Label: PRAZOSIN HYDROCHLORIDE capsule

Prazosin hydrochloride capsules, USP a quinazoline derivative, is the first of a new chemical class of antihypertensives. It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is:

Molecular formula C19H21N5O4•HCl

It is white or almost white crystalline powder, very slightly soluble in water, slightly soluble in methanol, in dimethylformamide, in dimethylacetamide and in alcohol; practically insoluble in chloroform and in acetone, and has a molecular weight of 419.87. Each capsule, for oral use, contains prazosin hydrochloride, USP equivalent to 1 mg, 2 mg or 5 mg of prazosin.

Inert ingredients in the formulations are: colloidal silicon dioxide, magnesium stearate, sodium starch glycolate, sucrose. The empty hard gelatin capsule shells contain gelatin and titanium dioxide. In addition, the 2 mg and 5 mg empty hard gelatin capsule shells contains D&C Red 28, FD&C Blue 1, FD&C Red 3 and FD&C Red 40. The Imprint ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac.

FDA approved dissolution test specifications differ from USP.

The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin causes a decrease in total peripheral resistance and was originally thought to have a direct relaxant action on vascular smooth muscle. Recent animal studies, however, have suggested that the vasodilator effect of prazosin is also related to blockade of postsynaptic alpha-adrenoceptors. The results of dog forelimb experiments demonstrate that the peripheral vasodilator effect of prazosin is confined mainly to the level of the resistance vessels (arterioles). Unlike conventional alpha-blockers, the antihypertensive action of prazosin is usually not accompanied by a reflex tachycardia. Tolerance has not been observed to develop in long termtherapy.

Hemodynamic studies have been carried out in man following acute single dose administration and during the course of long term maintenance therapy. The results confirm that the therapeutic effect is a fall in blood pressure unaccompanied by a clinically significant change in cardiac output, heart rate, renal blood flow and glomerular filtration rate. There is no measurable negative chronotropic effect.

In clinical studies to date, prazosin hydrochloride has not increased plasma renin activity.

In man, blood pressure is lowered in both the supine and standing positions. This effect is most pronounced on the diastolic blood pressure.

Following oral administration, human plasma concentrations reach a peak at about three hours with a plasma half-life of two to three hours. The drug is highly bound to plasma protein. Bioavailability studies have demonstrated that the total absorption relative to the drug in a 20% alcoholic solution is 90%, resulting in peak levels approximately 65% of that of the drug in solution. Animal studies indicate that prazosin hydrochloride is extensively metabolized, primarily by demethylation and conjugation, and excreted mainly via bile and feces. Less extensive human studies suggest similar metabolism and excretion in man.
In clinical studies in which lipid profiles were followed, there were generally no adverse changes noted between pre- and post-treatment lipid levels.

Prazosin hydrochloride capsules is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and    most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
  

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Prazosin hydrochloride capsules can be used alone or in combination with other antihypertensive drugs such as diuretics or beta-adrenergic blocking agents. 

Prazosin hydrochloride capsules are contraindicated in patients with known sensitivity to quinazolines, prazosin, or any of the inert ingredients.

As with all alpha-blockers, Prazosin hydrochloride capsules may cause syncope with sudden loss of consciousness. In most cases, this is believed to  be due to  an excessive postural hypotensive effect,  although occasionally the syncopal episode has been preceded by a bout of severe tachycardia with heart rates of 120 to 160 beats  per minute. Syncopal episodes have usually occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have been reported in association with rapid dosage increases or the introduction of another antihypertensive drug into the regimen of a patient taking high doses of Prazosin hydrochloride capsules. The incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg or greater. Clinical trials conducted during the investigational phase of this drug suggest that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by subsequently increasing the dosage s lowly, and by introducing any additional antihypertensive drugs into the patient's regimen with caution (see DOSAGE AND ADMINISTRATION). Hypotension may develop in patients given Prazosin hydrochloride capsules who are also receiving a beta-blocker such as propranolol.

 

If syncope occurs, the patient should be placed in the recumbent position and treated supportively as necessary. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration.

Patients should always be started on the 1 mg capsules of Prazosin hydrochloride capsules. The 2 and 5 mg capsules are not indicated for initial therapy.

 

More common than loss of consciousness are the symptoms often associated with lowering of the blood pressure, namely, dizziness and lightheadedness. The patient should be cautioned about these possible adverse effects and advised what measures to take should they develop. The patient should also be cautioned to avoid situations where injury could result should syncope occur during the initiation of Prazosin hydrochloride capsules therapy.

Clinical trials were conducted on more than 900 patients. During these trials and subsequent marketing experience, the most frequent reactions associated with Prazosin hydrochloride capsules therapy are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%, palpitations 5.3%, and nausea 4.9%. In most instances, side effects have disappeared with continued therapy or have been tolerated with no decrease in dose of drug.

Less frequent adverse reactions which are reported to occur in 1 to 4% of patients are:

Gastrointestinal:  vomiting, diarrhea, constipation.

Cardiovascular: edema, orthostatic hypotension, dyspnea, syncope.

Central Nervous System: vertigo, depression, nervousness.

Dermatologic: rash.

Genitourinary: urinary frequency.

EENT: blurred vision, reddened sclera, epistaxis, dry mouth, nasal congestion.

In addition, fewer than 1% of patients have reported the following (in some instances, exact causal relationships have not been established):

Gastrointestinal: abdominal discomfort and/or  pain, liver function abnormalities, pancreatitis.

Cardiovascular: tachycardia.

Central Nervous System: paresthesia, hallucinations.

Dermatologic: pruritus, alopecia, lichen planus.

Genitourinary: incontinence, impotence, priapism.

EENT: tinnitus.

Other: diaphoresis, fever, positive ANA titer, arthralgia.

Single reports of pigmentary mottling and serous retinopathy, and a few reports of cataract development or disappearance have been reported. In these instances, the exact causal relationship has not been established because the baseline observations were frequently inadequate.

In more specific slit-lamp and funduscopic studies, which included adequate baseline examinations, no drug-related abnormal ophthalmological findings have  been reported.

Literature reports exist associating Prazosin hydrochloride capsules therapy with a worsening of pre-existing narcolepsy. A causal relationship is uncertain in these cases.

In post-marketing experience, the following adverse events  have  been reported:

Autonomic Nervous System: flushing.

Body As A Whole: allergic reaction, asthenia, malaise, pain.

Cardiovascular, General: angina pectoris, hypotension.

Endocrine: gynecomastia.

Heart Rate/Rhythm: bradycardia.

Psychiatric: insomnia.

Skin/Appendages: urticaria.

Vascular (Extracardiac): vasculitis.

Vision: eye pain.

Special Senses: During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS).

Accidental ingestion of at least 50 mg of Prazosin hydrochloride capsules in a two year old child resulted in profound drowsiness and depressed reflexes. No decrease in blood pressure was noted. Recovery was uneventful.

Should overdosage lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressors should then be used. Renal function should be monitored and supported as needed. Laboratory data indicate Prazosin hydrochloride capsules is not dialysable because it is protein bound.

The dose of Prazosin hydrochloride capsules should be adjusted according to the patient's individual blood pressure response. The following is a guide to its administration:

Initial Dose

1 mg two or three times a day (see WARNINGS.)

Maintenance Dose

Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses. The therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in divided doses. Doses higher than 20 mg usually do not increase efficacy, however a few patients may benefit from further increases up to a daily dose of 40 mg given in divided doses. After initial titration some patients can be maintained adequately on a twice daily dosage regimen.

Use With Other Drugs

When adding a diuretic or other antihypertensive agent, the dose of Prazosin hydrochloride capsules should be reduced to 1 mg or 2 mg three times a day and retitration then carried out.

Concomitant administration of Prazosin hydrochloride capsules with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking Prazosin hydrochloride capsules.

Prazosin Hydrochloride Capsules, USP are available containing prazosin hydrochloride, USP equivalent to 1 mg, 2 mg, or 5 mg of prazosin.

• The 1 mg capsule is a hard gelatin capsule with white opaque body and white opaque cap imprinted with “AC” on cap and ‘540’ on body in black ink filled with white to off white powder. They are available as follows:

                 bottles of 100 capsules (NDC 70377-066-11)

• The 2 mg capsule is a hard gelatin capsule with white opaque body and pink opaque cap imprinted with ‘AC” on cap and ‘541’ on body in black ink filled with white to off white powder. They are available as follows:

                  bottles of 100 capsules (NDC 70377-067-11)

• The 5 mg capsule is a hard gelatin capsule with pink opaque body and pink opaque cap imprinted with “AC” on cap and ‘542’ on body in black ink filled with white to off white powder. They are available as follows:

                  bottles of 100 capsules (NDC 70377-068-11)

Store at 25oC (77oF); excursions permitted to 15 to 30oC (59 to 86oF) [See USP Controlled Room Temperature].

Protect from moisture and light.

Dispense in a well-closed, light-resistant container as defined by the USP using a child-resistant closure.

1.     Lubbe, WF, and Hodge, JV: New Zealand Med J, 94(691) 169–172, 1981.

2.     Davey, DA, and Dommisse, J: S.A. Med J, Oct. 4, 1980 (551–556).
Manufactured for:

Biocon Pharma Inc,

Islein, New Jersey 08830-3009 USA

Manufactured by:

Appco Pharma LLC,

Piscataway, New Jersey 08854.

200617

Revision: 11/2022

BPCM0164/01