Terazosin

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.

Oral solution: 1 mg/mL terazosin, clear, cherry flavored solution, free from visible particulate matter. Oral solution: 1 mg/mL of terazosin (3)

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)

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.

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. […]

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.

8.2 Lactation Risk Summary There are no available data on the presence of terazosin in human milk, effects on the breastfed infant, or the effects on milk production.

8.3 Females and Males of Reproductive Potential Infertility Males Possible effects on male fertility could be observed based on findings in rats at exposures that were at least 15 times higher than at the maximum recommended human dose on a body surface area basis. The clinical relevance of this finding is unknown [see Nonclincal Toxicology (13.1)] .

8.4 Pediatric Use The safety and effectiveness of terazosin have not been established in pediatric patients.

Benign Prostatic Hyperplasia The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha-1-adrenoceptors, which is reent in high density in the prostate stroma, prostatic capsule, prostatic urethra, and bladder neck. Blockade of the alpha-1 receptor decreases urethral resistance and may relieve the obstruction of BPH symptoms and improve urine flow Hypertension The mechanism of action of terazosin is selective blockade of the alpha-1 subtype of adrenergic receptors. The antihypertensive effect of terazosin results from a decrease in systemic vascular resistance. 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 antagonism of alpha-1 adrenoceptors. Terazosin decreases blood pressure within 15 minutes following oral administration.