Midodrine Hydrochloride

INDICATIONS AND USAGE Midodrine hydrochloride tablets, USP are indicated for the treatment of symptomatic orthostatic hypotension (OH). Because midodrine hydrochloride tablets, USP 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, USP 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, USP 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, USP. After initiation of treatment, midodrine hydrochloride tablets, USP should be continued only for patients who report significant symptomatic improvement.

DOSAGE AND ADMINISTRATION The recommended dose of Midodrine Hydrochloride Tablets, USP is 10 mg, 3 times daily.Dosing should take place during the daytime hours when the patient needs to be upright, pursuing the activities of daily living. A suggested dosing schedule of approximately 4-hour intervals is as follows: shortly before, or upon arising in the morning, midday and late afternoon (not later than 6 P.M.). Doses may be given in 3-hour intervals, if required, to control symptoms, but not more frequently. Single doses as high as 20 mg have been given to patients, but severe and persistent systolic supine hypertension occurs at a high rate (about 45%) at this dose. In order to reduce the potential for supine hypertension during sleep, Midodrine Hydrochloride Tablets, USP should not be given after the evening meal or less than 4 hours before bedtime. Total daily doses greater than 30 mg have been tolerated by some patients, but their safety and usefulness have not been studied systematically or established. Because of the risk of supine hypertension, Midodrine Hydrochloride Tablets, USP should be continued only in patients who appear to attain symptomatic improvement during initial treatment. The supine and standing blood pressure should be monitored regularly, and the administration of Midodrine Hydrochloride Tablets, USP should be stopped if supine blood pressure increases excessively. Because desglymidodrine is excreted renally, dosing in patients with abnormal renal function should be cautious; although this has not been systematically studied, it is recommended that treatment of these patients be initiated using 2.5-mg doses. Dosing in children has not been adequately studied. Blood levels of midodrine and desglymidodrine were similar when comparing levels in patients 65 or older vs. younger than 65 and when comparing males vs. females, suggesting dose modifications for these groups are not necessary.

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.

ADVERSE REACTIONS 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: Adverse Events Placebo n=88 Midodrine n=82 Event # of reports % of patients # of reports % of patients Total # of reports 22 77 Paresthesia 1 4 4.5 15 18.3 Piloerection 0 0 11 13.4 Dysuria 2 0 0 11 13.4 Pruritis 3 2 2.3 10 12.2 Supine hypertension 4 0 0 6 7.3 Chills 0 0 4 4.9 Pain 5 0 0 4 4.9 Rash 1 1.1 2 2.4 1 Includes hyperesthesia and scalp paresthesia 2 Includes dysuria (1), increased urinary frequency (2), impaired urination (1), urinary retention (5), urinary urgency (2) 3 Includes scalp pruritus 4 Includes patients who experienced an increase in supine hypertension 5 Includes abdominal pain and pain increase 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 hydrochloride 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions When administered concomitantly with midodrine, 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 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. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of midodrine. Potential for Drug Interaction 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 secretionof such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs.

Mechanism of Action Midodrine hydrochloride tablets form an active metabolite, desglymidodrine, that is an alpha 1 -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.

DESCRIPTION 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 Structural formula: Molecular formula: C 12 H 18 N 2 O 4 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 Chemical Structure

OVERDOSAGE Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. There are 2 reported cases of overdosage with midodrine hydrochloride tablets, both in young males. One patient ingested midodrine hydrochloride drops, 250 mg, experienced systolic blood pressure greater than 200 mmHg, was treated with an IV injection of 20 mg of phentolamine, and was discharged the same night without any complaints. The other patient ingested 205 mg of midodrine hydrochloride (41 5 mg tablets), and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. 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 LD 50 is approximately 30 mg/kg to 50 mg/kg in rats, 675 mg/kg in mice, and 125 mg/kg to 160 mg/kg in dogs. Desglymidodrine is dialyzable. Recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine).

HOW SUPPLIED Midodrine hydrochloride tablets, USP 2.5 mg are available for oral administration as white, round, scored tablets, imprinted "APO" on one side and "MID" above bisect "2.5" on the other side. They are supplied as follows: Carton of 50 tablets (10 tablets each blister pack x 5), NDC 0904-6817-06 Carton of 100 tablets (10 tablets each blister pack x 10), NDC 0904-6817-61 Midodrine hydrochloride tablets, USP 5 mg are available for oral administration as orange, round, scored tablets, imprinted "APO" on one side and "MID" above bisect "5" on the other side. They are supplied as follows: Carton of 50 tablets (10 tablets each blister pack x 5), NDC 0904-6818-06 Carton of 100 tablets (10 tablets each blister pack x 10), NDC 0904-6818-61 Midodrine hydrochloride tablets, USP 10 mg are available for oral administration as light blue, round, scored tablets, imprinted "APO" on one side and "MID" above bisect "10" on the other side. They are supplied as follows: Carton of 30 tablets (6 tablets each blister pack x 5), NDC 0904-6819-07 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. APOTEX INC. MIDODRINE HYDROCHLORIDE TABLETS , USP 2.5 mg, 5 mg and 10 mg Manufactured by Apotex Inc. Toronto, Ontario Canada M9L 1T9 Manufactured for Apotex Corp. Weston, Florida 33326 Manufactured by Piramal Pharma Limited, Plot No: 67-70 Sector-2 Pithampur 454775 Dist. Dhar, Madhya Pradesh, INDIA Mfg Lic. No.: 25/10/92 Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: February 2017 Rev. 2