Tezruly Drug Information

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. 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.

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.

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.

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.

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.

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 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%

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 .

Co-administration of verapamil with terazosin increases the systemic exposure of terazosin , which may increase the risk of hypotenstion. To reduce the risk of hypotension, dosage reduction and re-titration of either agent may be necessary . 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.

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.

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.

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

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.

There is limited experience regarding overdosage with terazosin. Following a single oral dose of 300 mg (15 times the maximum recommended human dose of 20 mg), signs and symptoms of ovedosage included hypothermia, bradycardia and hypotension. Management of overdose leading to hypotension should concentrate on support of the cardiovascular system.

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.

Close medical supervision and monitoring should continue until the patient recovers. Dialysis is unlikely to be effective as terazosin is highly protein bound. Consult the National Capital Poison Center (1-800-222-1222 or www.poison.org) for up-to-date guidance and advice regarding a TEZRULY overdosage.