Midodrine hydrochloride is used in the management of symptomatic orthostatic hypotension; the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use. 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. The drug should only be continued in patients who report substantial symptomatic improvement after initiation of treatment. Midodrine should be used only after nondrug therapies (e.g., support hose, increased sodium intake, life-style modifications) and fluid expansion have failed.
Clinical studies indicate that midodrine is more effective than placebo and at least as effective as ephedrine, fludrocortisone, or dihydroergotamine 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.
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. 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. 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. FDA stated that neither the original manufacturer (Shire) nor any generic manufacturer has demonstrated the drug's clinical benefit. 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. 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'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. 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 approved an extended deadline until March 31, 2015 for final submission of study results and analyses for FDA review.
Midodrine increases supine, sitting, and standing diastolic and systolic blood pressures, and may attenuate postural symptoms (e.g., dizziness, lightheadedness, syncope, impaired ability to stand). In several clinical studies, midodrine decreased supine and standing pulse rates in patients with orthostatic hypotension; however, the manufacturer states that clinically important changes in pulse rates generally do not occur in patients with impaired autonomic function receiving the drug. 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.
The most potentially serious adverse effect of midodrine is supine hypertension (systolic blood pressure of 180 mm Hg or higher), reported in up to 25% of patients receiving the usual dosage (10 mg 3 times daily) of midodrine hydrochloride and in up to 50% of patients receiving 20-mg doses 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). If supine hypertension occurs, the dosage of midodrine may be reduced; withdrawal of the drug may be necessary, particularly if supine hypertension persists. Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.
Concomitant use of midodrine and some vasoconstricting agents (e.g., phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine) may cause an exaggerated hypertensive response. Patients receiving midodrine concomitantly with a vasoconstricting agent should be observed for possible additive hypertensive effects.
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. 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).
Concomitant use of midodrine and agents that can cause bradycardia (e.g., cardiac glycosides, β-adrenergic blocking agents) may cause an exaggerated bradycardic response. Patients receiving midodrine concomitantly with such agents should be observed for possible additive bradycardic effects.
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.