DOXAZOSIN

Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha-adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C 23 H 25 N 5 O 5 • CH 4 O 3 S and the molecular weight is 547.6. It has the following structure: Doxazosin mesylate is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. Each Doxazosin Tablet, USP, for oral administration, contains 1 mg, 2 mg, 4 mg and 8 mg of doxazosin as the free base. In addition, each Doxazosin Tablet, USP contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. doxazosin-structure

A. Benign Prostatic Hyperplasia (BPH). Doxazosin Tablets, USP are indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin Tablets, USP may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with Doxazosin Tablets, USP monotherapy. Doxazosin Tablets, USP provide rapid improvement in symptoms and urinary flow rate in 66 to 71% of patients. Sustained improvements with Doxazosin Tablets, USP were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies. B. Hypertension. Doxazosin Tablets, USP are 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. Doxazosin Tablets, USP may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers, or angiotensin-converting enzyme inhibitors.

DOSAGE MUST BE INDIVIDUALIZED. The initial dosage of doxazosin tablets in patients with hypertension and/or BPH is 1 mg given once daily in the a.m. or p.m. This starting dose is intended to minimize the frequency of postural hypotension and first-dose syncope associated with doxazosin. Postural effects are most likely to occur between 2 and 6 hours after a dose. Therefore, blood pressure measurements should be taken during this time period after the first dose and with each increase in dose. If doxazosin tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen. Concomitant administration of doxazosin 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 doxazosin. A. BENIGN PROSTATIC HYPERPLASIA 1 to 8 mg once daily. The initial dosage of doxazosin is 1 mg, given once daily in the a.m. or p.m. Depending on the individual patient’s urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose for BPH. The recommended titration interval is 1 to 2 weeks. Blood pressure should be evaluated routinely in these patients. B. HYPERTENSION 1 to 16 mg once daily. The initial dosage of doxazosin is 1 mg given once daily. Depending on the individual patient’s standing blood pressure response (based on measurements taken at 2 to 6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. Increases in dose beyond 4 mg increase the likelihood of excessive postural effects, including syncope, postural dizziness/vertigo and postural hypotension. At a titrated dose of 16 mg once daily, the frequency of postural effects is about 12% compared to 3% for placebo.

Doxazosin Tablets, USP are contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients.

A. Benign Prostatic Hyperplasia (BPH) The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below (Table 3) are based on combined data from seven placebo-controlled trials involving once-daily administration of doxazosin in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. The adverse events when the incidence in the doxazosin group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared to placebo was seen except for dizziness, fatigue, hypotension, edema, and dyspnea. Dizziness and dyspnea appeared to be dose-related. TABLE 3 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES BENIGN PROSTATIC HYPERPLASIA DOXAZOSIN PLACEBO Body System (N=665) (N=300) BODY AS A WHOLE Back Pain 1.8% 2.0% Chest Pain 1.2% 0.7% Fatigue 8.0% p ≤0.05 for treatment differences 1.7% Headache 9.9% 9.0% Influenza-like Symptoms 1.1% 1.0% Pain 2.0% 1.0% CARDIOVASCULAR SYSTEM Hypotension 1.7% 0.0% Palpitation 1.2% 0.3% DIGESTIVE SYSTEM Abdominal Pain 2.4% 2.0% Diarrhea 2.3% 2.0% Dyspepsia 1.7% 1.7% Nausea 1.5% 0.7% METABOLIC AND NUTRITIONAL DISORDERS Edema 2.7% 0.7% NERVOUS SYSTEM Dizziness Includes vertigo 15.6% 9.0% Mouth Dry 1.4% 0.3% Somnolence 3.0% 1.0% RESPIRATORY SYSTEM Dyspnea 2.6% 0.3% Respiratory Disorder 1.1% 0.7% SPECIAL SENSES Vision Abnormal 1.4% 0.7% UROGENITAL SYSTEM Impotence 1.1% 1.0% Urinary Tract Infection 1.4% 2.3% SKIN & APPENDAGES Sweating Increased 1.1% 1.0% PSYCHIATRIC DISORDERS Anxiety 1.1% 0.3% Insomnia 1.2% 0.3% In these placebo-controlled studies of 665 doxazosin patients treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with an incidence of less than 1% but of clinical interest are (doxazosin vs. placebo): Cardiovascular System: angina pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0.0%), tachycardia (0.9% vs. 0.0%); Urogenital System: dysuria (0.5% vs. 1.3%); and Psychiatric Disorders: libido decreased (0.8% vs. 0.3%). The safety profile in patients treated for up to three years was similar to that in the placebo-controlled studies. The majority of adverse experiences with doxazosin were mild. B. Hypertension Doxazosin has been administered to approximately 4000 hypertensive patients, of whom 1679 were included in the hypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. In placebo-controlled studies, adverse effects occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuation were postural effects (2%), edema, malaise/fatigue, and some heart rate disturbance, each about 0.7%. In controlled hypertension clinical trials directly comparing doxazosin to placebo, there was no significant difference in the incidence of side effects, except for dizziness (including postural), weight gain, somnolence, and fatigue/malaise. Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once-daily administration of doxazosin at doses ranging from 1 to 16 mg. Table 4 summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction is of particular interest. TABLE 4 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES HYPERTENSION DOXAZOSIN PLACEBO (N=339) (N=336) CARDIOVASCULAR SYSTEM Dizziness 19% 9% Vertigo 2% 1% Postural Hypotension 0.3% 0% Edema 4% 3% Palpitation 2% 3% Arrhythmia 1% 0% Hypotension 1% 0% Tachycardia 0.3% 1% Peripheral Ischemia 0.3% 0% SKIN & APPENDAGES Rash 1% 1% Pruritus 1% 1% MUSCULOSKELETAL SYSTEM Arthralgia/Arthritis 1% 0% Muscle Weakness 1% 0% Myalgia 1% 0% CENTRAL & PERIPHERAL N.S. Headache 14% 16% Paresthesia 1% 1% Kinetic Disorders 1% 0% Ataxia 1% 0% Hypertonia 1% 0% Muscle Cramps 1% 0% AUTONOMIC Mouth Dry 2% 2% Flushing 1% 0% SPECIAL SENSES Vision Abnormal 2% 1% Conjunctivitis/Eye Pain 1% 1% Tinnitus 1% 0.3% PSYCHIATRIC Somnolence 5% 1% Nervousness 2% 2% Depression 1% 1% Insomnia 1% 1% Sexual Dysfunction 2% 1% GASTROINTESTINAL Nausea 3% 4% Diarrhea 2% 3% Constipation 1% 1% Dyspepsia 1% 1% Flatulence 1% 1% Abdominal Pain 0% 2% Vomiting 0% 1% RESPIRATORY Rhinitis 3% 1% Dyspnea 1% 1% Epistaxis 1% 0% URINARY Polyuria 2% 0% Urinary Incontinence 1% 0% Micturition Frequency 0% 2% GENERAL Fatigue/Malaise 12% 6% Chest Pain 2% 2% Asthenia 1% 1% Face Edema 1% 0% Pain 2% 2% Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and 1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reported by <0.5% of 3960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including international studies. Cardiovascular System: angina pectoris, myocardial infarction, cerebrovascular accident; Autonomic Nervous System: pallor; Metabolic: thirst, gout, hypokalemia; Hematopoietic: lymphadenopathy, purpura; Reproductive System: breast pain; Skin Disorders: alopecia, dry skin, eczema; Central Nervous System: paresis, tremor, twitching, confusion, migraine, impaired concentration; Psychiatric: paroniria, amnesia, emotional lability, abnormal thinking, depersonalization; Special Senses: parosmia, earache, taste perversion, photophobia, abnormal lacrimation; Gastrointestinal System: increased appetite, anorexia, fecal incontinence, gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary System: renal calculus; General Body System: hot flushes, back pain, infection, fever/rigors, decreased weight, influenza-like symptoms. Doxazosin has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin has been associated with decreases in white blood cell counts (see PRECAUTIONS , Leukopenia/Neutropenia ). In post-marketing experience, the following additional adverse reactions have been reported: Autonomic Nervous System: priapism; Central Nervous System: hypoesthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: allergic reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia; Liver/Biliary System: hepatitis, hepatitis cholestatic; Respiratory System: bronchospasm aggravated; Skin Disorders: urticaria; Special Senses: Intraoperative Floppy Iris Syndrome (see PRECAUTIONS , Cataract Surgery ); Urinary System: hematuria, micturition disorder, micturition frequency, nocturia. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug/Laboratory Test Interactions Doxazosin does not affect the plasma concentration of prostate-specific antigen in patients treated for up to 3 years. Both doxazosin, an alpha 1 inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein-bound and hepatically metabolized. There is no definitive controlled clinical experience on the concomitant use of alpha 1 inhibitors and 5-alpha reductase inhibitors at this time. Drug Interactions Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin. There is no information on the effect of other highly plasma protein- bound drugs on doxazosin binding. Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p=0.006), and a slight but not statistically significant increase in mean C max and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown. In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies. Concomitant administration of doxazosin with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION ).