Methyldopa (methyldopa)

Dosage of methyldopa must be adjusted according to the patient's blood pressure response and tolerance. Adverse effects such as drowsiness may be minimized by starting dosage increases in the evening or by giving a larger dose at bedtime than in the morning. Geriatric patients may respond to smaller doses of methyldopa.

Patients with impaired renal function may respond to smaller doses of methyldopa.

Methyldopa is administered orally; methyldopate hydrochloride is administered by IV infusion. IM or subcutaneous administration of methyldopate hydrochloride is not recommended because of unpredictable absorption.

Methyldopate hydrochloride IV infusions are prepared by adding the required dose of the drug to 100 mL of 5% dextrose injection. Alternatively, the required dose may be administered in 5% dextrose injection in a concentration of 100 mg/10 mL. The IV infusion should be administered slowly over a period of 30-60 minutes. ADD-Vantage(R) vials labeled as containing 50 mg/mL of methyldopate hydrochloride should be diluted and administered according to the manufacturer's directions. Vials containing solutions of methyldopate hydrochloride for injection and reconstituted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Methyldopa/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Monoamine oxidase inhibitors (MAOI's) may inhibit the antihypertensive effects of methyldopa.(1)

CLINICAL EFFECTS: Concurrent use of MAOI's and methyldopa may result in hypertensive crisis(2) and/or hallucinations.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(4) UK,(1) and US(5,6) manufacturers of methyldopa state that concurrent use of MAOI's is contraindicated. The US manufacturer of phenelzine states that concurrent use of methyldopa is contraindicated.(2)

DISCUSSION: In a case report, a patient maintained on pargyline developed hallucinations following the increase of her methyldopa from 250 mg daily to 250 mg twice daily.(2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(7,8) Metaxalone is a weak inhibitor of MAO.(9,10)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Alpha-2 Agonists/Tizanidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with other alpha-2 agonists may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of alpha-2 agonists and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tizanidine states concurrent use with other alpha-2 agonists is not recommended.(1) Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4) Alpha-2 agonists linked include: clonidine, dexmedetomidine, guanabenz, guanadrel, guanethidine, guanfacine, methyldopa, and moxonidine.

Methyldopa/Beta-Blockers (Nonselective)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unopposed alpha-adrenergic vasoconstriction produced by alpha-methylnorepinephrine in the presence of beta-blockade.

CLINICAL EFFECTS: Severe hypertension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure during concomitant administration of methyldopa and a nonselective beta-blocker. If hypertension occurs, treatment with phentolamine should be considered.

DISCUSSION: Although methyldopa and propranolol have been used together to treat hypertension, severe increases in blood pressure, including death in one patient, has been reported during administration of these drugs. In addition, methyldopa alone has been reported to cause paradoxical hypertension. Additional studies are needed to define the specific population at risk.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Comt-Metabolized Agents/Entacapone; Opicapone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone and opicapone are selective and reversible inhibitors of catechol-O-methyltransferase (COMT) and drugs that are metabolized by COMT can not be fully metabolized when given with entacapone or opicapone.(1)

CLINICAL EFFECTS: COMT-metabolized agents can interact with entacapone or opicapone and may result in an increased heart rates, arrhythmias, or an excessive change in blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of entacapone and opicapone recommend using caution when administering entacapone or opicapone and a COMT-metabolized agent regardless of the route of administration (including inhalation).(1-3)

DISCUSSION: In an interaction study, ventricular tachycardia was observed after epinephrine and entacapone administration.(1) Another study on the effect of entacapone given with isoproterenol and epinephrine concluded that entacapone may potentiate the chronotropic and arrhythmogenic effects of isoproterenol and epinephrine.(4)

Methyldopa/Sympathomimetics (Direct, Mixed-Acting)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: The pressor response to sympathomimetics may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Start with low doses of sympathomimetics and monitor blood pressure of patients during concurrent administration of sympathomimetics and methyldopa.

DISCUSSION: The pressor response to sympathomimetics has been reported to be increased during methyldopa administration. In addition to increased duration of pressor response, severe hypertension has been reported.

Oral Methyldopa/Oral Iron

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Iron, in several forms, binds strongly to methyldopa, producing iron complexes thereby reducing methyldopa absorption.

CLINICAL EFFECTS: Concomitant use of methyldopa with iron supplementation may decrease the clinical efficacy of methyldopa.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients requiring iron supplementation should be advised to take methyldopa two hours prior to any iron products.

DISCUSSION: In a randomized crossover trial with 12 subjects, concurrent use of methyldopa (500 mg daily) and ferrous sulfate (325 mg daily) showed a 28.4% decrease in the proportion of "free" methyldopa (p<0.01), a 28% increase in the proportion excreted as methyldopa sulfate (p<0.01), and a 21.2% decrease in total absorbed methyldopa (p<0.01). Similar results were found when administering ferrous gluconate (600 mg daily). Antihypertensive effects of methyldopa while taking ferrous sulfate were also assessed in five patients chronically taking methyldopa. All participants showed an increase in systolic blood pressure (p=0.03) after two weeks of ferrous sulfate administration. Diastolic blood pressure increased in four patients (p>0.05). After 14 days, three patients had an increase in systolic pressure greater than 15 mm Hg and two patients had an increase of greater than 10 mm Hg in diastolic blood pressures. Both systolic and diastolic pressures decreased after ferrous sulfate was discontinued.(2)

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

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• Hepatic cirrhosis
• Pheochromocytoma

• Autoimmune hemolytic anemia
• Depression
• Disease of liver
• Hypotension
• Porphyria

• Anemia
• Angina
• Chronic heart failure
• Edema
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Parkinsonism
• Severe cerebrovascular disease

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More Frequent

• Peripheral edema

Less Frequent

• Altered mental status
• Drug fever

Rare or Very Rare

• Acute pancreatitis
• Autoimmune hemolytic anemia
• Cholestasis
• Colitis
• Drug-induced hepatitis
• Granulocytopenic disorder
• Hepatocellular damage
• Leukopenia
• Myocarditis
• Systemic lupus erythematosus
• Thrombocytopenic disorder

More Frequent

• Drowsy
• Headache disorder
• Xerostomia

Less Frequent

• Abnormal sexual function
• Diarrhea
• Erectile dysfunction
• Libido changes
• Nasal congestion
• Nausea
• Orthostatic hypotension

Rare or Very Rare

• Hyperprolactinemia
• Paresthesia
• Sinus bradycardia
• Vomiting

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Reproduction studies in mice, rabbits, and rats using oral methyldopa in dosages of 1000, 200, and 100 mg/kg, respectively, have not revealed evidence of harm to the fetus. These dosages are 16.6, 3.3, and 1.7 times, respectively, the maximum daily human dosage when compared on the basis of body weight and 1.4, 1.1, and 0.2 times, respectively, the maximum daily human dosage when compared on the basis of body surface area.

Methyldopa has been used for many years in the management of hypertension in pregnant women, and the drug is generally considered safe for mother and fetus when used in association with careful prenatal management. Uteroplacental blood flow and fetal hemodynamics have been reported to be stable during therapy with the drug. Although no teratogenic effects have been reported, the possibility that methyldopa may cause fetal injury (e.g., secondary to reduced placental blood flow or fetotoxicity) cannot be excluded.

In neonates born to women treated with methyldopa, systolic blood pressure may be decreased during the first 2-3 days after delivery; in some neonates, tremors have also been reported. Studies to date, including a long-term follow-up study, of children born to women who received methyldopa during pregnancy have not revealed evidence of substantial adverse effects of the drug on the offspring; however, in the longest follow-up study, treatment with methyldopa was associated with a smaller head circumference (without an apparent effect on intelligence quotient) in male offspring of those women whose therapy was initiated between 16 and 20 weeks' gestation. At 4 years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers received methyldopa during pregnancy than in those whose mothers were untreated. Children born to mothers receiving methyldopa scored consistently higher on indices of intellectual and motor development than children born to untreated hypertensive mothers; however, these differences were not apparent by 7.5 years of age.

Methyldopa should be used during pregnancy only when clearly needed. In addition, excessive reduction in blood pressure should be avoided, and a conservative approach to treatment generally should be followed. (See Hypertension during Pregnancy under Uses: Hypertension.)

Since methyldopa is distributed into milk, the drug should be used with caution in nursing women; the possibility of adverse effects on a nursing infant cannot be excluded. The extent to which methyldopa distributes into milk has not been clearly established, but the amount of drug a nursing infant would ingest is believed to be too small to be clinically important; however, if a woman receiving methyldopa breastfeeds, the infant (particularly if preterm) should be monitored for potential systemic effects of the drug (e.g., decreased respiration, blood pressure, or alertness).

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