Note: Methyldopate injection is no longer available in the United States.
Hypertension (alternative agent):
Oral: Initial: 250 mg 2 to 3 times daily; titrate daily dose at least every 2 days based on response; usual dose range: 250 mg to 1 g daily in 2 to 4 divided doses; maximum dose: 3 g/day in divided doses (ACC/AHA [Whelton 2018]; manufacturer's labeling). Note: When administered with other antihypertensives other than thiazide diuretics, limit initial daily dose of methyldopa to 500 mg/day in divided doses.
IV: 250 mg to 1 g every 6 to 8 hours; maximum dose: 1 g every 6 hours.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
There are no dosage adjustments provided in the manufacturer's labeling; use is contraindicated in patients with active hepatic disease.
(For additional information see "Methyldopa: Pediatric drug information")
Note: Methyldopate injection is no longer available in the US.
Hypertension: Note: Use has been replaced by other agents; methyldopa not suggested as a treatment option for hypertension (NHLBI 2011). Children and Adolescents: Oral: Initial: 10 mg/kg/day in 2 to 4 divided doses; titrate no more frequently than every 2 days until adequate response to maximum daily dose: 65 mg/kg/day or 3,000 mg/day whichever is less (Park 2014).
Hypertensive crisis: Note: Use has been replaced by other agents; methyldopa not suggested by experts as a treatment option (Flynn 2009; NHBPEP 2004; Thomas 2011): Children and Adolescents: IV: Initial: 2 to 4 mg/kg/dose every 6 to 8 hours; titrate as needed to a recommended daily dose of 20 to 40 mg/kg/day in divided doses or higher if needed up to maximum daily dose: 65 mg/kg/day or 3,000 mg/day whichever is less (Park 2014).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; based on experience in adult patients, dosing adjustment suggested.
There are no dosage adjustments provided in the manufacturer's labeling; use is contraindicated in patients with active hepatic disease.
Avoid use (Beers Criteria [AGS 2019]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Generic: 250 mg [DSC], 500 mg [DSC]
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 125 mg, 250 mg, 500 mg
Methyldopate injection is no longer available in the US.
IV: Infuse over 30 to 60 minutes.
Oral: Administer new dosage increases in the evening to minimize sedation.
Oral: May be administered without regard to food; administer new dosage increases in the evening to minimize sedation
Parenteral: IV: Infuse over 30 to 60 minutes
Hypertension: Management of hypertension. Note: Not recommended for the initial treatment of hypertension (ACC/AHA [Whelton 2018]).
Methyldopa may be confused with L-dopa, levodopa
Beers Criteria: Methyldopa is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to high risk of CNS adverse effects and risk of bradycardia and orthostatic hypotension associated with central alpha blockers; not recommended as routine treatment for hypertension (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Methyldopa is identified as a high-risk medication in patients 65 years and older on the PQA’s Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).
Aldomet [Multiple international markets] may be confused with Aldactone brand name for spironolactone [US, Canada, multiple international markets]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Bradycardia, cardiac failure, exacerbation of angina pectoris, myocarditis, orthostatic hypotension, paradoxical pressor response (intravenous use), pericarditis, peripheral edema, prolonged carotid sinus syncope, vasculitis
Central nervous system: Bell’s palsy, cerebrovascular insufficiency (symptoms), choreoathetosis, decreased mental acuity, depression, dizziness, drug fever, headache, nightmares, paresthesia, Parkinson’s disease, sedation
Dermatologic: Skin rash, toxic epidermal necrolysis
Endocrine & metabolic: Amenorrhea, decreased libido, gynecomastia, hyperprolactinemia, weight gain
Gastrointestinal: Abdominal distention, colitis, constipation, diarrhea, flatulence, glossalgia, melanoglossia, nausea, pancreatitis, sialadenitis, vomiting, xerostomia
Genitourinary: Breast hypertrophy, impotence, lactation
Hematologic & oncologic: Bone marrow depression, eosinophilia, granulocytopenia, hemolytic anemia, leukopenia, positive ANA titer, positive direct Coombs test, thrombocytopenia
Hepatic: Abnormal hepatic function tests, hepatic disease (hepatitis), jaundice
Neuromuscular & skeletal: Arthralgia, lupus-like syndrome, myalgia, positive rheumatoid factor, weakness
Renal: Increased blood urea nitrogen
Respiratory: Nasal congestion
Miscellaneous: Positive LE cell preparation
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
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.
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.
Substrate of COMT
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk D: Consider therapy modification
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
COMT Inhibitors: May increase the serum concentration of COMT Substrates. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Haloperidol: May enhance the adverse/toxic effect of Methyldopa. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Iobenguane Radiopharmaceutical Products: Methyldopa may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer methyldopa until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Iron Preparations: May decrease the serum concentration of Methyldopa. Management: Consider separating doses of methyldopa and orally administered iron preparation by 2 or more hours. Monitor for decreased efficacy of methyldopa if an oral iron preparation is initiated/dose increase, or increased efficacy if discontinued/dose decreased. Risk D: Consider therapy modification
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Lithium: Methyldopa may enhance the adverse/toxic effect of Lithium. This may occur without notable changes in serum lithium concentrations. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: 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. Risk D: Consider therapy modification
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Methyldopa. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Riluzole: Methyldopa may enhance the adverse/toxic effect of Riluzole. Specifically, the risk of hepatotoxicity may be increased. Management: Consider alternatives to methyldopa in patients receiving treatment with riluzole due to the potential for additive hepatotoxicity. Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the therapeutic effect of Alpha2-Agonists. Risk C: Monitor therapy
Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider therapy modification
Triptorelin: Hyperprolactinemic Agents may diminish the therapeutic effect of Triptorelin. Risk X: Avoid combination
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Methyldopa crosses the placenta.
Available data show use during pregnancy does not cause fetal harm and improves fetal outcomes.
Chronic maternal hypertension may increase the risk of birth defects, low birth weight, preterm delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, myocardial infarction, preeclampsia, stroke, and delivery complications (ACOG 203 2019).
If treatment for chronic hypertension during pregnancy is needed, oral methyldopa is an option; however, other agents may be preferred due to adverse events and decreased effectiveness when compared to other medications (ACOG 203 2019). Females with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (Regitz-Zagrosek [ESC 2018]).
Methyldopa is present in breast milk (Jones 1978; White 1985).
The relative infant dose (RID) of methyldopa is 1.2% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 1,000 mg per day.
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
The RID of methyldopa was calculated using a milk concentration of 1.14 mcg/mL, providing an estimated daily infant dose via breast milk of 0.1716 mg/kg/day. This milk concentration was obtained following chronic maternal administration oral methyldopa 1,000 mg/day in a patient who was 1 week postpartum; the peak milk concentration was observed at 6 hours post-administration (White 1985). In addition, methyldopa was detected in the infant’s serum (White 1985); no adverse effects were noted in this infant or two additional exposed infants (White 1985).
According to the World Health Organization (WHO), methyldopa is compatible with breastfeeding (WHO 2002). However, because maternal depression has been reported following methyldopa administration, use of methyldopa should be avoided in the postnatal period due to the underlying risk of depression already present in this patient population (ACOG 203 2019; Regitz-Zagrosek [ESC 2018]).
Dietary requirements for vitamin B12 and folate may be increased with high doses of methyldopa.
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
The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):
Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended
Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable
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
Onset of action: Peak effect: Hypotensive: Oral, IV: Single-dose: Within 3 to 6 hours; Multiple-dose: 48 to 72 hours
Duration: Oral: Single-dose: 12 to 24 hours, Multiple-dose: 24 to 48 hours; IV: 10 to 16 hours
Absorption: Oral: Incomplete due to presystemic gut metabolism (Skerjanec 1995)
Distribution: Vd: 0.23 L/kg (Myhre 1982)
Protein binding: 10% to 15% (Myhre 1982)
Metabolism: Intestinal and hepatic
Bioavailability: ~42% (Skerjanec 1995)
Half-life elimination: Neonates: 10 to 20 hours; Adults: 1.5 to 2 hours; End-stage renal disease: Prolonged (Myhre 1982)
Time to peak, plasma: Oral: 2 to 4 hours (Myhre 1982)
Excretion: Urine (~70% as parent drug and metabolites); excretion complete within 36 hours
Tablets (Methyldopa Oral)
250 mg (per each): $0.37
500 mg (per each): $0.66
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