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Methyldopa

Pronunciation

Pronunciation

(meth il DOE pa)

Index Terms

  • Aldomet
  • Methyldopate Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride:

Generic: 250 mg/5 mL (5 mL)

Tablet, Oral:

Generic: 250 mg, 500 mg

Pharmacologic Category

  • Alpha2-Adrenergic Agonist
  • Antihypertensive

Pharmacology

Stimulation of central alpha-adrenergic receptors by a false neurotransmitter (alpha-methylnorepinephrine) that results in a decreased sympathetic outflow to the heart, kidneys, and peripheral vasculature

Absorption

Oral: Incomplete due to presystemic gut metabolism (Skerjanec 1995)

Distribution

Vd: 0.23 L/kg (Myhre 1982)

Metabolism

Intestinal and hepatic

Excretion

Urine (~70% as parent drug and metabolites); excretion complete within 36 hours

Onset of Action

Peak effect: Hypotensive: Oral, IV: Single-dose: Within 3 to 6 hours; Multiple-dose: 48 to 72 hours

Time to Peak

Plasma: Oral: 2 to 4 hours (Myhre 1982)

Duration of Action

Oral: Single-dose: 12 to 24 hours, Multiple-dose: 24 to 48 hours; IV: 10 to 16 hours

Half-Life Elimination

Neonates: 10 to 20 hours; Adults:1.5 to 2 hours; End-stage renal disease: Prolonged (Myhre 1982)

Protein Binding

10% to 15% (Myhre 1982)

Use: Labeled Indications

Hypertension: Management of hypertension

Note: According to the Eighth Joint National Committee (JNC 8) guidelines, methyldopa is not recommended for the initial treatment of hypertension (James 2013).

Contraindications

Hypersensitivity to methyldopa or any component of the formulation; active hepatic disease (eg, acute hepatitis, active cirrhosis); hepatic disorders previously associated with use of methyldopa; concurrent use of MAO inhibitors

Dosing: Adult

Hypertension:

Oral: Initial: 250 mg 2 to 3 times daily; increase or decrease daily dose every 2 days based on response (maximum dose: 3,000 mg/day); usual dose range (ASH/ISH [Weber 2014]): 250 to 500 mg twice daily. Note: When administered with other antihypertensives other than thiazide diuretics, limit initial daily dose of methyldopa to 500 mg/day.

IV: 250 to 1,000 mg every 6 to 8 hours; maximum: 1,000 mg every 6 hours

Dosing: Geriatric

Refer to adult dosing. Initiate at the lower end of the dosage range.

Dosing: Pediatric

Hypertension:

Oral: Initial: 10 mg/kg/day in 2 to 4 divided doses; increase or decrease daily dose every 2 days based on response; maximum dose: 65 mg/kg/day or 3,000 mg/day.

IV: 5 to 10 mg/kg/dose every 6 to 8 hours; maximum dose: 65 mg/kg/day or 3,000 mg/day.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007):

CrCl >50 mL/minute: Administer every 8 hours.

CrCl 10 to 50 mL/minute: Administer every 8 to 12 hours.

CrCl <10 mL/minute: Administer every 12 to 24 hours.

Intermittent hemodialysis: Moderately dialyzable (up to 60% with a 6-hour session): Administer after hemodialysis on dialysis days (Yeh 1970).

Peritoneal dialysis (PD): Administer every 12 to 24 hours.

Continuous renal replacement therapy (CRRT): Administer every 8 to 12 hours. Note: Use of antihypertensives in patients requiring CRRT is generally not recommended since CRRT is typically employed when patient cannot tolerate intermittent hemodialysis due to hypotension.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use is contraindicated in patients with active hepatic disease.

Reconstitution

Standard diluent: 250 to 500 mg/100 mL D5W

Extemporaneously Prepared

A 50 mg/mL oral suspension may be made with tablets and either unpreserved Simple Syrup, N.F. or a 1:1 mixture of simple syrup (containing 0.5% citric acid) and hydrochloric acid 0.2 N. Crush ten 250 mg tablets in a glass mortar and reduce to a fine powder. To make formulation with unpreserved simple syrup, add small portions of vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 50 mL; transfer to a calibrated bottle; rinse the mortar and pestle several times with vehicle, and add quantity of vehicle sufficient to make 50 mL. To make formulation with the second vehicle, mix powdered tablets with 25 mL of hydrochloric acid 0.2 N (0.73% w/v); dilute this mixture to 50 mL with simple syrup containing 0.5% citric acid by the method described above. Label "shake well" and "protect from light." Stable for 14 days when stored in glass prescription bottles in the dark at room temperature or refrigerated.

Newton DW, Rogers AG, Becker CH, et al, "Extemporaneous Preparation of Methyldopa in Two Syrup Vehicles," Am J Hosp Pharm, 1975, 32(8):817-21.238389

Administration

IV: Infuse over 30 to 60 minutes.

Oral: Administer new dosage increases in the evening to minimize sedation.

Dietary Considerations

Dietary requirements for vitamin B12 and folate may be increased with high doses of methyldopa.

Compatibility

Stable in dextran 6% in NS, D5NS, D5W, sodium bicarbonate 5%, NS.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Injectable dosage form is most stable at acid to neutral pH. Stability of parenteral admixture in D5W at room temperature (25°C) is 24 hours. Parenteral admixture is stable at room temperature for up to 125 hours (Newton 1981).

Tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

COMT Inhibitors: May decrease the metabolism of COMT Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Iobenguane I 123: Methyldopa may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Iron Salts: May decrease the serum concentration of Methyldopa. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: Methyldopa may enhance the adverse/toxic effect of Lithium. This may occur without notable changes in serum lithium concentrations. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Methyldopa. Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Methyldopa. Management: Consider separating doses of these products by 2 or more hours to minimize this interaction; however, the success of this action appears limited. Monitor for decreased therapeutic effects of methyldopa with concurrent use. Consider therapy modification

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Consider therapy modification

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

Methyldopa interferes with the following laboratory tests: urinary uric acid (phosphotungstate method), serum creatinine (alkaline picrate method), AST (colorimetric method), and urinary catecholamines (falsely high levels)

Adverse Reactions

Frequency not defined.

Cardiovascular: Angina pectoris aggravation, bradycardia, carotid sinus hypersensitivity prolonged, heart failure, myocarditis, orthostatic hypotension, paradoxical pressor response (IV use), pericarditis, peripheral edema, symptoms of cerebrovascular insufficiency, vasculitis

Central nervous system: Bell’s palsy, dizziness, drug fever, headache, lightheadedness, mental acuity decreased, mental depression, nightmares, parkinsonism, sedation

Dermatologic: Rash, toxic epidermal necrolysis

Endocrine & metabolic: Amenorrhea, breast enlargement, gynecomastia, hyperprolactinemia, lactation, libido decreased

Gastrointestinal: Abdominal distension, colitis, constipation, diarrhea, flatulence, nausea, pancreatitis, sialadenitis, sore or “black” tongue, vomiting, weight gain, xerostomia

Genitourinary: Impotence

Hematologic: Bone marrow suppression, eosinophilia, granulocytopenia, hemolytic anemia; positive tests for ANA, LE cells, rheumatoid factor, Coombs test (positive); leukopenia, thrombocytopenia

Hepatic: Abnormal LFTs, liver disorders (hepatitis), jaundice

Neuromuscular & skeletal: Arthralgia, choreoathetosis, myalgia, paresthesias, weakness

Renal: BUN increased

Respiratory: Nasal congestion

Miscellaneous: SLE-like syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Edema: May produce clinical edema or weight gain; discontinue if edema worsens or signs of heart failure arise. Mild edema may be controlled with the concomitant use of diuretic therapy.

• Hematologic effects: Rare cases of reversible granulocytopenia and thrombocytopenia have been reported. May rarely produce hemolytic anemia; positive Coombs test occurs in 10% to 20% of patients usually occurring between 6 and 12 months of therapy; perform complete blood count (CBC) periodically. If methyldopa-induced Coombs-positive hemolytic anemia occurs during therapy, discontinue use and do not reinitiate; Coombs test may not revert back to normal for weeks to months following discontinuation.

• Hepatic effects: May rarely produce hepatic disorders including fatal hepatic necrosis. Discontinue use and do not reinitiate if fever, abnormal liver function tests, or jaundice is present.

• Sedation: Usually transient, sedation may occur with initiation or whenever the dose is increased.

Disease-related concerns:

• Cerebrovascular disease: Patients with severe bilateral cerebrovascular disease have exhibited involuntary choreoathetotic movements (rare); discontinue use if these symptoms develop.

• Hepatic impairment: Use with caution in patients with history of hepatic disease or impairment.

• Pheochromocytoma: Not recommended in patients with pheochromocytoma.

• Renal impairment: Use with caution in patients with renal impairment; may respond to smaller doses. The active metabolites of methyldopa accumulate in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Surgical patients: Patients on methyldopa may need less anesthetic agents (Miller 1968; Miller 2010).

Dosage form specific issues:

• Injection: Do not use injectable if bisulfite allergy.

Other warnings/precautions:

• Tolerance: May occur usually between the second and third month of therapy; adding a diuretic or increasing the dosage of methyldopa frequently restores blood pressure control.

Monitoring Parameters

Blood pressure (standing and sitting/lying down), CBC, liver enzymes (periodically during the first 6 to 12 weeks or when unexplained fever occurs), Coombs test (direct) (may obtain prior to initiation and at 6 and 12 months); blood pressure monitor required during IV administration

Pregnancy Risk Factor

B/C (injectable)

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Methyldopa crosses the placenta and appears in cord blood. Available data show use during pregnancy does not cause fetal harm and improves fetal outcomes. Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for chronic hypertension during pregnancy is needed, methyldopa is one of the preferred agents. If an injectable agent is needed for the urgent control of acute hypertension in pregnancy, other agents are preferred (ACOG, 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue or headache. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe dizziness, passing out, severe loss of strength and energy, bruising, bleeding, shortness of breath, excessive weight gain, swelling of arms or legs, angina, bradycardia, chills, pharyngitis, mood changes, nightmares, abnormal movements, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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