TEZRULY

1 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.

2 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.

5 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, s…

4 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)

7 DRUG INTERACTIONS Co-administration of verapamil with terazosin increases the systemic exposure of terazosin [see Clinical Pharmacology (12.3)] , which may increase the risk of hypotenstion. To reduce the risk of hypotension, dosage reduction and re-titration of either agent may be necessary [see Warnings and Precautions (5.3)] . Co-administration of verapamil with terazosin increases the systemic exposure of terazosin and may lead to hypotension. Dosage reduction and re-titration of either agent may be necessary. (7)

8.1 Pregnancy Risk Summary The limited available data on terazosin use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed when terazosin was orally administered to pregnant rats and rabbits during the period of organogenesis at doses of up to 230 and 60 times, respectively, the maximum recommended human dose on a body surface area (mg/m 2 ) basis. In the rat and rabbit oral doses at 230 and 60 times, respectively, the maximum recommended human dose on a body surface area basis, reduced fetal survival was observed [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Studies in rats and rabbits at oral doses up to 230 and 60 times, respectively, the maximum recommended human dose on a body surface area (mg/m 2 ) basis, have revealed no evidence of adverse developmental effects. In rats, fetal resorptions were observed at 480 mg/kg/day, approximately 230 times the maximum recommended human dose on a body surface area basis. In rabbits,. increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed at 60 mg/kg/day, 60 times the maximum recommended human dose on a body surface area basis. These findings (in both species) were most likely secondary to maternal toxicity. In a peri- and post-natal development study in rats, significantly more pups died at 120 mg/kg/day (60 times the maximum recommended human dose on a body surface area basis) than in the control group during the three-week postpartum period.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Syncope and ‘‘First-dose’’ Effect [see Warnings and Precautions (5.1)] Orthostatic Hypotension [see Warnings and Precautions (5.2)] Priapism [see Warnings and Precautions (5.3)] Intraoperative Floppy Iris Syndrome [see Warnings and Precautions (5.5)] In treatment of BPH, the most common adverse reactions (≥1% of patients and at a higher incidence than placebo) were asthenia, flu syndrome, postural hypotension, nausea, somnolence, vertigo, dyspnea, nasal congestion/rhinitis, blurred vision/amblyopia and erectile dysfunction. (6.1) In treatment of hypertension, the most common adverse reactions where the incidence on terazosin was ≥ 5%, where the incidence on terazosin was at least 2% and greater than placebo or where the reaction was of particular interest were asthenia, back pain, pain in the extremities, headache, palpitations, postural hypotension, tachycardia, nausea, edema, peripheral edema, weight gain, depression, dizziness, libido, decreased, nervousness, paresthesia, somnolence, dyspnea, nasal congestion, sinusitis, blurred vision, and erectile dysfunction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Benign Prostatic Hyperplasia The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-daily 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 reactions [see Warnings and Precautions (5.1, 5.2)] adjusted for the length of drug treatment has shown that the risk of the reactions is greatest during the initial seven days of treatment but continues at all time intervals. Table 1. Adverse Reactions Reported During Placebo-Controlled Studies of Terazosin in Patients with Benign Prostatic Hyperplasia Body System Terazosin (N=636) % Placebo (N=360) % BODY AS A WHOLE †Asthenia 7* 3 Flu Syndrome 2 2 Headache 5 6 CARDIOVASCULAR SYSTEM Hypotension 1 1 Palpitations 1 1 Postural Hypotension 4* 1 Syncope 1 0 DIGESTIVE SYSTEM Nausea 2 1 METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 1 0 Weight Gain 1 0 NERVOUS SYSTEM Dizziness 9* 4 Somnolence 4 2 Vertigo 1 0 RESPIRATORY SYSTEM Dyspnea 2 1 Nasal Congestion/Rhinitis 2* 0 UROGENITAL SYSTEM Erectile Dysfunction 2* 1 Urinary Tract Infection 1 4* † Includes weakness, tiredness, lassitude and fatigue. * p ≤ 0.05, comparison between groups. 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 safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. Adverse reactions 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 rea…