Class: Central alpha-Agonists
Note: This monograph also contains information on methyldopate hydrochloride
VA Class: CV490
CAS Number: 41372-08-1
Brands: Aldoril
- 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
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
|
ActionsActions
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
|
Mylan
|
|
|
250 mg with Hydrochlorothiazide 25 mg*
|
Aldoril (with propylene glycol)
|
Merck
|
|
|
|
Methyldopa and Hydrochlorothiazide Tablets
|
Mylan
|
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 04/2011. 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
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 01, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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