Terazosin

INDICATIONS AND USAGE Terazosin capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH). There is a rapid response, with approximately 70% of patients experiencing an increase in urinary flow and improvement in symptoms of BPH when treated with terazosin capsules. The long-term effects of terazosin on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined. Terazosin capsules are also indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive agents such as diuretics or beta-adrenergic blocking agents.

DOSAGE AND ADMINISTRATION If terazosin capsules administration is discontinued for several days, therapy should be reinstituted using the initial dosing regimen. Benign Prostatic Hyperplasia Initial Dose 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded as an initial dose. Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response. Subsequent Doses The dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. Doses of 10 mg once daily are generally required for the clinical response. Therefore, treatment with 10 mg for a minimum of 4 weeks to 6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. Although some additional patients responded at a 20 mg daily dose, there was an insufficient number of patients studied to draw definitive conclusions about this dose. There are insufficient data to support the use of higher doses for those patients who show inadequate or no response to 20 mg daily. If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. Use with Other Drugs Caution should be observed when terazosin capsules are administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. When using terazosin and other antihypertensive agents concomitantly, dosage reduction and retitration of either agent may be necessary (see PRECAUTIONS ). Hypotension has been reported when terazosin capsules have been used with phosphodiesterase-5 (PDE-5) inhibitors. Hypertension The dose of terazosin capsules and the dose interval (12 hours or 24 hours) should be adjusted according to the patient's individual blood pressure response. The following is a guide to its administration: Initial Dose 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded. This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects. Subsequent Doses The dose may be slowly increased to achieve the desired blood pressure response. The usual recommended dose range is 1 mg to 5 mg administered once a day; however, some patients may benefit from doses as high as 20 mg per day. Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied. Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. It may also be helpful to measure blood pressure 2 hours to 3 hours after dosing to see if the maximum and minimum responses are similar, and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response. If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. In clinical trials, except for the initial dose, the dose was given in the morning. Use with other drugs : (see above)

ADVERSE REACTIONS Benign Prostatic Hyperplasia The incidence of treatment-emergent adverse events has been ascertained from clinical trials conducted worldwide. All adverse events reported during these trials were recorded as adverse reactions. The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-a-day administration of terazosin at doses ranging from 1 mg to 20 mg. Table 1 summarizes those adverse events reported for patients in these trials when the incidence rate in the terazosin group was at least 1% and was greater than that for the placebo group, or where the reaction is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in patients receiving terazosin than in patients receiving placebo. The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events (see PRECAUTIONS ) adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. TABLE 1: ADVERSE REACTIONS DURING PLACEBO-CONTROLLED TRIALS BENIGN PROSTATIC HYPERPLASIA BODY SYSTEM TERAZOSIN (N = 636) PLACEBO (N = 360) BODY AS A WHOLE †Asthenia 7.4% * 3.3% Flu Syndrome 2.4% 1.7% Headache 4.9% 5.8% CARDIOVASCULAR SYSTEM Hypotension 0.6% 0.6% Palpitations 0.9% 1.1% Postural Hypotension 3.9% * 0.8% Syncope 0.6% 0.0% DIGESTIVE SYSTEM Nausea 1.7% 1.1% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.9% 0.3% Weight Gain 0.5% 0.0% NERVOUS SYSTEM Dizziness 9.1% * 4.2% Somnolence 3.6% * 1.9% Vertigo 1.4% 0.3% RESPIRATORY SYSTEM Dyspnea 1.7% 0.8% Nasal Congestion/Rhinitis 1.9% * 0.0% SPECIAL SENSES Blurred Vision/Amblyopia 1.3% 0.6% UROGENITAL SYSTEM Impotence 1.6% * 0.6% Urinary Tract Infection 1.3% 3.9% * † Includes weakness, tiredness, lassitude and fatigue. * p ≤ 0.05 comparison between groups. Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 2. TABLE 2: DISCONTINUATION DURING PLACEBO-CONTROLLED TRIALS BENIGN PROSTATIC HYPERPLASIA BODY SYSTEM TERAZOSIN (N = 636) PLACEBO (N = 360) BODY AS A WHOLE Fever 0.5% 0.0% Headache 1.1% 0.8% CARDIOVASCULAR SYSTEM Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.0% DIGESTIVE SYSTEM Nausea 0.5% 0.3% NERVOUS SYSTEM Dizziness 2.0% 1.1% Vertigo 0.5% 0.0% RESPIRATORY SYSTEM Dyspnea 0.5% 0.3% SPECIAL SENSES Blurred Vision/Amblyopia 0.6% 0.0% UROGENITAL SYSTEM Urinary Tract Infection 0.5% 0.3% Hypertension The prevalence of adverse reactions has been ascertained from clinical trials conducted primarily in the United States. All adverse experiences (events) reported during these trials were recorded as adverse reactions. The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once-a-day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 mg to 40 mg. Table 3 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common in patients receiving terazosin than in patients receiving placebo. Similar adverse reaction rates were observed in placebo-controlled monotherapy trials. TABLE 3: ADVERSE REACTIONS DURING PLACEBO-CONTROLLED TRIALS HYPERTENSION Body System Terazosin (N = 859) Placebo (N = 506) BODY AS A WHOLE †Asthenia 11.3%* 4.3% Back Pain 2.4% 1.2% Headache 16.2% 15.8% CARDIOVASCULAR SYSTEM Palpitations 4.3%* 1.2% Postural Hypotension 1.3% 0.4% Tachycardia 1.9% 1.2% DIGESTIVE SYSTEM Nausea 4.4%* 1.4% METABOLIC AND NUTRITIONAL DISORDERS Edema 0.9% 0.6% Peripheral Edema 5.5%* 2.4% Weight Gain 0.5% 0.2% MUSCULOSKELETAL SYSTEM Pain-Extremities 3.5% 3.0% NERVOUS SYSTEM Depression 0.3% 0.2% Dizziness 19.3%* 7.5% Libido Decreased 0.6% 0.2% Nervousness 2.3% 1.8% Paresthesia 2.9% 1.4% Somnolence 5.4%* 2.6% RESPIRATORY SYSTEM Dyspnea 3.1% 2.4% Nasal Congestion 5.9%* 3.4% Sinusitis 2.6% 1.4% SPECIAL SENSES Blurred Vision 1.6%* 0.0% UROGENITAL SYSTEM Impotence 1.2% 1.4% * Includes weakness, tiredness, lassitude, and fatigue. † Statistically significant at p = 0.05 level. 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 terazosin. The following additional adverse reactions were reported by at least 1% of 1,987 patients who received terazosin in controlled or open, short- or long-term clinical trials or have been reported during marketing experience: Body as a Whole: chest pain, facial edema, fever, abdominal pain, neck pain, shoulder pain. Cardiovascular System: arrhythmia, vasodilation. Digestive System: constipation, diarrhea, dry mouth, dyspepsia, flatulence, vomiting. Metabolic/Nutritional Disorders: gout. Musculoskeletal System: arthralgia, arthritis, joint disorder, myalgia. Nervous System: anxiety, insomnia. Respiratory System: bronchitis, cold symptoms, epistaxis, flu symptoms, increased cough, pharyngitis, rhinitis. Skin and Appendages: pruritus, rash, sweating. Special Senses: abnormal vision, conjunctivitis, tinnitus. Urogenital System: urinary frequency, urinary incontinence primarily reported in postmenopausal women, urinary tract infection. The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 4. TABLE 4: DISCONTINUATIONS DURING PLACEBO-CONTROLLED TRIALS HYPERTENSION Body System Terazosin (N = 859) Placebo (N = 506) BODY AS A WHOLE Asthenia 1.6% 0.0% Headache 1.3% 1.0% CARDIOVASCULAR SYSTEM Palpitations 1.4% 0.2% Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.2% Tachycardia 0.6% 0.0% DIGESTIVE SYSTEM Nausea 0.8% 0.0% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.6% 0.0% NERVOUS SYSTEM Dizziness 3.1% 0.4% Paresthesia 0.8% 0.2% Somnolence 0.6% 0.2% RESPIRATORY SYSTEM Dyspnea 0.9% 0.6% Nasal Congestion 0.6% 0.0% SPECIAL SENSES Blurred Vision 0.6% 0.0% Post-marketing Experience Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. There have been reports of priapism and thrombocytopenia during post-marketing surveillance. Atrial fibrillation has been reported. 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 ). To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pharmacokinetics Terazosin hydrochloride administered as terazosin capsules is essentially completely absorbed in man. Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14 hours and 11.4 hours for the age group ≥ 70 years and the age group of 20 years to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 years to 39 years of age. The drug is 90% to 94% bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man.