FDA label 0dcffd96-9417-410a-8431-4b9995a6e635

WARNINGS Syncope and “First-dose” Effect: Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2 and 4 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION section) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution. Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night. In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope. In multiple dose clinical trials in hypertension involving over 1500 hypertensive patients with dose titration every one to two weeks, syncopewas reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16 mg/day. In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients were taking1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. Priapism Rarely (probably less frequently than once in every several thousand patients), alpha 1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition(see PRECAUTIONS, Information for Patients ).

ADVERSE REACTIONS A. Benign Prostatic Hyperplasia 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 mesylate in doses of 1 to 16 mg in hypertensives and 0.5-8 mg in normotensives. The adverse events when the incidence in the doxazosin mesylate 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 fordizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related. In these placebo-controlled studies of 665 doxazosin mesylate 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 mesylate 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. 14 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 mesylate were mild. B. Hypertension Doxazosin mesylate 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 mesylate 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. 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 less than 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 : aroniria, 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 mesylate 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 mesylatehas been associated with decreases in white blood cell counts (see PRECAUTIONS ).In post-marketing experience the following additional adverse reactions have been reported: Autonomic Nervous System : priapism; CentralNervous 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. Picture of Doxazosin Table 4 Part 1 Picture of Doxazosin Table 4 Part 2