Also has been used with other hypotensive agents, permitting a reduction in the dosage of each drug and, in some patients, minimizing adverse effects while maintaining BP control.

Initial hypotensive agent of choice for management of hypertension in pregnant women.109 110 111 115 118 126 129 130

Preferred oral antihypertensive for women with preeclampsia when delivery likely will be delayed for more than 48 hours.148

Hypertensive Crises

Used IV for the management of hypertensive crises.f Because of the slow onset of action, other agents (e.g., sodium nitroprusside) are preferred.126

Avoid excessive falls in BP since they may precipitate renal, cerebral, or coronary ischemia.118 126

Methyldopa Dosage and Administration

General

Hypertension

  • Adjust dosage according to the patient’s BP response and tolerance.b c

  • Monitor BP during initial titration or subsequent upward dosage adjustment; large or abrupt reductions in BP generally should be avoided.126 144

  • Fixed combination with a thiazide diuretic is not recommended for initial combination therapy; adjust initial and subsequent dosages by administering each drug separately.b d

  • Consider fixed combination if the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation.d

  • Tolerance to antihypertensive effect may develop;122 126 127 may be necessary to increase dosage or use a diuretic concomitantly.122 126 127 Manufacturers recommend addition of a thiazide diuretic at any time during methyldopa therapy or if effective BP control cannot be maintained on 2 g of oral methyldopa daily.c e

Administration

Administer methyldopa orally and methyldopate hydrochloride by IV infusion.c d e f

Usually administer orally; may be administered IV if parenteral administration is required.c f

IM or sub-Q administration not recommended because of unpredictable absorption.b

Oral Administration

Minimize adverse effects (e.g., drowsiness) by initiating dosage increases in the evening.e

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Dilution

Dilute methyldopate hydrochloride injection in 5% dextrose in water injection.f

Add the required dose of the drug to 100 mL of 5% dextrose in water injection.f Alternatively, dilute the required dose in 5% dextrose in water injection to provide a solution containing 100 mg/10 mL.f

Rate of Administration

Administer slowly by IV infusion over 30–60 minutes.f

Dosage

Available as methyldopa or methyldopate hydrochloride; dosage expressed in terms of methyldopa or methyldopate hydrochloride, respectively.c d e f

Pediatric Patients

Hypertension
Monotherapy
Oral

Initially, 10 mg/kg daily given in 2–4 divided doses.c e

Adjust dosage until an adequate response is achieved.b c Maximum dosage is 65 mg/kg daily or 3 g daily, whichever is less.c

IV

Usual dosage: 20–40 mg/kg per 24 hours administered in equally divided doses at 6-hour intervals.f

Maximum dosage is 65 mg/kg daily or 3 g daily, whichever is less.f

When BP is controlled, should substitute oral therapy at the same dosage.b f

Adults

Hypertension
Monotherapy
Oral

Initially, 250 mg 2 or 3 times daily for 2 days.b Increase or decrease dosage every 2 days until an adequate response is achieved.b c c

For maintenance, manufacturers recommend 500–2000 mg daily given in 2–4 divided doses.c

JNC 7 recommends a lower usual dosage range of 125–500 mg twice daily;144 if needed, add another antihypertensive agent to the regimen rather than increasing maximum dosage >1 g daily because of poor patient tolerance.149

IV

Usual dosage: 250–500 mg every 6 hours as required.f Maximum dosage is 1 g every 6 hours.f

Combination Therapy
Oral

Methyldopa in fixed combination with hydrochlorothiazide: Initially, 250 mg of methyldopa and 15 mg of hydrochlorothiazide given 2–3 times daily, or 250 mg of methyldopa and 25 mg of hydrochlorothiazide given twice daily.b d Alternatively, 500 mg of methyldopa and either 30 or 50 mg of hydrochlorothiazide once daily.138 d

If tolerance occurs, add separate dosages of methyldopa or replace the fixed combination with each drug separately until the new effective dosage is reestablished by titration.d

Combination with hypotensive drugs other than thiazide diuretics: Initially, maximum recommended dosage is 500 mg daily in divided doses.d Adjust dosage of other hypotensive drugs if necessary.c d

Hypertensive Crises
IV

Usual dosage: 250–500 mg every 6 hours as required.f

Initial goal is to reduce mean arterial BP by no more than 25% (within minutes to 1 hour), then if stable, to 160/100 to 110 mm Hg within the next 2–6 hours.126 Avoid excessive declines in pressure.126

If this BP is well tolerated and the patient is clinically stable, implement further gradual reductions toward normal in the next 24–48 hours.148 In patients with aortic dissection, reduce SBP to <100 mm Hg if tolerated.148

Prescribing Limits

Pediatric Patients

Hypertension
Oral

Maximum 65 mg/kg daily or 3 g daily, whichever is less.c

IV

Maximum 65 mg/kg daily or 3 g daily, whichever is less.f

Adults

Hypertension
Oral

Maximum 3 g daily as maintenance therapy recommended by manufacturers.c e JNC 7 recommends maximum 1 g daily because of poor patient tolerance.149

Combination therapy with hypotensive drugs other than thiazide diuretics: Initially, maximum 500 mg daily in divided doses.d

IV

Maximum 1 g every 6 hours.f

Hypertensive Crises
IV

Maximum 1 g every 6 hours.f

Special Populations

Renal Impairment

Consider dosage reduction.b c d f

Geriatric Patients

Consider dosage reduction to avoid syncope.e f (See Geriatric Use under Cautions.)

Cautions for Methyldopa

Contraindications

  • Active hepatic disease (e.g., acute hepatitis, active cirrhosis).b f (See Hepatic Effects under Cautions.)

  • Liver disorders with previous methyldopa therapy.b c d e f

  • Direct Coombs’ positive hemolytic anemia with previous methyldopa therapy.b

  • Concomitant therapy with MAO inhibitors or ferrous sulfate or gluconate.123 124 125 c d e c f (See Specific Drugs and Laboratory Tests under Interactions.)

  • Pheochromocytoma.b e

  • Known hypersensitivity to methyldopa or any ingredient in formulations, including sulfites (with IV injection).b f

Warnings/Precautions

Warnings

Hematologic Effects

Positive direct antiglobulin (Coombs’) test results reported, usually after 6–12 months of therapy; rarely associated with potentially fatal hemolytic anemia.b e n After discontinuance of the drug, positive Coombs’ test reverses within weeks to months.b e

At treatment initiation, perform a hemoglobin, hematocrit, or a red blood cell count.b e Periodic blood counts recommended during therapy to detect hemolytic anemia.b e

May be useful to obtain a direct Coombs’ test before treatment initiation and after 6 and 12 months of therapy.b e If a positive Coombs’ test occurs, perform appropriate laboratory studies to determine if hemolytic anemia is present.e If there is evidence of hemolytic anemia, discontinue the drug; do not reinstitute therapy if anemia is related to methyldopa.b e

Hemolytic anemia usually resolves promptly; if not, corticosteroids may be given and other causes of anemia should be considered and investigated.b f

If a blood transfusion is required, perform a direct and indirect Coombs’ test prior to transfusion.b A positive direct Coombs’ test alone will not interfere with typing or crossmatching.c If both the indirect and direct Coombs’ tests are positive, problems with major crossmatching may occur, and the assistance of an expert may be required.c

Reversible leukopenia (primarily granulocytopenia) and immune thrombocytopenia reported rarely.b c

Hepatic Effects

Possible abnormal liver function test results (e.g., increased serum concentrations of alkaline phosphatase, aminotransferases, and bilirubin and abnormal PT).c e f

Rarely, reversible jaundice, with or without fever, reported, usually within the first 2–3 months of therapy.c f These effects may be associated with cholestasis, hepatitis, hepatocellular injury, or cirrhosis.b c Potentially fatal hepatic necrosis reported rarely.b c

Hepatic dysfunction may represent hypersensitivity reactions.e n (See Sensitivity Reactions under Cautions.)

Assess hepatic function periodically, especially during the first 6–12 weeks of therapy or whenever unexplained fever occurs.c f If unexplained fever, abnormal liver function test results, or jaundice occurs, discontinue methyldopa.b c If methyldopa is the causative agent, temperature and liver function generally return to normal within a few months after methyldopa is discontinued;b c f do not reinstitute therapy in such patients.b c

Use with caution in patients with a history of previous liver disease or dysfunction.f Use contraindicated in patients with active hepatic disease.c f (See Contraindications under Cautions.)

Sensitivity Reactions

Eosinophilia, myocarditis, pericarditis, vasculitis, and lupus-like syndrome reported.c f

Fever may be associated with eosinophilia or hepatic dysfunction and may represent hypersensitivity reactions.e n (See Hepatic Effects under Cautions.)

Positive Coombs’ test and hemolytic anemia may represent hypersensitivity reactions.n (See Hematologic Effects under Cautions.)

IV formulation contain sulfites, which can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes.b f Such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.b f

General Precautions

Nervous System Effects

Involuntary choreoathetotic movements reported rarely in patients with severe bilateral cerebrovascular disease.c If such symptoms occur, discontinue therapy.c

Cardiovascular Effects

Sodium retention resulting in edema and weight gain reported;b f usually controlled by concomitant administration of a thiazide diuretic.b f Discontinue therapy if edema progresses or leads to CHF.b f

Possible paradoxical pressor response following IV administration.f n

Rebound hypertension has occurred rarely following abrupt withdrawal of oral methyldopa or following dialysis.b f n

Neonatal Morbidity

In neonates born to women treated with methyldopa, SBP may be decreased during the first 2–3 days after delivery;112 tremors also have been reported.113

Specific Populations

Pregnancy

Category C (IV injection);f Category B (tablets).e

Lactation

Distributed into milk.b Caution if used in nursing women;b monitor nursing infant (particularly if preterm) for potential systemic effects of the drug (e.g., decreased respiration, BP, or alertness).103

Pediatric Use

No well-controlled studies in pediatric patients; dosage recommendations based on published literature.123 124

Safety and efficacy of preparations containing methyldopa in fixed combination with hydrochlorothiazide not established.125

Geriatric Use

Possibility exists of greater sensitivity to the drug in some geriatric individuals.126

Possible syncope; may be related to an increased sensitivity to the drug and advanced arteriosclerotic vascular disease.e f (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with a history of previous liver disease or dysfunction.b

Renal Impairment

Generally considered to be safe for use; however, reduced dosage may be required.b c d e f

Common Adverse Effects

Drowsiness or sedation.b

Interactions for Methyldopa

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Anesthetics

Potential for hypotensionb c

Reduced doses of general anesthetics may be requirede

Hypotension usually controlled by vasopressor agentsc e

Antidepressants, tricyclic

Possible decreased hypotensive effectb

BP monitoring recommendedb

Antihypertensive agents

Additive/potentiated hypotensive effectb c

Usually used to therapeutic advantage in antihypertensive therapy; however, carefully adjust dosageb and monitor for adverse effectsc

Diuretics

Additive/potentiated hypotensive effectb c

Usually used to therapeutic advantage in antihypertensive therapy; however, carefully adjust dosageb and monitor for adverse effectsc

Haloperidol

Possible psychomotor retardation, memory impairment, and inability to concentrate in nonschizophrenic patientsb

Symptoms resolved upon discontinuance of haloperidolb

Iron preparations, oral

Concomitant administration may decrease oral absorption and alter the metabolism of methyldopa116

Possible increased BP 116

Concomitant administration with ferrous sulfate or ferrous gluconate is not recommended138 c

Levodopa

Possible additive hypotensive effect and toxic CNS effects (e.g., psychosis)b

Use with cautionb

Lithium

Possible increased risk of lithium toxicityb

Monitor for lithium toxicity and adjust therapy accordinglyb c

MAO inhibitors

Possible marked hypotensive effecto

Concomitant use contraindicated123 124 125

Phenothiazines

Possible decreased hypotensive effectb

BP monitoring recommendedb

Test for AST

May interfere with measurement of AST by colorimetric methodsb c

Test for serum creatinine

May interfere with measurement of creatinine by the alkaline picrate methodb c

Test for urinary catecholamines

May cause a false report of elevated urinary catecholaminesc e

Causes fluorescence in urine samples at the same wavelengths as catecholaminesc

Test for urinary uric acid

May interfere with measurement of uric acid by the phosphotungstate method at concentrations of the drug that are several times higher than therapeutic concentrationsb f

Methyldopa Pharmacokinetics

Absorption

Bioavailability

Generally about 50% of an oral dose is absorbed with peak plasma concentrations usually attained in approximately 3–6 hours.b

Onset

Following oral administration, maximum decrease in BP occurs in 4–6 hours.b c

Following IV administration, BP begins to decrease in 4–6 hours.b f

Duration

Following discontinuance of oral therapy, BP returns to pretreatment levels within 24–48 hours.c

Following IV administration, hypotensive effect lasts for 10–16 hours and hypertension recurs within 48 hours.b f

Distribution

Extent

Crosses the blood-brain barrier.h j

Methyldopa crosses the placenta in humans101 102 and is distributed into milk.101 103

Plasma Protein Binding

Weakly bound to plasma proteins.b

Elimination

Metabolism

Metabolized in the brain to α-methylnorepinephrine, the pharmacologically active metabolite.j n Other active metabolites include α-methylepinephrine and α-methyldopamine.k n

Extensively metabolized, probably in the GI tract and the liver, to sulfate conjugates.b c f

Elimination Route

49% of an IV dose is excreted in the urine (via glomerular filtration) as the parent drug and the sulfate conjugate.b f

70% of an oral dose is excreted in the urine as parent drug and metabolites.c

Unabsorbed methyldopa is excreted in the feces unchanged.b

Half-life

Plasma half-life is 105 or 90–127 minutes for methyldopa or methyldopate, respectively.d e f

Special Populations

In patients with renal impairment, renal clearance is decreased.b e

Removed by hemodialysis and peritoneal dialysis.b c

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C.d e Protect methyldopa in fixed combination with hydrochlorothiazide from moisture and freezing.d

Parenteral

Solution for Injection

15–30°C.f

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextran 6% in sodium chloride 0.9%

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Normosol M in dextrose 5% in water

Normosol R

Ringer’s injection

Sodium bicarbonate 5%

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Aminophylline

Ascorbic acid injection

Chloramphenicol sodium succinate

Diphenhydramine HCl

Heparin sodium

Magnesium sulfate

Multivitamins

Potassium chloride

Sodium bicarbonate

Succinylcholine chloride

Verapamil HCl

Vitamin B complex with C

Incompatible

Amphotericin B

Methohexital sodium

Y-Site Compatibility

Compatible

Esmolol HCl

Heparin sodium

Meperidine HCl

Morphine sulfate

Theophylline

Actions

  • Central effects: Appears to stimulate α2-adrenergic receptors in the CNS (mainly in the medulla oblongata), causing inhibition of sympathetic vasomotor centers.h Contributes predominantly to hypotensive effects.b h k

  • Central effects result in reduced peripheral sympathetic nervous system activity, total peripheral resistance, and BP.b h i

  • Reduces BP in both supine and standing patients.c

  • Produces little change in cardiac output and heart rate.b c

  • Stimulates peripheral α2-adrenergic receptors leading to a decrease in the release of norepinephrine and a reduction in sympathetic tone.g

  • Inhibits the decarboxylation of dihydroxyphenylalanine (dopa)—the precursor of norepinephrine—and of 5-hydroxytryptophan (5-HTP)—the precursor of serotonin—in the CNS and in most peripheral tissues.b c f Not a major mechanism of action.b n

  • Renal and metabolic effects: Usually does not reduce renal blood flow or GFR.c

  • Causes sodium and water retention and increased plasma volume.b n

  • Reduces plasma renin activity (PRA).f

  • Increases serum prolactin concentrations.b m

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.e

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.e

  • Importance of informing patients of other important precautionary information.e (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Methyldopa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg*

Methyldopa Tablets

Mylan, Teva, UDL

500 mg*

Methyldopa Tablets

Mylan, Teva, UDL

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Methyldopa and Hydrochlorothiazide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg with Hydrochlorothiazide 15 mg*

Methyldopa and Hydrochlorothiazide Tablets

250 mg with Hydrochlorothiazide 25 mg*

Aldoril ()

Merck

Methyldopa and Hydrochlorothiazide Tablets

Methyldopate Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

50 mg/mL

Methyldopate Hydrochloride Injection (with parabens and sulfites)

American Regent

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Methyldopa 250MG Tablets (TEVA PHARMACEUTICALS USA): 120/$25.98 or 180/$28.96

Methyldopa-Hydrochlorothiazide 250-25MG Tablets (MYLAN): 60/$22.99 or 180/$46.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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