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Midodrine Hydrochloride

Pronunciation

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, ProAmatine

Warning(s)

  • Possible marked supine hypertension; use recommended only in patients whose lives are considerably impaired despite standard care.22 Clinical benefits of therapy likely correspond with increases in 1-minute SBP (surrogate marker of therapeutic efficacy).22 However, clinical benefits of midodrine therapy (e.g., improved ability to carry out activities of daily living) not established.22 (See Orthostatic Hypotension under Uses.)

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 Hydrochloride

Orthostatic Hypotension

Treatment of symptomatic orthostatic hypotension1 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

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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 have not been done.23 24 25 FDA stated that neither the original manufacturer (Shire) nor any generic manufacturer has demonstrated clinical benefit (e.g., performance of life activities); data submitted have 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'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

Midodrine Hydrochloride 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 Hydrochloride

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

Interactions for Midodrine Hydrochloride

Specific Drugs

Drug

Interaction

Comment

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

Possible antagonistic effects1

Antiarrhythmic agents (flecainide, procainamide, quinidine)

Possible pharmacokinetic interaction due to shared active renal tubular secretion 1

β-Adrenergic blocking agents

Possible additive bradycardic effects1 17 20

Observe for additive bradycardic effects when administered concomitantly1

Cardiac glycosides

Possible additive bradycardic effects1 17 20

Observe for additive bradycardic effects when administered concomitantly1

Fludrocortisone

Possible increased risk of supine hypertension22

Possible increased intraocular pressure and precipitation or aggravation of glaucoma1 18

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 therapy1

Use concomitantly with caution in patients with ocular conditions 1 18

Histamine H2-receptor antagonists (cimetidine, ranitidine)

Possible pharmacokinetic interaction due to shared active renal tubular secretion 1

Metformin

Possible pharmacokinetic interaction due to shared active renal tubular secretion 1

Psychopharmacologic agents

Possible additive bradycardic effects1 17 20

Observe for additive bradycardic effects when midodrine is administered concomitantly with agents that decrease heart rate1

Triamterene

Possible pharmacokinetic interaction due to shared active renal tubular secretion 1

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

Possible additive hypertensive effects1

Observe for additive hypertensive effects when administered concomitantly1

Midodrine Hydrochloride 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 agonist1 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 DBP1 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.

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.23 24 25 26 28

(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

ProAmatine (scored)

Shire

5 mg*

Midodrine Hydrochloride Tablets

Orvaten

Upsher-Smith

ProAmatine (scored)

Shire

10 mg*

Midodrine Hydrochloride Tablets

Orvaten

Upsher-Smith

ProAmatine (scored)

Shire

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Shire US Inc. ProAmatine (midodrine hydrochloride) tablets prescribing information. Florence, KY; 2002 Feb.

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. [IDIS 216072] [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. [IDIS 360182] [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. [IDIS 317913] [PubMed 7687093]

6. Schirger A, Sheps SG, Thomas JE et al. Midodrine. A new agent in the management of idiopathic orthostatic hypotension and Shy-Drager syndrome. Mayo Clin Proc. 1981; 56:429-33. [IDIS 134137] [PubMed 6166817]

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. [IDIS 242650] [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. [IDIS 347684] [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. [IDIS 219781] [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. [IDIS 330851] [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.

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.

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.

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.

26. Food and Drug Administration. Midodrine update. Rockville, MD; 2010 Sep 10. Available from FDA website (). Accessed 2010 Nov 29.

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.

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.

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