terazosin 2 MG Oral Capsule

INDICATIONS & USAGE TEZRULY TM (terazosin) is an alpha-1 adrenoceptor antagonist indicated for: The treatment of signs and symptoms of benign prostatic hyperplasia (BPH) (1.1) The treatment of hypertension alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarction. (1.2) 1.1 Benign Prostatic Hyperplasia TEZRULY is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in adult males [see Clinical Studies (14.1)] . 1.2 Hypertension TEZRULY is indicated for the treatment of hypertension, to lower blood pressure in adults [see Clinical Studies (14.2)] . Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. TEZRULY may be used alone or in combination with other antihypertensive agents.

DOSAGE & ADMINISTRATION For the treatment of BPH: Initiate therapy at 1 mg orally once daily at bedtime. Titrate the dose upwards step-wise from 2 mg to 10 mg once daily. Doses of 10 mg once daily are generally required for a clinical response. Data is insufficient to support doses greater than 20 mg once daily. (2.1) For the treatment hypertension: Initiate therapy at 1 mg orally once daily at bedtime. Usual recommended dose range is 1 mg to 5 mg once daily. If response is substantially diminished at 24 hours, increase the dose or use twice daily. Dose may be titrated as needed up to 20 mg once daily. (2.2) If terazosin is discontinued for more than a few days, restart using the initial dosing regimen. (2.1) 2.1 Recommended Dosage for Benign Prostatic Hyperplasia Initial Dose: 1 mg orally once daily at bedtime. This dose should not be exceeded as an initial dose. Closely follow patients during initial administration in order to minimize the risk of severe hypotensive response, including syncope. For administration instructions, see Dosage and Administration (2.3). Subsequent Doses: The dose should be increased in a stepwise fashion from 2 mg to 10 mg orally once daily to achieve the desired improvement of symptoms and/or flow rates. Doses of 10 mg once daily are generally required for a 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. Although some patients responded to 20 mg per daily, data are insufficient to draw definitive conclusions about this dose. There are insufficient data to support the use of doses higher than 20 mg daily. If TEZRULY is discontinued for more than a few days, therapy should be restarted using the initial dosing regimen. For administration instructions, see Dosage and Administration (2.3). 2.2 Recommended Dosage for Hypertension Initial Dose: 1 mg orally once daily at bedtime. Do not exceed the initial dosing regimen to minimize the potential for severe hypotensive effects, including syncope. For administration instructions, see Dosage and Administration (2.3). Subsequent Doses: Slowly increase the dose to achieve the desired blood pressure response. The usual recommended dose range is 1 mg to 5 mg orally once daily; 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 ensure control throughout the dosing 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, consider increasing the dose or use a twice daily dosing regimen. In clinical trials, except for the initial dose, the dose was given in the morning. If TEZRULY is discontinued for more than a few days, therapy should be restarted using the initial dosing regimen. For administration instructions, see Dosage and Administration (2.3). TEZRULY may be used alone or in combination with other antihypertensive agents. Adjust the dose of TEZRULY and the dose frequency (every 12 hours or 24 hours) based on the patient’s individual blood pressure response. 2.3 Administration Information Take TEZRULY orally with or without food. A calibrated measuring device, such as an oral syringe or oral dosing cup, is recommended to measure and deliver the prescribed dose accurately. A household measuring cup, teaspoon, or tablespoon is not an adequate measuring device.

WARNINGS AND PRECAUTIONS Syncope and “First-dose” Effect: Advise patients about the possibility of symptoms related to postural hypotension and to avoid situations where injury could result should syncope occur, especially when starting TEZRULY. (5.1) Orthostatic Hypotension: Dizziness, lightheadedness, and palpitations can occur with use of TEZRULY. Advise patients to take their first dose of TEZRULY at bedtime and to avoid driving or hazardous tasks for 12 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. (5.2) Risk of Hypotension with Concomitant Use of Other Antihypertensive Agents and Phospodiesterase Type 5 Inhibitors (PDE5-I): Concomitant administration of TEZRULY with antihypertensives or phosphodiesterase-5 (PDE-5) inhibitors can result in additive blood pressure lowering effects and symptomatic hypotension (5.3). Priapism: Advise patients about the possibility and seriousness of priapism. (5.4) Intraoperative Floppy Iris Syndrome: Advise patients considering cataract surgery to tell their ophthalmologist that they have taken terazosin as Intraoperative Floppy Iris Syndrome as been observed during cataract surgery in some patients. (5.5) Prostatic Cancer: Screen for the presence of prostatic cancer prior to treatment for BPH and at regular intervals afterwards. (5.6) 5.1 Syncope and ‘‘First-dose’’ Effect TEZRULY, like other alpha-1-adrenoceptors antagonists, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy [see Warnings and Precautions (5.2)] . A similar effect can be anticipated if therapy is interrupted for several days and then restarted. Syncope has also been reported with other alpha-1-adrenoceptors antagonists 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 120-160 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, initiate treatment with a 1 mg dose of terazosin, given at bedtime. Higher doses (e.g., 2 to 10 mg) are not indicated as initial therapy. Then slowly increase the dose [see Dosage and Administration (2.1 and 2.2)] , and add additional antihypertensive agents with caution. Advise patients 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 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 (1 2 )] , 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, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, place the patient in a recumbent position and treat supportively as necessary. There is evidence that the orthostatic effect of terazosin 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. 5.2 Orthostatic Hypotension While syncope is the most severe orthostatic effect of terazosin, other symptoms of lowered blood pressure [see Warnings and Precautions (5.1)] , such as dizziness, lightheadedness and palpitations were more common and occurred in some 28% of patients in clinical trials of hypertension. In BPH clinical trials, 21% of the patients experienced one or more of the following: dizziness, hypotension, postural hypotension, syncope, and vertigo. Patients with occupations in which such events represent potential problems should be treated with particular caution. Advise patients to take their first dose of TEZRULY at bedtime and to avoid driving or hazardous tasks for 12 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. 5.3 Risk of Hypotension with Concomitant Use of Other Antihypertensive Agents and Phosphodiesterase Type 5 Inhibitors (PDE5-I) Concomitant use of TEZRULY with other anti-hypertensive agents, especially the calcium channel blocker verapamil, can increase the risk of hypotension. To reduce the risk of hypotension, dosage reduction and re-titration of either agent may be necessary [see Warnings and Precautions (5.1 and 5.2)] . Hypotension has been reported when terazosin has been used with phosphodiesterase-5 (PDE-5) inhibitors. Therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking TEZRULY. 5.4 Priapism Rarely (probably less than once in every several thousand patients) terazosin and other alpha-1-selective adrenoceptor antagonist have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, advise patients about the seriousness of the condition and the need to seek immediate medical attention at an emergency room. 5.5 Prostatic Cancer Carcinoma of the prostate and BPH present with many of the same symptoms and frequently co-exist. Therefore, examine patients thought to have BPH prior to starting TEZRULY therapy to rule out the presence of carcinoma of the prostate. 5.6 Intraoperative Floppy Iris Syndrome Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in some patients on/or previously treated with alpha-1-adrenoceptor antagonists. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible implementation of intraoperative preventive measures and modifications to surgical techniques during phacoemulsification surgery to reduce overall complication rates. There does not appear to be a benefit of stopping alpha-1-adrenoceptor antagonists therapy prior to cataract surgery. 5.7 Laboratory Tests Small but statistically significant decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin were observed in controlled clinical trials. These laboratory findings suggested the possibility of hemodilution. Treatment with terazosin for up to 24 months had no significant effect on prostate specific antigen (PSA) levels.

CONTRAINDICATIONS TEZRULY is contraindicated in patients known to be hypersensitive to terazosin or any component of TEZRULY. Hypersensitivity to terazosin hydrochloride or any other ingredient in TEZRULY. (4)

CLINICAL PHARMACOLOGY Pharmacodynamics A. Benign Prostatic Hyperplasia (BPH) The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: a static component and a dynamic component. The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity of BPH symptoms or the degree of urinary obstruction. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-1 adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-1 adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-1 adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. Terazosin has been studied in 1222 men with symptomatic BPH. In three placebo-controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0 to 3, for a total score of 27 points. Results from these studies indicated that terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows: Symptom Score Change % Peak Flow Rate Change % Range (0-27) (mL/sec) Mean Mean Mean Mean N Baseline N Baseline Study 1 (10 mg) a Titration to fixed dose (12 wks) Placebo 55 9.7 -2.3 (24) 54 10.1 +1.0 (10) Terazosin 54 10.1 -4.5 (45)* 52 8.8 +3.0 (34)* Study 2 (2, 5, 10, 20 mg) b Titration to Response (24 wks) Placebo 89 12.5 -3.8 (30) 88 8.8 +1.4 (16) Terazosin 85 12.2 -5.3 (43)* 84 8.4 +2.9 (35)* Study 3 (1, 2, 5, 10 mg) c Titration to response (24 wks) Placebo 74 10.4 -1.1 (11) 74 8.8 +1.2 (14) Terazosin 73 10.9 -4.6 (42)* 73 8.6 +2.6 (30)* a Highest dose 10 mg shown. b 23% of patients on 10mg, 41% of patients on 20 mg. c 67% of patients on 10 mg. * Significantly (p ≤ 0.05) more improvement than placebo. In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with terazosin capsules from week 2 (or the first clinic visit) and throughout the study duration. Analysis of the effect of terazosin capsules on individual urinary symptoms demonstrated that compared to placebo, terazosin significantly improved the symptoms of hesitancy, intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia. Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. In studies 1 and 3, patients treated with terazosin had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. In a short term study (Study 1), patients were randomized to either 2, 5 or 10 mg of terazosin or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo (Figure 1). FIGURE 1., STUDY 1 † for baseline values see above table * p ≤ 0.05, compared to placebo group In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3): FIGURE 2. Mean Change in Total Symptom Score from Baseline Long-Term, Open-Label, Non-Placebo Controlled Study (N=494) *p ≤ 0.05 vs. baseline mean baseline = 10.7 FIGURE 3. Mean Change in Peak Flow Rate from Baseline Long-Term, Open-Label, Non-Placebo Controlled Study (N=494) *p ≤ 0.05 vs. baseline; mean baseline = 9.9 In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect: Mean Changes in Blood Pressure from Baseline to Final Visit in all Double-Blind, Placebo-Controlled Studies Group Normotensive Patients DBP ≤ 90 mm Hg Hypertensive Patients DBP > 90 mm Hg N Mean Change N Mean Change SBP (mm Hg) Placebo Terazosin 293 519 -0.1 -3.3 p ≤ 0.05 vs. placebo 45 65 -5.8 -14.4 DBP (mm Hg) Placebo Terazosin 293 519 +0.4 -2.2 45 65 -7.1 -15.1 Figure 1 Figure 2 Figure 3 B. Hypertension In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. Terazosin decreases blood pressure gradually within 15 minutes following oral administration. Patients in clinical trials of terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5 to 20 mg/day, and had mild (about 77%, diastolic pressure 95 to 105 mmHg) or moderate (23%, diastolic pressure 105 to 115 mmHg) hypertension. Because terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). Blood pressure responses were measured at the end of the dosing interval (usually 24 hours) and effects were shown to persist throughout the interval, with the usual supine responses 5 to 10 mmHg systolic and 3.5 to 8 mmHg diastolic greater than placebo. The responses in the standing position tended to be somewhat larger, by 1 to 3 mmHg, although this was not true in all studies. The magnitude of the blood pressure responses was similar to prazosin and less than hydrochlorothiazide (in a single study of hypertensive patients). In measurements 24 hours after dosing, heart rate was unchanged. Limited measurements of peak response (2 to 3 hours after dosing) during chronic terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5 to 20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-