Prescription Drug Information: Midodrine Hydrochloride

MIDODRINE HYDROCHLORIDE- midodrine hydrochloride tablet
Xiromed, LLC

midodrine2-5mgmidodrine-5mgmidodrine-10mg

MIDODRINE HYDROCHLORIDE
TABLETS, USP
2.5 mg, 5 mg and 10 mg

WARNING

Because midodrine hydrochloride tablets 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 hydrochloride tablets 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 one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine hydrochloride tablets, principally improved ability to carry out activities of daily living, have not been verified.

DESCRIPTION

Midodrine hydrochloride is a vasopressor/antihypotensive. The chemical name for midodrine hydrochloride is acetamide, 2-amino-N -[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-, monohydrochloride, (±)-. The molecular weight of midodrine hydrochloride is 290.7. Its structural formula and molecular formula are:

Structural Formula

Midodrine hydrochloride, USP is an odorless, white, crystalline powder. It is soluble in water and sparingly soluble in methanol and has a pKa of 7.8 (0.3% aqueous solution) and a pH of 3.5 to 5.5 (5% aqueous solution). It has a melting range of 200° to 203°C.

Each midodrine hydrochloride tablet, USP for oral administration contains 2.5 mg, 5 mg or 10 mg of midodrine hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

CLINICAL PHARMACOLOGY

Mechanism of Action

Midodrine hydrochloride tablets form an active metabolite, desglymidodrine, that is an alpha1 -agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system.

Administration of midodrine hydrochloride tablets results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 mmHg to 30 mmHg at 1 hour after a 10 mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine hydrochloride tablets have no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

Pharmacokinetics

Midodrine hydrochloride tablets are a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine, formed by deglycination of midodrine. After oral administration, midodrine hydrochloride tablets are rapidly absorbed. The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent.

Metabolism and Excretion

Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase.

Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases (see also PRECAUTIONS: Potential for Drug Interactions).

Clinical Studies

Midodrine has been studied in 3 principal controlled trials, one of 3-weeks duration and 2 of 1 to 2 days duration. All studies were randomized, double-blind and parallel-design trials in patients with orthostatic hypotension of any etiology and supine-to-standing fall of systolic blood pressure of at least 15 mmHg accompanied by at least moderate dizziness/light-headedness. Patients with preexisting sustained supine hypertension above 180/110 mmHg were routinely excluded. In a 3-week study in 170 patients, most previously untreated with midodrine, the midodrine-treated patients (10 mg t.i.d., with the last dose not later than 6 P.M.) had significantly higher (by about 20 mmHg) 1-minute standing systolic pressure 1 hour after dosing (blood pressures were not measured at other times) for all 3 weeks. After week 1, midodrine-treated patients had small improvements in dizziness/light-headedness/unsteadiness scores and global evaluations, but these effects were made difficult to interpret by a high early drop-out rate (about 25% vs. 5% on placebo). Supine and sitting blood pressure rose 16/8 mmHg and 20/10 mmHg, respectively, on average.

In a 2-day study, after open-label midodrine, known midodrine responders received midodrine 10 mg or placebo at 0, 3, and 6 hours. One-minute standing systolic blood pressures were increased 1 hour after each dose by about 15 mmHg and 3 hours after each dose by about 12 mmHg; 3-minute standing pressures were increased also at 1, but not 3, hours after dosing. There were increases in standing time seen intermittently 1 hour after dosing, but not at 3 hours.

In a 1-day, dose-response trial, single doses of 0 mg, 2.5 mg, 10 mg, and 20 mg of midodrine were given to 25 patients. The 10 mg and 20 mg doses produced increases in standing 1-minute systolic pressure of about 30 mmHg at 1 hour; the increase was sustained in part for 2 hours after 10 mg and 4 hours after 20 mg. Supine systolic pressure was ≥ 200 mmHg in 22% of patients on 10 mg and 45% of patients on 20 mg; elevated pressures often lasted 6 hours or more.

Special Populations

A study with 16 patients undergoing hemodialysis demonstrated that midodrine hydrochloride tablets are removed by dialysis.

INDICATIONS AND USAGE

Midodrine hydrochloride tablets are indicated for the treatment of symptomatic orthostatic hypotension (OH). Because midodrine hydrochloride tablets can cause marked elevation of supine blood pressure (BP > 200 mmHg systolic), it should be used in patients whose lives are considerably impaired despite standard clinical care, including non-pharmacologic treatment (such as support stockings), fluid expansion, and lifestyle alterations. The indication is based on midodrine hydrochloride tablets’ effect on increases in 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine hydrochloride tablets, principally improved ability to perform life activities, have not been established. Further clinical trials are underway to verify and describe the clinical benefits of midodrine hydrochloride tablets. After initiation of treatment, midodrine hydrochloride tablets should be continued only for patients who report significant symptomatic improvement.

CONTRAINDICATIONS

Midodrine hydrochloride tablets are contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine hydrochloride tablets should not be used in patients with persistent and excessive supine hypertension.

WARNINGS

Supine Hypertension

The most potentially serious adverse reaction associated with midodrine hydrochloride tablets therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressures of about 200 mmHg were seen overall in about 13.4% of patients given 10 mg of midodrine hydrochloride tablets. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pre-treatment systolic blood pressures (mean 170 mmHg). There is no experience in patients with initial supine systolic pressure above 180 mmHg, as those patients were excluded from the clinical trials. Use of midodrine hydrochloride tablets in such patients is not recommended. Sitting blood pressures were also elevated by midodrine hydrochloride tablets therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine. Uncontrolled hypertension increases the risk of cardiovascular events, particularly stroke.

PRECAUTIONS

General

The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine hydrochloride tablets therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine, i.e., sleeping with the head of the bed elevated. The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. The patient should be advised to discontinue the medication immediately if supine hypertension persists.

Blood pressure should be monitored carefully when midodrine hydrochloride tablets are used concomitantly with other agents that cause vasoconstriction, such as phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, or pseudoephedrine.

A slight slowing of the heart rate may occur after administration of midodrine hydrochloride tablets, primarily due to vagal reflex. Caution should be exercised when midodrine hydrochloride tablets are used concomitantly with cardiac glycosides (such as digitalis), psychopharmacologic agents, beta blockers or other agents that directly or indirectly reduce heart rate. Patients who experience any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) should be advised to discontinue midodrine hydrochloride tablets and should be reevaluated.

Midodrine hydrochloride tablets should be used cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck.

Midodrine hydrochloride tablets should be used with caution in orthostatic hypotensive patients who are also diabetic, as well as those with a history of visual problems who are also taking fludrocortisone acetate, which is known to cause an increase in intraocular pressure and glaucoma.

Midodrine hydrochloride tablets use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys, and higher blood levels would be expected in such patients, midodrine hydrochloride tablets should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg (see DOSAGE AND ADMINISTRATION). Renal function should be assessed prior to initial use of midodrine hydrochloride tablets.

Midodrine hydrochloride tablets use has not been studied in patients with hepatic impairment. Midodrine hydrochloride tablets should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine.

Information for Patients

Patients should be told that certain agents in over-the-counter products, such as cold remedies and diet aids, can elevate blood pressure, and therefore, should be used cautiously with midodrine hydrochloride tablets, as they may enhance or potentiate the pressor effects of midodrine hydrochloride tablets (see Drug Interactions). Patients should also be made aware of the possibility of supine hypertension. They should be told to avoid taking their dose if they are to be supine for any length of time, i.e., they should take their last daily dose of midodrine hydrochloride tablets 3 to 4 hours before bedtime to minimize nighttime supine hypertension.

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