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 capsules 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. Terazosin capsules 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.)

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

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 less than or equal to 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 * Includes weakness, tiredness, lassitude, and fatigue. † p less than or equal to 0.05 comparison between groups. 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% † 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 thos …

Drug Interactions In controlled trials, terazosin has been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin). 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole). 3) anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride). 4) antigout (e.g., allopurinol). 5) antihistamines (e.g., chlorpheniramine). 6) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol). 7) corticosteroids. 8) gastrointestinal agents (e.g., antacids). 9) hypoglycemics. 10) sedatives and tranquilizers (e.g., diazepam). Use with Other Drugs In a study (n = 24) where terazosin and verapamil were administered concomitantly, terazosin's mean AUC 0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in C max (25%) and C min (32%) means. Terazosin mean T max decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. In a study (n = 6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril (see DOSAGE AND ADMINISTRATION ). Carcinogenesis, Mutagenesis, Impairment of Fertility Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay). Terazosin, administered in the feed to rats at doses of 8 mg/kg/day, 40 mg/kg/day, and 250 mg/kg/day (70 mg/m 2 /day, 350 mg/m 2 /day, and 2,100 mg/m 2 /day), for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum recommended human dose of 20 mg (12 mg/m 2 ). Female rats were unaffected. Terazosin was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day (110 mg/m 2 ; 9 times the maximum recommended human dose). The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man. The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8 mg/kg/day, 30 mg/kg/day and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg (240 mg/m 2 ; 20 times the maximum recommended human dose) and five of 19 male rats given 120 mg/kg (960 mg/m 2 ; 80 times the maximum recommended human dose) failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 mg/kg/day and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy. Oral administration of terazosin for one or two years elicited a s …

DESCRIPTION Terazosin hydrochloride, USP an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name and structural formula: (RS)-Piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-, monohydrochloride, dihydrate. Terazosin hydrochloride, USP is a white to pale yellow crystalline powder, slightly soluble in water pH 1.3 (HCl), water pH 12.6 (NaOH), ethanol 95% and chloroform, sparingly soluble in water pH 6, soluble in methanol, and practically insoluble in n-hexane. Its molecular formula is C 19 H 25 N 5 O 4 •HCl•2H 2 O and has a molecular weight of 459.93 g/mole. Each capsule, for oral administration, contains terazosin hydrochloride, USP equivalent to 1 mg, 2 mg, 5 mg, or 10 mg of terazosin. In addition, each capsule contains the following inactive ingredients: Colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pregelatinized starch. The capsule shell contains D&C yellow no. 10 (2 mg, 5 mg and 10 mg), D&C red no. 28 (5 mg), FD& C green no. 3 (10 mg), FD&C red no. 40 (5 mg), gelatin, iron oxide black (1 mg), sodium lauryl sulfate, and titanium dioxide. The capsules are printed with black ink composed of ammonia solution, black iron oxide, potassium hydroxide, propylene glycol, and shellac. FDA approved dissolution test specifications differ from USP. image description

OVERDOSAGE Should overdosage of terazosin capsules lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that terazosin is 90-94% protein bound; therefore, dialysis may not be of benefit.

HOW SUPPLIED Terazosin capsules, USP are available in four dosage strengths 1 mg gray capsules available as hard gelatin capsule with gray opaque cap and gray opaque body filled with white to off white powder blend. The capsule is printed with “ TE1 ” in black ink on the body, free from physical defects. Bottles of 100....................................................( NDC 69452-330-20) Bottles of 1000..................................................( NDC 69452-330-32) 2 mg yellow capsules available as hard gelatin capsule with ivory opaque cap and ivory opaque body filled with white to off white powder blend. The capsule is printed with “ TE2 ” in black ink on the body, free from physical defects. Bottles of 100....................................................( NDC 69452-331-20) Bottles of 1000..................................................( NDC 69452-331-32) 5 mg red capsules available as hard gelatin capsule with orange opaque cap and orange opaque body filled with white to off white powder blend. The capsule is printed with “ TE3 ” in black ink on the body, free from physical defects. Bottles of 100....................................................( NDC 69452-332-20) Bottles of 1000..................................................( NDC 69452-332-32) 10 mg blue capsules available as hard gelatin capsule with green opaque cap and green opaque body filled with white to off white powder blend. The capsule is printed with “ TE4 ” in black ink on the body, free from physical defects. Bottles of 100....................................................( NDC 69452-333-20) Bottles of 1000..................................................( NDC 69452-333-32) Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in tight, light-resistant container as defined in USP. Distributed by: Bionpharma Inc. Princeton, NJ 08540 MADE IN INDIA Revised: 05/24 FDA-03