TEZRULY

TEZRULY (terazosin), an alpha-1-selective adrenoceptor antagonist, is a quinazoline derivative represented by the following chemical name and structural formula: 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride dihydrate Terazosin hydrochloride is racemic and is a white to pale yellow crystalline substance, sparingly soluble in water. The molecular formula is C 19 H 25 N 5 O 4 . HCl. 2H 2 O and the molecular weight is 459.92. TEZRULY (terazosin) oral solution is supplied in one dosage strength containing 1 mg/mL of terazosin (equivalent to 1.1 mg/mL of terazosin hydrochloride) and the following inactive ingredients: anhydrous citric acid, artificial cherry flavor, glycerin, methylparaben, propylparaben, purified water, sodium citrate dihydrate and sucralose. structure

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.

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)

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 reactions were not statistically different between the placebo and terazosin groups. Adverse reactions that were bothersome, reported as the reason for discontinuation of therapy by at least 0.5% of the terazosin group and reported more often than in the placebo group are shown in Table 2. Table 2. Discontinuation Rates During Placebo-Controlled Studies of Terazosin in Patients with 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 0.6% 0.0% Hypertension The prevalence rates presented below are based on combined data from fourteen placebo-controlled studies involving once-daily 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 reactions 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 Reported During Placebo-Controlled Studies of Terazosin in Patients with Hypertension Body System Terazosin (N=859) % Placebo (N=506) % BODY AS A WHOLE †Asthenia 11* 4 Back Pain 2 1 CARDIOVASCULAR SYSTEM Palpitations 4* 1 Postural Hypotension 1 0 Tachycardia 2 1 DIGESTIVE SYSTEM Nausea 4* 1 METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 6* 2 Weight Gain 1 0 MUSCULOSKELETAL SYSTEM Pain-Extremities 4 3 NERVOUS SYSTEM Dizziness 19* 8 Libido Decreased 1 0 Paresthesia 3 1 Somnolence 5* 3 RESPIRATORY SYSTEM Dyspnea 3 2 Nasal Congestion 6* 3 Sinusitis 3 1 SPECIAL SENSES Blurred Vision 2* 0 UROGENITAL SYSTEM Erectile Dysfunction 1 1 † Includes weakness, tiredness, lassitude and fatigue. * Statistically significant at p=0.05 level. The following adverse reactions associated with the use of terazosin were identified in clinical studies (≥1%) or during post-approval use of terazosin. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Body as a Whole: edema, facial edema; Cardiovascular System: chest pain, arrhythmia, vasodilation; Digestive System: abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, flatulence, vomiting; Metabolic/Nutritional Disorders: gout; Musculoskeletal System: arthralgia, arthritis, joint disorder, myalgia, neck pain, shoulder pain; Nervous System: anxiety, insomnia, nervousness, depression; Respiratory System: bronchitis, cold symptoms, epistaxis, increased cough, pharyngitis; Skin and Appendages: pruritus, rash, sweating; Special Senses: abnormal vision, conjunctivitis, tinnitus; Urogenital System: urinary frequency, urinary incontinence primarily reported in postmenopausal women; Adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. The adverse reactions that were most bothersome, reported as reason for discontinuation 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 Studies of Terazosin in Patients with 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% 6.2 Post-marketing Experience The following adverse reactions have been identified during postapproval use of terazosin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: thrombocytopenia Cardiovascular System: atrial fibrillation Skin and Appndages: allergic reactions, including anaphylaxis Urogenital System: priapism During cataract surgery, a variant of small pupil syndrome known as intraoperative floppy iris syndrome (IFIS) has been reported in association with alpha-1 antagonist therapy [see Warnings and Precautions (5.5)] .

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)