MIDODRINE HYDROCHLORIDE- midodrine hydrochloride tablet
NCS HealthCare of KY, LLC dba Vangard Labs
Warning: Because midodrine hydrochloridecan 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 hydrochloridein 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, principally improved ability to carry out activities of daily living, have not been verified.
Name: Midodrine Hydrochloride Tablets, USP
Dosage Form: 2.5 mg, 5 mg and 10 mg tablets for oral administration
Active Ingredient: Midodrine hydrochloride USP, 2.5 mg, 5 mg and 10 mg
Inactive Ingredients: Colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (maize) and talc.
Pharmacological Classification: Vasopressor/Antihypotensive
Chemical Names (USAN: Midodrine Hydrochloride): (1) Acetamide, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-monohydrochloride, (±)-; (2) (±)-2-amino-N-(ß-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride BAN, INN, JAN: Midodrine
Molecular formula: C12 H18 N2 O4 HCl; Molecular Weight: 290.7
Organoleptic Properties: White crystalline powder
Solubility: Freely soluble in formic acid, soluble in water, slightly soluble in ethanol, very slightly soluble in glacial acetic acid, sparingly soluble in methanol, practically insoluble in ethyl ether.
pKa: 7.8 (0.3% aqueous solution)
pH: 4.0 to 5.0 (5% solution in water)Melting Range: About 200ºC
Mechanism of Action: Midodrine hydrochloride forms 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 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 to 30 mmHg at 1 hour after a 10 mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine hydrochloridehas no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.
Pharmacokinetics: Midodrine hydrochlorideis 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 is 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 Potential for Drug Interactions).
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/lightheadedness. Patients with pre-existing 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/lightheadedness/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 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 12mmHg; 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, 2.5, 10, and 20 mg of midodrine were given to 25 patients. The 10 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.
A study with 16 patients undergoing hemodialysis demonstrated that midodrine hydrochloride is removed by dialysis.
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’s 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 tabletsshould be continued only for patients who report significant symptomatic improvement.
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.
Supine Hypertension: The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg were seen overall in about 13.4% of patients given 10 mg of midodrine hydrochloride. 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 in such patients is not recommended. Sitting blood pressures were also elevated by midodrine hydrochloride therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine hydrochloride. Uncontrolled hypertension increases the risk of cardiovascular events, particularly stroke.
The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine hydrochloride 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 is 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, primarily due to vagal reflex. Caution should be exercised when midodrine hydrochloride is 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 and should be re-evaluated.
Midodrine hydrochlorideshould be used cautiously in patients with urinary retention problems, as desglymidodrine acts on the alpha-adrenergic receptors of the bladder neck.
Midodrine hydrochloride 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 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 hydrochlorideshould 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.
Midodrine hydrochloride use has not been studied in patients with hepatic impairment. Midodrine hydrochlorideshould be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine.
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, as they may enhance or potentiate the pressor effects of midodrine hydrochloride(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 3 to 4 hours before bedtime to minimize nighttime supine hypertension.
Since desglymidodrine is eliminated by the kidneys and the liver has a role in its metabolism, evaluation of the patient should include assessment of renal and hepatic function prior to initiating therapy and subsequently, as appropriate.
When administered concomitantly with midodrine hydrochloride, cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia.
The risk of hypertension increases with concomitant administration of drugs that increase blood pressure (phenylephrine, pseudoephedrine, ephedrine, dihydroergotamine, thyroid hormones, or droxidopa). Avoid concomitant use of drugs that increase blood pressure. If concomitant use cannot be avoided, monitor blood pressure closely.
Avoid use of MAO inhibitors or linezolid with midodrine.
Midodrine hydrochloride has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with midodrine hydrochloride. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of midodrine hydrochloride.
It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desyglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs.
Long-term studies have been conducted in rats and mice at dosages 3 to 4 times the maximum recommended daily human dose on a mg/m2 basis, with no indication of carcinogenic effects related to midodrine hydrochloride. Studies investigating the mutagenic potential of midodrine hydrochloriderevealed no evidence of mutagenicity. Other than the dominant lethal assay in male mice, where no impairment of fertility was observed, there have been no studies on the effects of midodrine hydrochlorideon fertility.
Midodrine hydrochlorideincreased the rate of embryo resorption, reduced fetal body weight in rats and rabbits, and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/m2). There are no adequate and well-controlled studies in pregnant women. Midodrine hydrochlorideshould be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects have been observed in studies in rats and rabbits.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when midodrine hydrochloride is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
The most frequent adverse reactions seen in controlled trials were supine and sitting hypertension; paresthesia and pruritus, mainly of the scalp; goosebumps; chills; urinary urge; urinary retention and urinary frequency.
The frequency of these events in a 3-week placebo-controlled trial is shown in the following table:
|1 Includes hyperesthesia and scalp paresthesia2 Includes dysuria (1), increased urinary frequency (2), impaired urination (1), urinary retention (5), urinary urgency (2)3 Includes scalp pruritus4 Includes patients who experienced an increase in supine hypertension5 Includes abdominal pain and pain increase|
|Placebo n=88||Midodrine n=82|
|Event||# of reports||% of patients||# of reports||% of patients|
|Total # of reports||22||77|
Less frequent adverse reactions were headache; feeling of pressure/fullness in the head; vasodilation/flushing face; confusion/thinking abnormality; dry mouth; nervousness/anxiety and rash. Other adverse reactions that occurred rarely were visual field defect; dizziness; skin hyperesthesia; insomnia; somnolence; erythema multiforme; canker sore; dry skin; dysuria; impaired urination; asthenia; backache; pyrosis; nausea; gastrointestinal distress; flatulence and leg cramps.
The most potentially serious adverse reaction associated with midodrine hydrochloridetherapy is supine hypertension. The feelings of paresthesia, pruritus, piloerection and chills are pilomotor reactions associated with the action of midodrine on the alpha-adrenergic receptors of the hair follicles. Feelings of urinary urgency, retention and frequency are associated with the action of midodrine on the alpha-receptors of the bladder neck.
DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.