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 (Ref). Note: When administered with other antihypertensives other than thiazide diuretics, limit initial daily dose of methyldopa to 500 mg/day in divided doses.
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 (Ref):
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 (Ref).
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.
Avoid use (Ref).
(For additional information see "Methyldopa: Pediatric drug information")
Hypertension: Note: Use has been replaced by other agents; methyldopa not suggested as a treatment option for hypertension (Ref).
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 (Ref).
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.
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Bradycardia, edema, exacerbation of angina pectoris, heart failure, myocarditis (Webster 1996), orthostatic hypotension (Paykel 1982), pericarditis, prolonged carotid sinus syncope (Bauernfeind 1978), vasculitis (Matteson 1989)
Dermatologic: Lichenoid eruption (Holt 1974), skin rash (including eczema, papular rash, seborrheic dermatitis, and urticaria) (Gidseg 1986, Holt 1974), toxic epidermal necrolysis
Endocrine & metabolic: Amenorrhea (Arze 1981), decreased libido (Newman 1974), gynecomastia (Caldwell 1981), hyperprolactinemia (Arze 1981), weight gain (Caldwell 1981)
Gastrointestinal: Abdominal distention, cholestasis, colitis, constipation, diarrhea (Caldwell 1981), flatulence, glossalgia, melanoglossia, nausea (Caldwell 1981), pancreatitis (Van der Heide 1981), sialadenitis, vomiting, xerostomia (Caldwell 1981)
Genitourinary: Breast hypertrophy (Pettinger 1964), impotence (Caldwell 1981), lactation (Pettinger 1964), nocturia (Caldwell 1981)
Hematologic & oncologic: Bone marrow depression, eosinophilia, granulocytopenia, hemolytic anemia (including autoimmune hemolytic anemia) (Böttiger 1973, Surveyor 1968), leukopenia, neutropenia (Greene 1967), positive ANA titer (Dupont 1982), positive direct Coombs test (Dupont 1982), thrombocytopenia
Hepatic: Abnormal hepatic function tests (Shashaty 1979), cholestatic hepatitis (Toghill 1974), cholestatic jaundice (Hoffbrand 1974), hepatic cirrhosis (Shashaty 1979), hepatic necrosis (Toghill 1974), hepatitis (Thomas 1997), hepatocellular hepatitis, hepatotoxicity (Toghill 1974), jaundice (Toghill 1974)
Nervous system: Asthenia, Bell palsy, cerebrovascular insufficiency (symptoms), decreased mental acuity (Paykel 1982), depression (Caldwell 1981), dizziness (Caldwell 1981), drowsiness (Caldwell 1981), drug fever (Kumar 1986), fatigue (Caldwell 1981), headache (Caldwell 1981), involuntary choreoathetoid movements (Neil 1981), paresthesia (Caldwell 1981), parkinsonism (Strang 1966), psychic disorder (including nightmares, psychosis) (Webster 1996), sedated state (Paykel 1982), sleep disturbance (including insomnia and nightmares) (Paykel 1982)
Neuromuscular & skeletal: Arthralgia, lupus-like syndrome (Dupont 1982), myalgia, positive rheumatoid factor
Renal: Increased blood urea nitrogen
Respiratory: Nasal congestion (Caldwell 1981)
Miscellaneous: Fever, positive LE cell preparation (Harth 1968)
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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 250 mg, 500 mg
Yes
Tablets (Methyldopa Oral)
250 mg (per each): $9.00
500 mg (per each): $12.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 125 mg, 250 mg, 500 mg
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.
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: Central alpha-agonists (methyldopa) are identified in the Beers Criteria as potentially inappropriate medications 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 2023]).
Aldomet [Multiple international markets] may be confused with Aldactone brand name for spironolactone [US, Canada, multiple international markets]
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
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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
Indoramin: May enhance the hypotensive effect of Antihypertensive 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-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. 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 more than 2 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
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. 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
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. 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
Urapidil: Antihypertensive Agents may enhance the hypotensive effect of Urapidil. Risk C: Monitor therapy
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
Medications considered acceptable for the treatment of chronic hypertension during pregnancy may generally be continued in patients trying to become pregnant. Methyldopa is an option patients can be transitioned to when one of the preferred agents cannot be used (ACC/AHA [Whelton 2018]; ACOG 2019; NICE 2019).
Methyldopa crosses the placenta.
Available data show use during pregnancy does not cause fetal harm and improves fetal outcomes.
Chronic maternal hypertension is associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to the duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 2019).
Patients with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]). 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 2019; ESC [Cífková 2020]; SOGC [Magee 2022]).
Methyldopa is present in breast milk.
Data related to the presence of methyldopa in breast milk are available from multiple reports:
• Breast milk was sampled 30 to 60 minutes following delivery in 4 patients taking methyldopa for at least 4 weeks. The highest breast milk concentrations were obtained in 1 patient taking methyldopa 500 mg every 6 hours. Twelve hours after the last dose, free and conjugated concentrations of methyldopa were 0.2 mcg/mL and 0.9 mcg/mL, respectively (Jones 1978).
• Data related to the presence of methyldopa in breast milk are available from a study of 3 patients. The highest breast milk concentration of free methyldopa (1.14 mcg/mL) was observed in 1 patient 8 weeks postpartum taking methyldopa 1,000 mg/day. In this patient, free methyldopa was ~37% of the total methyldopa (free + conjugate) present in breast milk; methyldopa was detected in the breastfed infant's serum. Using data from all 3 patients, peak breast milk concentrations occurred 3 to 6 hours after the maternal dose. Adverse events were not observed in the breastfed infants (White 1985).
• Methyldopa was also detected in the urine of a breastfed infant. Methyldopa 250 mg twice daily for 10 days was initiated 11 days postpartum to a patient following delivery at 38 weeks gestation. Adverse events were not observed in the infant (Hauser 1985).
• Using a milk concentration of 1.14 mcg/mL, the estimated daily infant dose of methyldopa via breast milk is 0.1716 mg/kg/day providing a relative infant dose (RID) of 1.2% compared to a weight adjusted maternal dose of 1,000 mg/day.
• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Methyldopa is compatible with breastfeeding (ESC [Cífková 2020]; SOGC [Magee 2022]; 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 2019; Regitz-Zagrosek [ESC 2018]).
Dietary requirements for vitamin B12 and folate may be increased with high doses of methyldopa.
Blood pressure; 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).
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: Single-dose: Within 3 to 6 hours; Multiple-dose: 48 to 72 hours.
Duration: Single-dose: 12 to 24 hours, Multiple-dose: 24 to 48 hours.
Absorption: 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: 2 to 4 hours (Myhre 1982).
Excretion: Urine (~70% as parent drug and metabolites); excretion complete within 36 hours.
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