Midodrine Hydrochloride (Page 2 of 3)

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.

Laboratory Tests

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.

Drug Interactions

When administered concomitantly with midodrine hydrochloride tablets, 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 tablets 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 tablets. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of midodrine hydrochloride tablets.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have been conducted in rats and mice at dosages of 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 tablets. Studies investigating the mutagenic potential of midodrine hydrochloride tablets revealed 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 hydrochloride tablets on fertility.

Pregnancy

Pregnancy Category C

Midodrine hydrochloride tablets increased 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 hydrochloride tablets should 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.

Nursing Mothers

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 tablets is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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
*
Includes hyperesthesia and scalp paresthesia
Includes dysuria (1), increased urinary frequency (2), impaired urination (1), urinary retention (5), urinary urgency (2)
Includes scalp pruritus
§
Includes patients who experienced an increase in supine hypertension
Includes abdominal pain and pain increase

Total # of reports

22

77

Paresthesia *

4

4.5

15

18.3

Piloerection

0

0

11

13.4

Dysuria

0

0

11

13.4

Pruritus

2

2.3

10

12.2

Supine hypertension §

0

0

6

7.3

Chills

0

0

4

4.9

Pain

0

0

4

4.9

Rash

1

1.1

2

2.4

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 tablets 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.

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