Terazosin Hydrochloride

INDICATIONS AND USAGE Terazosin capsules, USP 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, USP. The long-term effects of terazosin capsules, USP on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined. Terazosin capsules, USP are also indicated for the treatment of hypertension. Terazosin capsules, USP 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 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 is administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. When using terazosin capsules 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 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 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.)

CONTRAINDICATIONS Terazosin capsules are contraindicated in patients known to be hypersensitive to terazosin hydrochloride.

WARNINGS Syncope and “First-dose” Effect Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. A similar effect can be anticipated if therapy is interrupted for several days and then restarted. Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug. Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120 to 160 beats per minute. Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered. To decrease the likelihood of syncope or excessive hypotension, treatment should always be initiated with a 1 mg dose of terazosin capsules, given at bedtime. The 2 mg, 5 mg and 10 mg capsules are not indicated as initial therapy. Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution. The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy. In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the “first-dose” effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given terazosin capsules at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse effects all occurred within 90 minutes of dosing. In three placebo-controlled BPH studies 1, 2, and 3 (see CLINICAL PHARMACOLOGY ), the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively. In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin capsules, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. There is evidence that the orthostatic effect of terazosin capsules is greater, even in chronic use, shortly after dosing. The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. Priapism Rarely, (probably less than once in every several thousand patients), terazosin and other α 1 -antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported. 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 ).

Drug Interactions In controlled trials, terazosin capsules have been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. Terazosin capsules have also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin capsules have been used concomitantly in at least 50 patients on the following drugs or drug classes: analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin); antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole); anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride); antigout (e.g., allopurinol); antihistamines (e.g., chlorpheniramine); cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); corticosteroids; gastrointestinal agents (e.g., antacids); hypoglycemics sedatives and tranquilizers (e.g., diazepam).

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 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 Includes weakness, tiredness, lassitude, and fatigue. Asthenia Flu Syndrome Headache 7.4% p ≤ 0.05 comparison between groups. 2.4% 4.9% 3.3% 1.7% 5.8% CARDIOVASCULAR SYSTEM Hypotension Palpitations Postural Hypotension Syncope 0.6% 0.9% 3.9% 0.6% 0.6% 1.1% 0.8% 0.0% DIGESTIVE SYSTEM Nausea 1.7% 1.1% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema Weight Gain 0.9% 0.5% 0.3% 0.0% NERVOUS SYSTEM Dizziness Somnolence Vertigo 9.1% 3.6% 1.4% 4.2% 1.9% 0.3% RESPIRATORY SYSTEM Dyspnea Nasal Congestion/Rhinitis 1.7% 1.9% 0.8% 0.0% SPECIAL SENSES Blurred Vision/Amblyopia 1.3% 0.6% UROGENITAL SYSTEM Impotence Urinary Tract Infection 1.6% 1.3% 0.6% 3.9% 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 Headache 0.5% 1.1% 0.0% 0.8% CARDIOVASCULAR SYSTEM Postural Hypotension Syncope 0.5% 0.5% 0.0% 0.0% DIGESTIVE SYSTEM Nausea 0.5% 0.3% NERVOUS SYSTEM Dizziness Vertigo 2.0% 0.5% 1.1% 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 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 Includes weakness, tiredness, lassitude, and fatigue. Asthenia Back Pain Headache 11.3% Statistically significant at p=0.05 level. 2.4% 16.2% 4.3% 1.2% 15.8% CARDIOVASCULAR SYSTEM Palpitations Postural Hypotension Tachycardia 4.3% 1.3% 1.9% 1.2% 0.4% 1.2% DIGESTIVE SYSTEM Nausea 4.4% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Edema Peripheral Edema Weight Gain 0.9% 5.5% 0.5% 0.6% 2.4% 0.2% MUSCULOSKELETAL SYSTEM Pain – Extremities 3.5% 3.0% NERVOUS SYSTEM Depression Dizziness Libido Decreased Nervousness Paresthesia Somnolence 0.3% 19.3% 0.6% 2.3% 2.9% 5.4% 0.2% 7.5% 0.2% 1.8% 1.4% 2.6% RESPIRATORY SYSTEM Dyspnea Nasal Congestion Sinusitis 3.1% 5.9% 2.6% 2.4% 3.4% 1.4% SPECIAL SENSES Blurred Vision 1.6% 0.0% UROGENITAL SYSTEM Impotence 1.2% 1.4% 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 1987 patients who received terazosin in controlled or open, short- or long-term clinical trials studies 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. Discontinuation During Placebo-Controlled Trials Hypertension Body System Terazosin (N = 859) Placebo (N = 506) BODY AS A WHOLE Asthenia Headache 1.6% 1.3% 0.0% 1.0% CARDIOVASCULAR SYSTEM Palpitations Postural Hypotension Syncope Tachycardia 1.4% 0.5% 0.5% 0.6% 0.2% 0.0% 0.2% 0.0% DIGESTIVE SYSTEM Nausea 0.8% 0.0% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.6% 0.0% NERVOUS SYSTEM Dizziness Paresthesia Somnolence 3.1% 0.8% 0.6% 0.4% 0.2% 0.2% RESPIRATORY SYSTEM Dyspnea Nasal Congestion 0.9% 0.6% 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 ).

Pregnancy Teratogenic Effects Pregnancy Category C Terazosin capsules were not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose. Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose. Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. These findings (in both species) were most likely secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established. Terazosin capsules are not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus. Nonteratogenic Effects In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period.