Benign Prostatic Hyperplasia

The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented in TABLE 3 are based on combined data from seven placebo-controlled trials involving once daily administration of doxazosin mesylate in doses of 1-16 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 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 Mesylate (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 Nutritional Disorders
Edema	2.7%*	0.7%
Nervous System
Dizziness'	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%
* p £ 0.05 for treatment differences.
† Includes vertigo.

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%).

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 mesylate were mild.

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 1-16 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 (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.
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 Seneses
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 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 mesylate has 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; 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; Urinary System: hematuria, micturition disorder, micturition frequency, nocturia.

Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin mesylate 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 mesylate 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 mesylate 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 mesylate 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.

Drug/Laboratory Test Interactions

Doxazosin mesylate does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin, an alpha₁ 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 alpha₁ inhibitors and 5-alpha reductase inhibitors at this time.