Amatine

After oral administration, midodrine is rapidly and almost completely absorbed, with a mean absolute bioavailability (as desglymidodrine) of 93%.

After the oral administration of 2.5 mg midodrine in a single dose to 12 volunteers, the mean peak concentration of unchanged midodrine is approximately 10 ng/mL and it occurs after 20 to 30 minutes, with a terminal plasma half-life of 0.4 to 0.5 hours. The mean plasma concentration of the active metabolite, desglymidodrine, peaks in approximately 1 hour, with a plasma half-life of approximately 3 hours after the oral administration of 2.5 mg midodrine.

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.

Both midodrine and desglymidodrine are quickly eliminated from the body, mostly by the kidneys. The renal clearance of desglymidodrine is approximately 385 mL/min, most, about 80%, by active 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 Precautions, Drug Interactions). Approximately 91% of the administered dose is excreted in the urine in 24 hours. Of the urinary material, 40-60% is present as desglymidodrine and approximately 2-5%, as non-metabolized midodrine. Unidentified breakdown products do not exceed 3.9% of the urinary material. Midodrine diffuses poorly across the blood-brain barrier.

Glycosides: When administered concomitantly with midodrine, glycosides (e.g., digitalis) may enhance or precipitate bradycardia, A.V. block or arrhythmia.

Sympathomimetic and Other Vasopressor Agents: The use of drugs that stimulate alpha-adrenoceptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine, dihydroergotamine, sympathomimetic/vasopressor antidepressants, thyroid hormones, or MAO-inhibitors) may enhance or potentiate the pressor effects of midodrine. Therefore, midodrine should not be used concomitantly with vasoconstrictor sympathomimetic agents and the patient should be warned not to use over-the-counter preparations containing these drugs.

Sympatholytic Agents: Alpha-adrenoceptor antagonists such as phentolamine, prazosin, doxazosin and labetalol can inhibit the vasopressor effect of midodrine. Concomitant use of midodrine and alpha-receptor blocking agents and beta-receptor blocking agents which may reduce the heart rate; requires careful monitoring.

Corticosteroids: Patients on salt-retaining steroids (e.g., fludrocortisone), with or without salt supplementation, may experience an excessive pressor effect after midodrine therapy, especially in the supine posture. The possibility of hypertensive effects with midodrine can be minimized by either reducing the dose of fludrocortisone or decreasing the salt intake prior to initiation of treatment with midodrine. Patients being treated with midodrine in combination with mineralcorticoids or glucocorticoids (e.g., fludrocortisone) may be at increased risk of glaucoma/increased intraocular pressure, and should be carefully monitored.

Atropine: Midodrine may enhance or potentiate the blood-pressure raising effect of atropine.

Rauwolfia Alkaloids: The presence of rauwolfia alkaloids (reserpine) slightly increases the pressor effects of midodrine.

Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (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.

Effects of Ability to Drive and Use Machinery: negligible influence; However, in case of dizziness or lightheadedness, care should be taken when driving vehicles or operating machinery.

Evaluation of the patient should include assessment of renal and hepatic function prior to initiation of therapy, and during treatment, when appropriate.

It is not known if midodrine is excreted in human milk, therefore midodrine should not be used during lactation.

Safety and effectiveness in children under the age of 12 have not been established. In view of the lack of experience in children, the drug is not recommended for patients under 12 years of age.

The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine therapy. Supine hypertension can often be controlled by an adjustment in midodrine dosage and/or 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. Patients should be monitored for possible secondary events to hypertension. It is advisable always to monitor the blood pressure and renal function in patients undergoing long-term treatment with midodrine.

Diabetes Mellitus and/or Increased Intra-ocular Pressure: Midodrine 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. The use of midodrine in patients who have an increased risk of or suffer from glaucoma/increased intra-ocular pressure should be avoided or monitored very closely (see Contraindications).

Renal Impairment: Midodrine 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 should be used with caution in patients with renal impairment, with a starting dose not higher than 2.5 mg (see Dosage) and the patient's blood pressure should be monitored closely. Renal function should be assessed prior to initial use of midodrine and when appropriate during therapy (see Contraindications).

Hepatic Impairment: Midodrine has not been studied in patients with hepatic impairment. Midodrine should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine. It is therefore recommended to evaluate the hepatic parameters before starting treatment with midodrine and on a continuous basis thereafter.

Urinary Retention: Midodrine may induce an increase in the tone of the internal sphincter of the urinary bladder which may lead to urinary retention. Midodrine also may affect the bladder trigone which may result in a delayed response to bladder filling. Initial signs of urinary retention are manifested clinically as hesitancy or change in frequency of micturition. Patients should be told to report promptly any indication of urinary retention (e.g., hesitancy or frequency of micturition) which may be a sign of urinary retention (see Contraindications).

Midodrine should be used with caution in patients with urinary tract outflow obstruction, neurogenic bladder or similar conditions, since midodrine and desglymidodrine are eliminated by the kidneys and accumulation may occur in such patients.

No teratogenic effects have been observed in studies in animals. At very high doses (20 mg/kg/day) the drug was toxic to dams and fetal loss occurred. There are no data on the use of midodrine in pregnant women. It is therefore not advisable to use midodrine hydrochloride in women aiming at becoming pregnant. Any woman getting pregnant during treatment should be withdrawn from the treatment immediately upon established pregnancy.

Each oral, orange tablet, scored on one side with “RPC” engraved above the score line, “5.0” below, and “004” on the other side, contains: midodrine HCl 5 mg. Nonmedicinal ingredients: color FD&C Yellow No. 6 Lake, cornstarch, highly dispersed silicone dioxide, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and talc. Amber glass bottles of 100 with plastic cap to cap LDPE closures.

Store between 15 to 25°C.

Each oral, white tablet, scored on one side with “RPC” engraved above the score line, and “2.5” below, and “003” on the other side, contains: midodrine HCl 2.5 mg. Nonmedicinal ingredients: cornstarch, highly dispersed silicone dioxide, magnesium stearate, microcrystalline cellulose (Avicel PH 101) and talc. Amber glass bottles of 100 with plastic cap to cap LDPE closures.

In the 938 patients treated in controlled and uncontrolled trials, the following adverse events, regardless of causality, occurred at a frequency greater than 0.5% or occurred at a lower rate but were potentially important: asthenia, chills, dizziness, dyspepsia, dyspnea, hair disease, headache, hypertension, nausea, nervousness, pain, paresthesia, paresthesia of scalp, piloerection, vasodilation, pruritus, pruritus of scalp, rash, supine hypertension, urine retention, urine urgency.

The most potentially serious adverse reaction associated with midodrine therapy 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.

Laboratory Abnormalities: There were no clinically significant changes to laboratory parameters.

The following adverse events have also been reported with the use of midodrine: very common (>1/10); common ( >1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10 000, < 1/1000); very rare (<1/10 000).

Psychiatric Disorders: uncommon: sleep disorders, insomnia.

Nervous System Disorders: uncommon: restlessness, excitability, irritability.

Cardiac Disorders: uncommon: reflex bradycardia; rare: tachycardia.

Gastrointestinal Disorders: common: heartburn, stomatitis.

Hepatobiliary Disorders: rare: hepatic function abnormal, raised liver enzymes.

Skin and Subcutaneous Tissue Disorders: common: flushing, skin rash.

Vascular Disorders: common: supine hypertension (blood pressure above 180/110 mm Hg) with daily doses above 30 mg; uncommon: supine hypertension (blood pressure above 180/110 mm Hg) with daily doses above 7.5 mg.

Symptoms of overdose could include hypertension, piloerection (goose bumps), a sensation of coldness and urinary retention. There are 2 reported cases of overdosage with midodrine, both in young males. One patient ingested midodrine drops, 250 mg; experienced systolic blood pressure of greater than 200 mm Hg; was treated with an i.v. injection of 20 mg of phentolamine; and was discharged the same night without any complaints. The other patient ingested 205 mg of midodrine (41×5 mg tablets) and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardiac. Gastric lavage was performed, and the patient recovered fully by the next day without sequelae.

The single doses that would be associated with symptoms of overdosage or would be potentially life-threatening are unknown. The oral LD₅₀ is approximately 30 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 to 160 mg/kg in dogs.

Beside basic life support, recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine, nitroprusside, nitroglycerin). Bradycardia and bradycardic conduction defects can be counteracted by atropine.

Desglymidodrine is dialyzable.

Blood levels of midodrine and desglymidodrine were similar in patients 65 years or older versus those younger than 65 years suggesting that dosage adjustment is not necessary in elderly patients provided that their renal and liver functions are adequate.

Midodrine should be used cautiously and the starting dose should not be higher than 2.5 mg (see Precautions, Renal Impairment and Hepatic Impairment).

Dosing in children has not been studied as patients 18 years or younger were excluded from the clinical trials.