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Midodrine

Pronunciation

Pronunciation

(MI doe dreen)

Index Terms

  • Midodrine HCl
  • Midodrine Hydrochloride
  • ProAmatine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Generic: 2.5 mg, 5 mg, 10 mg

Pharmacologic Category

  • Alpha1 Agonist

Pharmacology

Midodrine forms an active metabolite, desglymidodrine, which is an alpha1-agonist. This agent increases arteriolar and venous tone resulting in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension.

Absorption

Rapid

Distribution

Poorly crosses blood-brain barrier

Metabolism

Hepatic and many other tissues; midodrine is a prodrug which undergoes rapid deglycination to desglymidodrine (active metabolite)

Excretion

Urine (Midodrine: Insignificant; Desglymidodrine: 80% by active renal secretion)

Onset of Action

~1 hour

Time to Peak

Desglymidodrine: 1 to 2 hours; Midodrine: 30 minutes

Duration of Action

2 to 3 hours

Half-Life Elimination

Desglymidodrine: ~3 to 4 hours; Midodrine: 25 minutes

Protein Binding

Minimal

Use: Labeled Indications

Orthostatic hypotension: Treatment of symptomatic orthostatic hypotension

Off Label Uses

Ascites, refractory

Based on American Association for the Study of Liver Diseases clinical practice guidelines for the management of adult patients with ascites due to cirrhosis, midodrine, in addition to diuretics, should be considered for the management of refractory ascites, especially in hypotensive patients.

Dialysis-induced hypotension (prevention)

Data from several small studies (observational, retrospective, prospective, crossover, or pre- and post-intervention) have demonstrated intradialytic and postdialytic hemodynamic improvements (eg, systolic and diastolic blood pressures, MAP) compared to dialysis sessions without the use of midodrine [Cruz 1998], [Prakash 2004].

Based on the KDOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients, midodrine is effective and recommended in the prevention of or the amelioration of the symptoms and severity of dialysis-induced hypotension (also known as intradialytic hypotension).

Hepatorenal Syndrome

Data from a small controlled trial in patients with type 1 hepatorenal syndrome (HRS) treated with midodrine, octreotide, and albumin showed significant improvement in renal plasma flow, glomerular filtration rate, and urinary sodium excretion, although the trial included only 13 patients. Retrospective data also suggest improvement in 30-day mortality with the combination of midodrine, octreotide, and albumin. Based on American Association for the Study of Liver Diseases (AASLD) clinical practice guidelines for the management of adult patients with ascites due to cirrhosis, midodrine in combination with octreotide and albumin should be considered for the treatment of type 1 HRS.

Vasovagal syncope

Data from two randomized, double-blind, placebo-controlled studies in a limited number of patients with frequent syncopal episodes who were not initially treated with non-pharmacologic therapy (eg, adequate fluid and salt intake, regular exercise, or physical counterpressure maneuvers) suggests that the use of midodrine may be beneficial in the treatment of vasovagal syncope [Perez-Lugones 2001], [Ward 1998]. One randomized, double-blind, cross-over, placebo-controlled trial in patients who were refractory to non-pharmacologic therapy found no statistically significant difference between midodrine and placebo for vasovagal syncope recurrence although the follow-up period was only 3 months [Romme 2011]. Clinical experience also suggests the utility of midodrine as first-line pharmacologic therapy in the treatment of patients with vasovagal syncope who are refractory to non-pharmacologic therapy [Schleifer 2015]. Additional studies may be necessary to further define the role of midodrine in the treatment of vasovagal syncope.

Based on the European Society of Cardiology Guidelines for the Diagnosis and Management of Syncope, chronic use of alpha-agonists (eg, midodrine) may be of little use in the treatment of vasovagal syncope and could not be recommended for occasional symptoms. The use of a single dose of midodrine 1 hour prior to an activity that is known to trigger a syncopal episode may be useful in selected patients.

Contraindications

Severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma, thyrotoxicosis, persistent and excessive supine hypertension

Dosing: Adult

Orthostatic hypotension: Oral: 10 mg 3 times daily during daytime hours (every 3 to 4 hours) when patient is upright

Ascites, refractory (off-label use): Oral: 7.5 mg 3 times daily (AASLD [Runyon 2012])

Hepatorenal syndrome (off-label use): Oral: Initial: 5 to 10 mg 3 times daily; may increase to 12.5 mg or 15 mg 3 times daily (with a goal to increase mean arterial pressure [MAP] by at least 15 mm Hg from baseline) (AASLD [Runyon 2012]; Angeli 1999; Esrailian 2007; Garcia-Tsao 2009)

Prevention of hemodialysis-induced hypotension (off-label use): Oral: 2.5 to 10 mg given 15 to 30 minutes prior to dialysis session (Cruz 1998; KDOQI 2005; Prakash 2004)

Vasovagal syncope (off-label use): Oral: Initial: 5 mg 3 times/day during daytime hours (every 6 hours) increased up to 15 mg/dose if necessary (Perez-Lugones 2001; Ward 1998)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Orthostatic hypotension: 2.5 mg 3 times daily; gradually increase as tolerated.

Hemodialysis: Dialyzable

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied); use with caution.

Administration

Doses may be given in approximately 3- to 4-hour intervals (eg, shortly before or upon rising in the morning, at midday, in the late afternoon not later than 6 PM). Avoid dosing after the evening meal or within 4 hours of bedtime. Continue therapy only in patients who appear to attain symptomatic improvement during initial treatment. Standing systolic blood pressure may be elevated 15-30 mm Hg at 1 hour after a 10 mg dose. Some effect may persist for 2-3 hours.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light and moisture.

Drug Interactions

Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha1-Agonists. Similarly, Alpha1-Agonists may antagonize Alpha1-Blocker vasodilation. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Benzylpenicilloyl Polylysine: Alpha1-Agonists may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Consider therapy modification

Beta-Blockers: May enhance the bradycardic effect of Midodrine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the bradycardic effect of Midodrine. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Cardiac Glycosides: May enhance the bradycardic effect of Midodrine. Monitor therapy

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Droxidopa: Midodrine may enhance the hypertensive effect of Droxidopa. Monitor therapy

Ergot Derivatives: May enhance the hypertensive effect of Alpha1-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha1-Agonists. Exceptions: Ergoloid Mesylates; Nicergoline. Avoid combination

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

MAO Inhibitors: May enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Exceptions: Linezolid; Tedizolid. Avoid combination

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha1-Agonists. Tricyclic Antidepressants may diminish the vasopressor effect of Alpha1-Agonists. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Supine hypertension (7% to 13%)

Central nervous system: Paresthesia (18%)

Dermatologic: Piloerection (13%), pruritus (12%)

Genitourinary: Dysuria (≤13%), urinary retention, urinary urgency

Renal: Polyuria

1% to 10%:

Central nervous system: Chills (5%), pain (5%)

Dermatologic: Skin rash (2%)

Gastrointestinal: Abdominal pain

<1% (Limited to important or life-threatening): Anxiety, aphthous stomatitis, back pain, confusion, dizziness, drowsiness, erythema multiforme, facial flushing, flatulence, flushing, gastrointestinal distress, headache, heartburn, hyperesthesia, increased intracranial pressure, insomnia, leg cramps, nausea, visual field defect, weakness, xeroderma, xerostomia

ALERT: U.S. Boxed Warning

Appropriate use:

Because midodrine can cause marked elevation of supine blood pressure, it should be used in patients whose lives are considerably impaired despite standard clinical care. The indication for use of midodrine in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured 1 minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine, principally improved ability to carry out activities of daily living, have not been verified.

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia: May slow heart rate primarily due to vagal reflex. Use caution when administered concurrently with negative chronotropes (eg, digoxin, beta blockers). Discontinue use if signs or symptoms of bradycardia occur.

• Hypertension: May cause supine hypertension; discontinue use immediately if supine hypertension persists. Use with caution when administered concurrently with vasoconstrictors (eg, phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine). Use is not recommended in patients with initial supine systolic pressure >180 mm Hg. Due to marked elevation of supine blood pressure (BP greater than 200 mm Hg systolic), use in patients whose lives are considerably impaired despite standard clinical care, including nonpharmacologic treatment (such as support stockings), fluid expansion, and lifestyle alterations. Supine and sitting blood pressure should be monitored.

Disease-related concerns:

• Diabetes: Use with caution in patients with diabetes mellitus.

• Hepatic impairment: Use with caution in patients with hepatic impairment; has not been studied.

• Renal impairment: Desglymidodrine, the active metabolite, is primarily renally excreted; assess renal function prior to initial dose; use with caution in patients with renal impairment (has not been studied) and initiate with a reduced dose; contraindicated in patients with acute renal failure.

• Visual problems: Use with caution in patients with visual problems, especially if receiving fludrocortisone.

Other warnings/precautions:

• Appropriate use: [U.S. Boxed Warning]: Indicated for patients for whom orthostatic hypotension significantly impairs their daily life despite standard clinical care. Use is not recommended with supine hypertension. Continue therapy only in patients who appear to attain symptomatic improvement during initial treatment.

Monitoring Parameters

Blood pressure; renal and hepatic function

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to the use of midodrine in pregnancy is limited (Glatter, 2005).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience, itching, goosebumps, chills, or polyuria. Have patient report immediately to prescriber bradycardia, severe dizziness, passing out, severe headache, vision changes, tinnitus, urinary retention, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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