VA Class:AU100
Midodrine, a synthetic sympathomimetic amine,2, 9 is a prodrug and 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 agonist1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 that acts almost exclusively by a direct effect on peripheral α-adrenergic receptors of the arterial and venous vasculature, increasing vascular tone.1, 2, 3, 4, 5, 6, 9, 11, 12, 13, 17, 18
Midodrine hydrochloride is used in the management of symptomatic orthostatic hypotension;1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 17, 18, 19 the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use.15 This indication is based on the drug's effect on increases in 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit; however, clinical benefits of midodrine (principally improved ability to perform activities of daily living) have not been established.22, 25 The drug should only be continued in patients who report substantial symptomatic improvement after initiation of treatment.22 Midodrine should be used only after nondrug therapies (e.g., support hose, increased sodium intake, life-style modifications) and fluid expansion have failed.1, 11, 12, 18, 20
Clinical studies indicate that midodrine is more effective than placebo2, 4, 5, 17, 18 and at least as effective as ephedrine,2, 4, 17, 18 fludrocortisone,2, 18 or dihydroergotamine2, 18 in the management of orthostatic hypotension. However, despite comparable increases in blood pressure, midodrine may be more effective than comparative drugs (e.g., ephedrine) in managing postural symptoms.2, 4
In 1996, FDA approved use of midodrine for treatment of symptomatic orthostatic hypotension under its accelerated approval regulations, which permit approval of drugs used to treat serious or life-threatening diseases or conditions based upon a surrogate end point (e.g., positive effect on blood pressure) that is believed to predict actual clinical benefits such as improved survival or decreased severity of the disease.23, 24, 25, 26 Pharmaceutical manufacturers that obtain approval under this program are required to conduct additional clinical trials after approval to confirm the drug's benefit; if those trials fail to confirm clinical benefit to patients or if the companies do not pursue the required confirmatory trials with due diligence, FDA can withdraw approval of the drug using expedited procedures.23, 24, 25 In August 2010, FDA proposed to withdraw approval of midodrine hydrochloride 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 has demonstrated the drug's clinical benefit.23, 24, 25 Although the company has conducted several clinical studies of the drug and literature regarding its efficacy has been published, the data submitted to the agency at that time had not verified the clinical benefit that the drug was expected to have.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's Center for Drug Evaluation and Research (CDER) 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 approved an extended deadline until March 31, 2015 for final submission of study results and analyses for FDA review.30, 31
Midodrine increases supine, sitting, and standing diastolic and systolic blood pressures,1, 2, 4, 5, 6, 19, 20, 21 and may attenuate postural symptoms (e.g., dizziness, lightheadedness, syncope, impaired ability to stand).2, 4, 5, 6, 10, 18, 20, 21 In several clinical studies, midodrine decreased supine and standing pulse rates in patients with orthostatic hypotension;2, 3, 4 however, the manufacturer states that clinically important changes in pulse rates generally do not occur in patients with impaired autonomic function receiving the drug.1, 5 There is some evidence that efficacy of midodrine is 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
The most potentially serious adverse effect of midodrine is supine hypertension (systolic blood pressure of 180 mm Hg or higher),1, 2, 9, 14, 17, 18, 20 reported in up to 25% of patients receiving the usual dosage (10 mg 3 times daily)1, 2, 4, 14, 18 of midodrine hydrochloride and in up to 50% of patients receiving 20-mg doses1, 2 of the drug in clinical studies. Patients should be advised to report promptly to their clinician symptoms of supine hypertension (e.g., cardiac awareness, pounding in the ears, headache, blurred vision).1 If supine hypertension occurs, the dosage of midodrine may be reduced;2, 20 withdrawal of the drug may be necessary, particularly if supine hypertension persists.1 Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.1, 5, 17, 18, 20
Concomitant use of midodrine and some vasoconstricting agents (e.g., phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine) may cause an exaggerated hypertensive response.1 Patients receiving midodrine concomitantly with a vasoconstricting agent should be observed for possible additive hypertensive effects.1
Although midodrine used concomitantly with fludrocortisone (with or without sodium supplementation) appears to be well tolerated, patients should be monitored closely for supine hypertension during combination therapy.1 In addition, caution should be exercised in patients with ocular conditions when midodrine is used concomitantly with fludrocortisone (which can increase intraocular pressure and precipitate or aggravate glaucoma).1, 18
Concomitant use of midodrine and agents that can cause bradycardia (e.g., cardiac glycosides, β-adrenergic blocking agents) may cause an exaggerated bradycardic response.1, 17, 20 Patients receiving midodrine concomitantly with such agents should be observed for possible additive bradycardic effects.1
The manufacturer states that midodrine also should be used with caution in patients with diabetes mellitus and in patients with a history of urinary retention.1, 16
Midodrine hydrochloride is administered orally, usually in 3 equally divided doses daily.1, 14 Since food does not appear to affect GI absorption of midodrine hydrochloride, the drug generally can be administered without regard to meals.1
Safety and efficacy of midodrine hydrochloride in children younger than 18 years of age have not been established.1, 16 The manufacturer states that midodrine hydrochloride dosage adjustment based solely on age is not necessary in geriatric patients.1 Dosage adjustment based solely on gender also is not necessary.1
For the management of symptomatic orthostatic hypotension in adults, the recommended initial dosage of midodrine hydrochloride is 10 mg 3 times daily.1, 20, 21 Alternatively, some clinicians recommend an initial dosage of midodrine hydrochloride of 2.5 mg administered 2 or 3 times daily;2, 18 this dosage may be gradually increased as needed in increments of 2.5 mg 3 times daily at approximately weekly intervals.2, 20 Administration of the drug should be during the hours in which the patient is awake, functioning, and pursuing the activities of daily life.1, 9, 18 For patients who are awake and functioning during daylight hours, a suggested dosing schedule is administering the drug 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, the dosing interval may be reduced to 3 hours; shorter intervals are not recommended.1 Because of the risk of supine hypertension during midodrine therapy, the drug should be continued only in patients who experience symptomatic relief.1, 18
Occasionally, midodrine hydrochloride dosages exceeding 30 mg daily (up to a maximum of 40 mg daily) have been tolerated in the management of orthostatic hypotension in adults;2 however, safety and efficacy of such dosages have not been studied systematically nor established.1 Although single doses as high as 20 mg have been used in some patients, the risk of severe and persistent systolic supine hypertension is increased substantially with such doses.1, 21
To reduce the occurrence of supine hypertension during sleep, midodrine hydrochloride should not be administered after the evening meal nor less than 4 hours before bedtime;1, 14, 16, 18 a dose also should be avoided if the patient plans to be supine during the day for a length of time.1, 14, 16 Supine and standing blood pressure should be monitored carefully in all patients receiving midodrine, and dosage should be reduced or therapy with the drug discontinued if supine blood pressure increases excessively.1, 2, 18
Dosage in Renal and Hepatic Impairment
The manufacturer recommends that renal function be assessed prior to initiating midodrine therapy.1 Because the drug's active metabolite (desglymidodrine) is eliminated by renal excretion and because safety and efficacy have not been studied systematically in patients with renal impairment to date, the manufacturer states that midodrine should be dosed cautiously in patients with abnormal renal function.1 The manufacturer recommends that midodrine hydrochloride therapy be initiated with 2.5-mg doses in such adults.1 Desglymidodrine is dialyzable.1
Midodrine has not been studied systematically in patients with hepatic impairment, and the effect of alterations in hepatic function on the disposition of the drug currently is not known.1 Therefore, while the manufacturer currently makes no specific recommendations for dosage adjustment in patients with hepatic impairment, midodrine should be used with caution in such patients.1
Midodrine is a synthetic sympathomimetic amine that is structurally similar to methoxamine.2, 9 Midodrine is a prodrug and has little pharmacologic activity until metabolized to desglymidodrine (St 1059).1, 2, 3, 4, 9, 10, 14, 17, 18
Desglymidodrine is a relatively long-acting α1-selective adrenergic agonist1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14 that acts almost exclusively by a direct effect on peripheral α-adrenergic receptors of the arterial and venous vasculature, increasing vascular tone.1, 2, 3, 4, 5, 6, 9, 11, 12, 13, 17, 18 Total peripheral resistance is increased,2, 5, 9, 17 resulting in increased systolic and diastolic blood pressure.1, 2, 4, 5, 8, 9, 17 Standing blood pressure is increased by about 10-30 mm Hg 1 hour after a 10-mg dose of midodrine hydrochloride in patients with orthostatic hypotension, with some effect persisting for 2-3 hours;1, 2, 5 a 10-mg dose of the drug produces only modest elevations in supine and standing blood pressure in healthy individuals.2 Some evidence suggests that midodrine's efficacy in improving standing blood pressure also may result in part from increased body weight during therapy with the drug, presumably secondary to expansion of extracellular fluid volume.4, 7, 12
Unlike most vasopressors, midodrine has virtually no stimulant effect on β-adrenergic receptors, including those of the heart.1, 2, 3, 4, 5, 6, 11, 13 In addition, because desglymidodrine crosses the blood-brain barrier poorly, the drug generally does not appear to produce appreciable CNS stimulation.1, 2, 3, 5 Because midodrine stimulates the trigone and sphincter of the urinary bladder, symptoms of urinary urgency can occur.1, 5, 9 The drug also stimulates pilomotor muscles, resulting in pilomotor effects (e.g., goose bumps, sensation of hair standing on end),2, 9 and contracts the radial muscle of the iris, resulting in pupillary dilation.9
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 2.5 mg* | Midodrine Hydrochloride Tablets | |
5 mg* | Midodrine Hydrochloride Tablets | |||
Orvaten® | Upsher-Smith | |||
10 mg* | Midodrine Hydrochloride Tablets | |||
Orvaten® | Upsher-Smith |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions November 2, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Roberts Pharmaceutical Corp. ProAmatine® (midodrine hydrochloride) tablets prescribing information (dated 1996 Sep). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:2408-10.
2. McTavish D, Goa KL. Midodrine. Drugs . 1989; 38:757-77. [PubMed 2480881]
3. Zachariah PK, Bloedow DC, Moyer TP et al. Pharmacodynamics of midodrine, an antihypotensive agent. Clin Pharmacol Ther . 1986; 39:586-91. [PubMed 2421958]
4. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med . 1995; 99:604-10. [PubMed 7503082]
5. Jankovic J, Gilden JL, Hiner BC et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med . 1993; 95:38-48. [PubMed 7687093]
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7. Kaufmann H, Brannan T, Krakoff L et al. Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology . 1988; 38:951-56. [PubMed 2452997]
8. Vukovich RA, Caruso FS, Cohen J et al. Correction of severe orthostatic hypotension by midodrine, a new alpha adrenoceptor agonist. Clin Pharmacol Ther . 1989; 45:123.
9. Robertson D, Davis TL. Recent advances in the treatment of orthostatic hypotension. Neurology . 1995; 45(Suppl 5):S26-32. [PubMed 7746370]
10. Low PA. Update on the evaluation, pathogenesis, and management of neurogenic orthostatic hypotension. Neurology . 1995; 45(Suppl 5):S4-5.
11. Bradshaw MJ, Edwards RTM. Postural hypotension-pathophysiology and management. Q J Med . 1986; 60:643-57. [PubMed 2876457]
12. Stumpf JL, Mitrzyk B. Management of orthostatic hypotension. Am J Health-Syst Pharm . 1994; 51:648-60.
13. Lathers CM, Charles JB. Orthostatic hypotension in patients, bed rest subjects, and astronauts. J Clin Pharmacol . 1994; 34:403-17. [PubMed 7522239]
14. Anon. Midodrine marketed for orthostatic hypotension. Am J Health-Syst Pharm . 1996; 53:2552-3. [PubMed 8913378]
15. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.
16. Roberts Pharmaceutical Corp. Eatontown, NJ; personal communication.
17. Anon. Midodrine for orthostatic hypotension. Med Lett Drugs Ther . 1997; 39:59-60. [PubMed 9205432]
18. McClellan KJ, Wiseman LR, Wilde MI. Midodrine: a review of its therapeutic use in the management of orthostatic hypotension. Drugs Aging . 1998; 12:75-86.
19. Jordan J, Shannon JR, Biaggioni I et al. Contrasting actions of pressor agents in severe autonomic failure. Am J Med . 1998;105:116-24. [PubMed 9727818]
20. Barber DB, Rogers SJ, Fredrickson MD et al. Midodrine hydrochloride and the treatment of orthostatic hypotension in tetraplegia: two cases and a review of the literature. Spinal Cord . 2000; 38:109-11. [PubMed 10762185]
21. Wright RA, Kaufmann HC, Perera R et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998; 15:120-4.
22. Shire US Inc. ProAmatine® (midodrine hydrochloride) tablets prescribing information. Newport, KY; 2003 Oct.
23. Food and Drug Administration. FDA alert: FDA Proposes Withdrawal of Low Blood Pressure Drug. Rockville, MD; 2010 Aug 16 (updated 2010 Sep 10). Available from FDA website. Accessed 2010 Nov 29. [Web]
24. Food and Drug Administration. FDA News Release: FDA Proposes Withdrawal of Low Blood Pressure Drug. Rockville, MD; 2010 Aug 16. From FDA website. Accessed 2010 Nov 29. [Web]
25. Woodcock J. Food and Drug Administration. FDA Letter re: Docket no. FDA-2007-N-0475: proposal to withdraw marketing approval; notice of opportunity for a hearing. Silver Spring, MD; 2010 Aug 16. From FDA website. Accessed 2010 Nov 29. [Web]
26. Food and Drug Administration. Midodrine update. Rockville, MD; 2010 Sep 10. Available from FDA website. Accessed 2010 Nov 29. [Web]
27. Shire Plc. Shire provides update on ProAmatine® (midodrine HCl). Phildelphia, PA; 2011 Sep 22. Press release.
28. Food and Drug Administration. Midodrine update. Rockville, MD; 2012 Feb 8. Available from FDA website. Accessed 2012 Oct 12. [Web]
29. Food and Drug Administration. FDA/CDER and Shire Development, Inc. to Margaret A. Hamburg, M.D., FDA Commissioner: Propose to Hold in Abeyance CDER's August 16, 2010 Notice of Opportunity for Hearing - Memo. Silver Spring, MD; 2011 Dec 2. Available from FDA website. Accessed 2012 Nov 3. [Web]
30. Food and Drug Administration. Amendment to Joint Agreement from FDA/CDER and Shire Development, Inc. to the FDA Commissioner re Midodrine Amendment August 25, 2014. Silver Spring, MD; 2014 Aug 25. Available from FDA website. Accessed 2015 Aug 14. [Web]
31. Food and Drug Administration. Response Letter from Office of the Commissioner Acting Chief Scientist to FDA/CDER and Shire Development, Inc., re Midodrine Amendment August 25, 2014. Silver Spring, MD; 2014 Sep 11. Available from FDA website. Accessed 2015 Aug 14. [Web]