ProAmatine

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-(2,5dimethoxyphenyl)-2-hydroxyethyl]-monohydrochloride, (±)-; (2) (±)-2-amino-N-(ß-hydroxy-2,5-dimethoxyphenethyl)acetamide monohydrochloride BAN, INN, JAN: Midodrine

Structural formula:

Molecular formula: C12H18N2O4HCl; 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® 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.

Midodrine is a prescription medication used to treat orthostatic hypotension (OH). This medication belongs to a group of drugs called alpha receptor agonists, which help to maintain adequate blood pressure and to prevent symptoms of OH including dizziness or lightheadedness.

This medication comes in tablet form and is taken 3 times a day, with or without food.

Common side effects include tingling sensations, itching, problems with urinating, and stomach pain.

Midodrine is a prescription medication used to treat orthostatic hypotension (OH). OH results in dizziness, lightheadedness, or even fainting after standing from a sitting or lying down position.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Mechanism of Action: ProAmatine® 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 ProAmatine® 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. ProAmatine® has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

Pharmacokinetics:ProAmatine® is 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, ProAmatine® 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).

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.

ProAmatine® is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. ProAmatine® should not be used in patients with persistent and excessive supine hypertension.

2.5mg Bottle Label

5mg Bottle Label

10mg Bottle Label

2.5mg Carton Label

5mg Carton Label

10mg Carton Label

Applies to midodrine: oral tablet

Along with its needed effects, midodrine (the active ingredient contained in ProAmatine) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking midodrine:

• Blurred vision
• cardiac awareness
• headache
• pounding in the ears

• Fainting
• increased dizziness
• slow pulse

Some side effects of midodrine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Burning, itching, or prickling of the scalp
• chills
• goosebumps
• urinary frequency, retention, or urgency

• Anxiety or nervousness
• confusion
• dry mouth
• flushing
• headache or feeling of pressure in the head
• skin rash

• Backache
• canker sores
• dizziness
• drowsiness
• dry skin
• leg cramps
• pain or sensitivity of the skin to touch
• stomach problems such as gas, heartburn, or nausea
• trouble seeing
• trouble with sleeping
• weakness

Applies to midodrine: oral tablet

General

The most common adverse reactions were paresthesia (includes hyperesthesia and scalp paresthesia), piloerection, dysuria (includes dysuria, increased urinary frequency, impaired urination, urinary retention, and urinary urgency), pruritus (includes scalp pruritus), and supine hypertension.[Ref]

Cardiovascular

Common (1% to 10%): Supine hypertension, flushing
Uncommon (0.1% to 1%): Reflex bradycardia
Rare (less than 0.1%): Tachycardia, palpitations
Frequency not reported: Vasodilation/flushing face[Ref]

Nervous system

Very common (10% or more): Paresthesia (18.3%)
Common (1% to 10%): Headache
Frequency not reported: Feeling of pressure/fullness in the head, dizziness, somnolence[Ref]

Dermatologic

Very common (10% or more): Piloerection (13.4%), pruritus (12.2%)
Common (1% to 10%): Rash
Frequency not reported: Skin hyperesthesia, erythema multiforme, dry skin[Ref]

Genitourinary

Very common (10% or more): Dysuria (13.4%)
Frequency not reported: Impaired urination[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, dyspepsia, stomatitis
Frequency not reported: Dry mouth, canker sore, pyrosis, gastrointestinal distress, flatulence, abdominal pain, vomiting, diarrhea[Ref]

Other

Common (1% to 10%): Chills, pain
Frequency not reported: Asthenia[Ref]

Psychiatric

Uncommon (0.1% to 1%): Sleep disorders, insomnia, restlessness, excitability, irritability
Frequency not reported: Confusion/thinking abnormality, nervousness/anxiety[Ref]

Hepatic

Rare (less than 0.1%): Abnormal hepatic function, raised liver enzymes[Ref]

Musculoskeletal

Frequency not reported: Backache, leg cramps[Ref]

Ocular

Frequency not reported: Visual field defect[Ref]

Some side effects of ProAmatine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.