Brand name: Orvaten
Drug 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

Medically reviewed by Drugs.com on Oct 26, 2023. Written by ASHP.

Introduction

A synthetic sympathomimetic amine structurally similar to methoxamine;^{2 9} a relatively long-acting α₁-selective adrenergic agonist.^{1 3 4 5 6 7 8 9 11 12 13 14}

Uses for Midodrine

Orthostatic Hypotension

Treatment of symptomatic orthostatic hypotension^{1 2 3 4 5 6 7 8 9 10 11 14 17 18 19} (designated an orphan drug by FDA for this use).¹⁵ 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.²² Continue the drug only in patients who report substantial symptomatic improvement.²²

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.^{1 11 12 18 20} May be more effective than comparative drugs (e.g., ephedrine) in managing postural symptoms.^{2 4}

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.^{23 24 25} 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.²⁶ 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.²⁶ 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.^{28 29} 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.²⁸ In September 2014, FDA extended the deadline to March 31, 2015 for final submission of study results and analyses for FDA review.^{30 31}

Midodrine Dosage and Administration

General

• Carefully monitor supine and standing BP in all patients; reduce dosage or discontinue therapy if supine BP increases excessively.^{1 2 18}

Administration

Oral Administration

Administer orally during the hours in which patient is awake, functioning, and pursuing the activities of daily life.^{1 9 18}

Usually administered in 3 equally divided doses daily, without regard to meals.^{1 14}

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.^{1 14} If necessary to provide adequate symptomatic relief, dosing interval may be reduced to 3 hours; shorter intervals are not recommended.¹

To reduce the occurrence of supine hypertension during sleep, do not administer after the evening meal nor <4 hours before bedtime;^{1 14 16 18} avoid a dose if the patient plans to be supine during the day for a length of time.^{1 14 16}

Dosage

Available as midodrine hydrochloride; dosage expressed in terms of the salt.¹

Adults

Orthostatic Hypotension

Oral

10 mg 3 times daily.^{1 20 21}

Alternatively, some clinicians recommend initial dosage of 2.5 mg 2 or 3 times daily;^{2 18} dosage may be gradually increased as needed in increments of 2.5 mg 3 times daily at approximately weekly intervals.^{2 20}

Prescribing Limits

Adults

Orthostatic Hypotension

Oral

Occasionally, dosages >30 mg daily (maximum 40 mg daily) have been tolerated;² however, safety and efficacy of such dosages not studied systematically nor established.¹ Single doses of 20 mg substantially increase the risk of severe and persistent systolic supine hypertension.^{1 21} (See Supine Hypertension under Cautions.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.¹

Renal Impairment

Initially, 2.5-mg doses are recommended.¹

Geriatric Patients

Dosage adjustment not required.¹

Cautions for Midodrine

Contraindications

Severe organic heart disease.¹

Acute renal disease.¹

Urinary retention.¹

Pheochromocytoma.¹

Thyrotoxicosis.¹

Persistent and excessive supine hypertension.¹

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.²² Increased risk of severe and persistent systolic supine hypertension in patients receiving higher than recommended dosages.^{1 21} (See Prescribing Limits under Dosage and Administration.)

Supine hypertension occurs most frequently in patients with increased pretreatment SBP (average 170 mm Hg).²² Use not recommended in patients with initial supine SBP >180 mm Hg.²² Elevated sitting BP also reported.²² Monitor supine and sitting BP during therapy.²²

If supine hypertension occurs, reduce dosage;^{2 20} if supine hypertension persists, withdrawal of the drug may be necessary.¹ Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.^{1 5 17 18 20}

General Precautions

Bradycardia

Possible decreased heart rate, due to vagal reflex.²² If symptoms of bradycardia occur (e.g., decreased pulse, increased dizziness, syncope, cardiac awareness), discontinue therapy and reevaluate patient.²² Use caution if used concomitantly with other agents that reduce heart rate.²² (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.^{1 16}

Diabetes Mellitus

Use with caution in orthostatic hypotensive patients with diabetes mellitus.^{1 16 22}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known if midodrine is distributed into milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 16}

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.²²

Hepatic Impairment

Not studied systematically in patients with hepatic impairment.¹ Use with caution since midodrine is metabolized in part by the liver.¹ (See Elimination under Pharmacokinetics.)

Renal Impairment

Possible increased plasma desglymidodrine concentrations.²² Use with caution and adjust initial dosage.²² Assess renal function prior to initiating therapy.¹

Common Adverse Effects

Supine and sitting hypertension, paresthesias and pruritus (mainly of the scalp), goosebumps, chills, urinary urge, urinary retention, urinary frequency.¹

Drug Interactions

Specific Drugs

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.²²

Absolute bioavailability of midodrine (measured as desglymidodrine) is 93%.²²

Onset

Standing BP is increased by about 10–30 mm Hg 1 hour after oral administration in patients with orthostatic hypotension.^{1 2 5}

Duration

Some effect persists for 2–3 hours.^{1 2 5}

Food

Food does not affect absorption.^{1 22}

Distribution

Extent

Distributed into many tissues; crosses the blood-brain barrier poorly.^{1 2 3 5 22}

Not known whether midodrine is distributed into milk.²²

Plasma Protein Binding

Not significantly bound to plasma proteins.²²

Elimination

Metabolism

Midodrine is deglycinated in many tissues, principally to an active metabolite, desglymidodrine.²²

Midodrine and desglymidodrine are metabolized in part by the liver.²² Neither is a substrate for MAO.¹

Elimination Route

Renal elimination of midodrine is insignificant.²²

Desglymidodrine is eliminated principally by active renal secretion.^{1 22}

Desglymidodrine is removed by dialysis.^{1 22}

Special Populations

Renal impairment may reduce clearance of desglymidodrine.²²

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions and Spectrum

• Midodrine is a prodrug; has little pharmacologic activity until metabolized to desglymidodrine.^{1 2 3 4 9 10 14 17 18}

• Desglymidodrine is a relatively long-acting α₁-selective adrenergic agonist^{1 3 4 5 6 7 8 9 11 12 13 14} that directly affects peripheral α-adrenergic receptors of the arterial and venous vasculature.^{1 2 3 4 5 6 9 11 12 13 17 18}

• Increases SBP and DBP^{1 2 4 5 8 9 17} by increasing vascular tone,^{1 2 3 4 5 6 9 11 12 13 17 18} increasing total peripheral resistance,^{2 5 9 17} and possibly by expansion of extracellular fluid volume.^{4 7 12}

• Has virtually no stimulant effect on β-adrenergic receptors, including those of the heart.^{1 2 3 4 5 6 11 13} Does not generally produce clinically important changes in pulse rates.^{1 5} Generally does not appear to produce appreciable CNS stimulation.^{1 2 3 5}

• 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.^{7 12}

Advice to Patients

• Risk of supine hypertension.¹

• Importance of reporting promptly to their clinician symptoms of supine hypertension (e.g., cardiac awareness, pounding in the ears, headache, blurred vision).¹

• Importance of administering last daily dose at least 4 hours before bedtime to reduce the occurrence of supine hypertension during sleep.^{1 14 16 18} Avoid taking a dose if patient will be supine for any length of time.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

• 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.

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

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