FDA label 3df82602-c1da-4abe-e054-00144ff8d46c

WARNINGS WARNINGSSyncope and "First-dose" EffectDoxazosin, 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 dosebut can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease thelikelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATIONsection) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agentsshould 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 beginningat 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. Inanother study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjectsexperienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. Inthis study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosindosing 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 1,500 hypertensive patients with dose titration every one to two weeks,syncope was 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 16mg/day.In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients weretaking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extensionfollow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient wastaking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mgexperienced syncope.If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.PriapismRarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin, have beenassociated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Becausethis condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition(see PRECAUTIONS:

ADVERSE REACTIONS ADVERSE REACTIONSBenign Prostatic HyperplasiaThe incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence ratespresented below (Table 3) are based on combined data from seven placebo-controlled trials involving once daily administration ofdoxazosin in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. The adverse events when the incidence in thedoxazosin group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared toplacebo 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 Body System DOXAZOSIN(N=665) PLACEBO(N=300) BODY AS A WHOLE Back pain 1.8% 2.0% Chest Pain 1.2% 0.7% Fatigue 8.0%* 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 NUTRITIONALDISORDERS Edema 2.7%* 0.7% NERVOUS SYSTEM Dizziness206 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 page 8 of 12 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% *p 243 0.05 for treatment differences206Includes vertigoIn these placebo-controlled studies of 665 doxazosin patients, treated for a mean of 85 days, additional adverse reactions have beenreported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with anincidence 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 wassimilar to that in the placebo-controlled studies.The majority of adverse experiences with doxazosin were mild.HypertensionDoxazosin mesylate has been administered to approximately 4,000 hypertensive patients, of whom 1,679 were included in thehypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation oftreatment in only 7% of patients. In placebo-controlled studies adverse effects occurred in 49% and 40% of patients in the doxazosinand placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuationwere 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 incidenceof side effects, except for dizziness (including postural), weight gain, somnolence and fatigue/malaise. Postural effects and edemaappeared to be dose related. The prevalence rates presented below are based on combined data from placebo-controlled studiesinvolving 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 atleast 0.5% or where the reaction is of particular interest.TABLE 4 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES HYPERTENSION DOXAZOSIN(N=339) PLACEBO(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. page 9 of 12 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 haveoccurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reportedby < 0.5% of 3,960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including internationalstudies. 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, page 10 of 12 gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary System: renal calculus; General BodySystem: 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 adverseeffects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin hasbeen 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;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 FloppyIris syndrome (see PRECAUTIONS: General: Cataract Surgery); Urinary System: hematuria, micturition disorder, micturitionfrequency, nocturia.