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Midodrine

Class: alpha-Adrenergic Agonists
VA Class: AU100
Chemical Name: 2-Amino-N-[2-(2,5-dimethoxyphenyl)-2 -hydroxyethyl]-acetamide monohydrochloride
Molecular Formula: C12H18N2O4 • HCl
CAS Number: 3092-17-9
Brands: Orvaten

Medically reviewed by Drugs.com on Oct 26, 2021. Written by ASHP.

Warning

  • Possible marked supine hypertension; use recommended only in patients whose lives are considerably impaired despite standard care. Clinical benefits of therapy likely correspond with increases in 1-minute SBP (surrogate marker of therapeutic efficacy). However, clinical benefits of midodrine therapy (e.g., improved ability to carry out activities of daily living) not established. (See Orthostatic Hypotension under Uses.)

Introduction

A synthetic sympathomimetic amine structurally similar to methoxamine; a relatively long-acting α1-selective adrenergic agonist.

Uses for Midodrine

Orthostatic Hypotension

Treatment of symptomatic orthostatic hypotension (designated an orphan drug by FDA for this use). Indication is based on effect on increases in 1-minute standing systolic BP, a surrogate marker; clinical benefits (principally improved ability to perform life activities) not established. Continue the drug only in patients who report substantial symptomatic improvement.

Use recommended only in patients whose lives are considerably impaired despite standard clinical care; use only after nondrug therapies (e.g., support hose, increased sodium intake, life-style modifications) and fluid expansion have failed. May be more effective than comparative drugs (e.g., ephedrine) in managing postural symptoms.

In August 2010, FDA proposed to withdraw approval of midodrine because required postapproval studies verifying the clinical benefit of the drug had not been done. FDA stated that neither the original manufacturer (Shire) nor any generic manufacturer had demonstrated clinical benefit (e.g., performance of life activities); data submitted had not verified expected clinical benefit. In September 2010, FDA clarified that its proposal was part of the regulatory process and that midodrine could remain on the market as that process moves forward. Subsequently, FDA and Shire reached an agreement that Shire would conduct 2 additional clinical studies to verify the clinical benefit of midodrine in patients with symptomatic orthostatic hypotension. In February 2012, FDA announced that the proposal to withdraw approval of midodrine will be deferred until these studies have been conducted; meanwhile, the drug remains approved and available on the US market. In September 2014, FDA extended the deadline to March 31, 2015 for final submission of study results and analyses for FDA review.

Midodrine Dosage and Administration

General

  • Carefully monitor supine and standing BP in all patients; reduce dosage or discontinue therapy if supine BP increases excessively.

Administration

Oral Administration

Administer orally during the hours in which patient is awake, functioning, and pursuing the activities of daily life.

Usually administered in 3 equally divided doses daily, without regard to meals.

Administer at approximately 4-hour intervals shortly before or upon arising in the morning, midday, and late afternoon, but not later than 6 p.m. If necessary to provide adequate symptomatic relief, dosing interval may be reduced to 3 hours; shorter intervals are not recommended.

To reduce the occurrence of supine hypertension during sleep, do not administer after the evening meal nor <4 hours before bedtime; avoid a dose if the patient plans to be supine during the day for a length of time.

Dosage

Available as midodrine hydrochloride; dosage expressed in terms of the salt.

Adults

Orthostatic Hypotension
Oral

10 mg 3 times daily.

Alternatively, some clinicians recommend initial dosage of 2.5 mg 2 or 3 times daily; dosage may be gradually increased as needed in increments of 2.5 mg 3 times daily at approximately weekly intervals.

Prescribing Limits

Adults

Orthostatic Hypotension
Oral

Occasionally, dosages >30 mg daily (maximum 40 mg daily) have been tolerated; however, safety and efficacy of such dosages not studied systematically nor established. Single doses of 20 mg substantially increase the risk of severe and persistent systolic supine hypertension. (See Supine Hypertension under Cautions.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.

Renal Impairment

Initially, 2.5-mg doses are recommended.

Geriatric Patients

Dosage adjustment not required.

Cautions for Midodrine

Contraindications

Severe organic heart disease.

Acute renal disease.

Urinary retention.

Pheochromocytoma.

Thyrotoxicosis.

Persistent and excessive supine hypertension.

Warnings/Precautions

Warnings

Supine Hypertension

Supine hypertension (SBP of about 200 mm Hg) has been reported in up to 13.4% of patients receiving the usual dosage (10 mg 3 times daily); symptoms may include cardiac awareness, pounding in the ears, headache, and blurred vision. Increased risk of severe and persistent systolic supine hypertension in patients receiving higher than recommended dosages. (See Prescribing Limits under Dosage and Administration.)

Supine hypertension occurs most frequently in patients with increased pretreatment SBP (average 170 mm Hg). Use not recommended in patients with initial supine SBP >180 mm Hg. Elevated sitting BP also reported. Monitor supine and sitting BP during therapy.

If supine hypertension occurs, reduce dosage; if supine hypertension persists, withdrawal of the drug may be necessary. Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.

General Precautions

Bradycardia

Possible decreased heart rate, due to vagal reflex. If symptoms of bradycardia occur (e.g., decreased pulse, increased dizziness, syncope, cardiac awareness), discontinue therapy and reevaluate patient. Use caution if used concomitantly with other agents that reduce heart rate. (See Specific Drugs under Interactions.)

Urinary Retention

Use with caution in patients with a history of urinary retention due to midodrine’s α-adrenergic activity at the bladder neck.

Diabetes Mellitus

Use with caution in orthostatic hypotensive patients with diabetes mellitus.

Specific Populations

Pregnancy

Category C.

Lactation

Not known if midodrine is distributed into milk. Use with caution.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Plasma midodrine and desglymidodrine concentrations in patients ≥65 years of age do not appear to differ from those in younger adults; dosage adjustment not required.

Hepatic Impairment

Not studied systematically in patients with hepatic impairment. Use with caution since midodrine is metabolized in part by the liver. (See Elimination under Pharmacokinetics.)

Renal Impairment

Possible increased plasma desglymidodrine concentrations. Use with caution and adjust initial dosage. Assess renal function prior to initiating therapy.

Common Adverse Effects

Supine and sitting hypertension, paresthesias and pruritus (mainly of the scalp), goosebumps, chills, urinary urge, urinary retention, urinary frequency.

Interactions for Midodrine

Specific Drugs

Drug

Interaction

Comment

α-Adrenergic blocking agents (e.g., prazosin, terazosin, doxazosin)

Possible antagonistic effects

Antiarrhythmic agents (flecainide, procainamide, quinidine)

Possible pharmacokinetic interaction due to shared active renal tubular secretion

β-Adrenergic blocking agents

Possible additive bradycardic effects

Observe for additive bradycardic effects when administered concomitantly

Cardiac glycosides

Possible additive bradycardic effects

Observe for additive bradycardic effects when administered concomitantly

Fludrocortisone

Possible increased risk of supine hypertension

Possible increased intraocular pressure and precipitation or aggravation of glaucoma

To minimize risk of supine hypertension, decrease fludrocortisone dose or decrease salt intake prior to initiating midodrine therapy; monitor closely for supine hypertension during combination therapy

Use concomitantly with caution in patients with ocular conditions

Histamine H2-receptor antagonists (cimetidine, ranitidine)

Possible pharmacokinetic interaction due to shared active renal tubular secretion

Metformin

Possible pharmacokinetic interaction due to shared active renal tubular secretion

Psychopharmacologic agents

Possible additive bradycardic effects

Observe for additive bradycardic effects when midodrine is administered concomitantly with agents that decrease heart rate

Triamterene

Possible pharmacokinetic interaction due to shared active renal tubular secretion

Vasoconstricting agents (e.g., phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine)

Possible additive hypertensive effects

Observe for additive hypertensive effects when administered concomitantly

Midodrine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, midodrine is rapidly absorbed and then undergoes deglycination to form desglymidodrine; peak plasma concentration of midodrine and desglymidodrine usually attained within 0.5 and 1–2 hours, respectively.

Absolute bioavailability of midodrine (measured as desglymidodrine) is 93%.

Onset

Standing BP is increased by about 10–30 mm Hg 1 hour after oral administration in patients with orthostatic hypotension.

Duration

Some effect persists for 2–3 hours.

Food

Food does not affect absorption.

Distribution

Extent

Distributed into many tissues; crosses the blood-brain barrier poorly.

Not known whether midodrine is distributed into milk.

Plasma Protein Binding

Not significantly bound to plasma proteins.

Elimination

Metabolism

Midodrine is deglycinated in many tissues, principally to an active metabolite, desglymidodrine.

Midodrine and desglymidodrine are metabolized in part by the liver. Neither is a substrate for MAO.

Elimination Route

Renal elimination of midodrine is insignificant.

Desglymidodrine is eliminated principally by active renal secretion.

Desglymidodrine is removed by dialysis.

Special Populations

Renal impairment may reduce clearance of desglymidodrine.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions and Spectrum

  • Midodrine is a prodrug; has little pharmacologic activity until metabolized to desglymidodrine.

  • Desglymidodrine is a relatively long-acting α1-selective adrenergic agonist that directly affects peripheral α-adrenergic receptors of the arterial and venous vasculature.

  • Increases SBP and DBP by increasing vascular tone, increasing total peripheral resistance, and possibly by expansion of extracellular fluid volume.

  • Has virtually no stimulant effect on β-adrenergic receptors, including those of the heart. Does not generally produce clinically important changes in pulse rates. Generally does not appear to produce appreciable CNS stimulation.

  • Efficacy may be related to autonomic function; patients with less severe autonomic dysfunction may benefit from midodrine therapy to a greater extent than those with severe autonomic dysfunction.

Advice to Patients

  • Risk of supine hypertension.

  • Importance of reporting promptly to their clinician symptoms of supine hypertension (e.g., cardiac awareness, pounding in the ears, headache, blurred vision).

  • Importance of administering last daily dose at least 4 hours before bedtime to reduce the occurrence of supine hypertension during sleep. Avoid taking a dose if patient will be supine for any length of time.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In August 2010, FDA proposed to withdraw approval of midodrine hydrochloride; however, the drug remains on the US market while additional clinical studies are conducted.

(See Orthostatic Hypotension under Uses.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Midodrine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg*

Midodrine Hydrochloride Tablets

Orvaten

Upsher-Smith

5 mg*

Midodrine Hydrochloride Tablets

Orvaten

Upsher-Smith

10 mg*

Midodrine Hydrochloride Tablets

Orvaten

Upsher-Smith

AHFS DI Essentials™. © Copyright 2022, Selected Revisions November 5, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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