midodrine HCl 10 MG Oral Tablet
WARNINGS
Supine Hypertension: The most potentially serious adverse reaction associated with ProAmatine ® 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 ProAmatine ® .
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 ProAmatine ® in such patients is not recommended.
Sitting blood pressures were also elevated by ProAmatine ® therapy.
It is essential to monitor supine and sitting blood pressures in patients maintained on ProAmatine ® .
Uncontrolled hypertension increases the risk of cardiovascular events, particularly stroke.
DRUG INTERACTIONS
Drug Interactions When administered concomitantly with ProAmatine ® , 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.
ProAmatine ® 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 ProAmatine ® .
Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine ® .
OVERDOSAGE
Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention.
There are 2 reported cases of overdosage with ProAmatine ® , both in young males.
One patient ingested ProAmatine ® 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 ProAmatine ® (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 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 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).
DESCRIPTION
Name: ProAmatine ® (midodrine hydrochloride) Tablets Dosage Form: 2.5-mg, 5-mg and 10-mg tablets for oral administration Active Ingredient: Midodrine hydrochloride, 2.5 mg, 5 mg and 10 mg Inactive Ingredients: Colloidal Silicone Dioxide NF, Corn Starch NF, FD&C Blue No.
2 Lake (10-mg tablets), FD&C Yellow No.
6 Lake (5-mg tablet), Magnesium Stearate NF, Microcrystalline Cellulose NF, Talc USP 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-(β-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: Odorless, white, crystalline powder Solubility: Water: Soluble Methanol: Sparingly soluble pKa: 7.8 (0.3% aqueous solution) pH: 3.5 to 5.5 (5% aqueous solution) Melting Range: 200 to 203°C proamatine-structure
CLINICAL STUDIES
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/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 10mg 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 ProAmatine ® is removed by dialysis.
HOW SUPPLIED
2.5-mg, 5-mg and 10-mg tablets for oral administration.
The 2.5-mg tablet is white, round, and biplanar, with a bevelled edge, and is scored on one side with “RPC” above and “2.5” below the score, and “003” on the other side.
The 5-mg tablet is orange, round, and biplanar, with a bevelled edge, and is scored on one side with “RPC” above and “5” below the score, and “004” on the other side.
The 10-mg is blue, round, and biplanar, with a bevelled edge, and is scored on one side with “RPC” above and “10” below the score, and “007” on the other side.
2.5-milligram Tablets (Bottle of 100): Shire US no longer markets this product 5.0-milligram Tablets (Bottle of 100): Shire US no longer markets this product 10-milligram Tablets (Bottle of 100): Shire US no longer markets this product Store at 25°C (77°F) Excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room Temperature] Shire US Inc.
, 300 Shire Way, Lexington, MA 02421, USA © 2017 Shire US Inc.
Rev.
01/17 Rx only
INDICATIONS AND USAGE
ProAmatine ® is indicated for the treatment of symptomatic orthostatic hypotension (OH).
Because ProAmatine ® 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 ProAmatine ® ‘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 ProAmatine ® , principally improved ability to perform life activities, have not been established.
Further clinical trials are underway to verify and describe the clinical benefits of ProAmatine ® .
After initiation of treatment, ProAmatine ® should be continued only for patients who report significant symptomatic improvement.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy Pregnancy Category C .
ProAmatine ® 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/m 2 ).
There are no adequate and well-controlled studies in pregnant women.
ProAmatine ® 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.
NUSRING MOTHERS
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 ProAmatine ® is administered to a nursing woman.
BOXED WARNING
Warning: Because ProAmatine ® 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 ProAmatine ® 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 ProAmatine ® , principally improved ability to carry out activities of daily living, have not been verified.
INFORMATION FOR PATIENTS
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 ProAmatine ® , as they may enhance or potentiate the pressor effects of ProAmatine ® (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 ProAmatine ® 3 to 4 hours before bedtime to minimize nighttime supine hypertension.
DOSAGE AND ADMINISTRATION
The recommended dose of ProAmatine ® 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, ProAmatine ® 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, ProAmatine ® 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 ProAmatine ® 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.