Uroxatral Drug Information

Important Limitations of Use

UROXATRAL is not indicated for the treatment of hypertension. UROXATRAL is not indicated for use in the pediatric population.

The recommended dosage is one 10 mg UROXATRAL (alfuzosin HCl) extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, Uroxatral should be taken with food and with the same meal each day.

The tablets should not be chewed or crushed. 10 mg once daily with food and with the same meal each day. Tablets should not be chewed or crushed

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The incidence of adverse reactions has been ascertained from 3 placebo-controlled clinical trials involving 1,608 men where daily doses of 10 and 15 mg alfuzosin were evaluated. In these 3 trials, 473 men received UROXATRAL (alfuzosin HCl) 10 mg extended-release tablets.

In these trials, 4% of patients taking UROXATRAL (alfuzosin HCl) 10 mg extended-release tablets withdrew from the trial due to adverse reactions, compared with 3% in the placebo group. Table 1 summarizes adverse reactions that occurred in ≥2% of patients receiving UROXATRAL, and at a higher incidence than that of the placebo group. In general, the adverse reactions seen in long-term use were similar in type and frequency to the events described below for the 3-month trials.

Table 1 — Adverse Reactions Occurring in ≥2% of UROXATRAL-Treated Patients and More Frequently than with Placebo in 3-Month Placebo-Controlled Clinical Trials Adverse Reaction Placebo (n=678) UROXATRAL (n=473) Dizziness 19 (2.8%) 27 (5.7%) Upper respiratory tract infection 4 (0.6%) 14 (3.0%) Headache 12 (1.8%) 14 (3.0%) Fatigue 12 (1.8%) 13 (2.7%) The following adverse reactions, reported by between 1% and 2% of patients receiving UROXATRAL and occurring more frequently than with placebo, are listed alphabetically by body system and by decreasing frequency within body system: Body as a whole: pain Gastrointestinal system: abdominal pain, dyspepsia, constipation, nausea Reproductive system: impotence Respiratory system: bronchitis, sinusitis, pharyngitis Signs and Symptoms of Orthostasis in Clinical Trials: The adverse reactions related to orthostasis that occurred in the double-blind phase 3 trials with alfuzosin 10 mg are summarized in Table 2. Approximately 20% to 30% of patients in these trials were taking antihypertensive medication. Table 2— Number (%) of Patients with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Trials Symptoms Placebo (n=678) UROXATRAL (n=473) Dizziness 19 (2.8%) 27 (5.7%) Hypotension or postural hypotension 0 2 (0.4%) Syncope 0 1 (0.2%) Testing for blood pressure changes or orthostatic hypotension was conducted in three controlled studies. Decreased systolic blood pressure (≤90 mm Hg, with a decrease ≥20 mm Hg from baseline) was observed in none of the 674 placebo patients and 1 (0.2%) of the 469 UROXATRAL patients.

Decreased diastolic blood pressure (≤50 mm Hg, with a decrease ≥15 mm Hg from baseline) was observed in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the UROXATRAL patients. A positive orthostatic test (decrease in systolic blood pressure of ≥20 mm Hg upon standing from the supine position) was seen in 52 (7.7%) of placebo patients and in 31 (6.6%) of the UROXATRAL patients.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of UROXATRAL. 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. General disorders: edema Cardiac disorders: tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillation Gastrointestinal disorders: diarrhea, vomiting Hepatobiliary disorders: hepatocellular and cholestatic liver injury (including cases with jaundice leading to drug discontinuation) Respiratory system disorders: rhinitis Reproductive system disorders: priapism Skin and subcutaneous tissue disorders: rash, pruritis, urticaria, angioedema, toxic epidermal necrolysis Vascular disorders: flushing Blood and lymphatic system disorders: thrombocytopenia During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in some patients on or previously treated with alpha adrenergic antagonists.

CYP3A4 Inhibitors

UROXATRAL is contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased .

Alpha Adrenergic Antagonists

The pharmacokinetic and pharmacodynamic interactions between UROXATRAL and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and UROXATRAL should not be used in combination with other alpha adrenergic antagonists.

Antihypertensive Medication and Nitrates

There may be an increased risk of hypotension/postural hypotension and syncope when taking UROXATRAL concomitantly with anti-hypertensive medication and nitrates .

PDE5 Inhibitors Caution is advised when alpha adrenergic antagonists, including

UROXATRAL, are co-administered with PDE5 inhibitors. Alpha adrenergic antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension .

Pregnancy Risk Summary Uroxatral is not indicated for use in women. There are no adequate data on the developmental risk associated with use of UROXATRAL in pregnant women. Based on findings from animal studies, alfuzosin administered during the period of organogenesis was not teratogenic, embryotoxic or fetotoxic at upto 1200 times the MRHD of 10 mg via AUC in rats and 3 times in rabbit, via body surface area.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. Data Animal data Alfuzosin was not teratogenic, embryotoxic or fetotoxic in rats at plasma exposure levels (based on AUC of unbound drug) up to 1200 times (maternal oral dose of 250 mg/kg/day) the maximum recommended human dose (MRHD) of 10 mg. In rabbits administered up to 3 times the MRHD (based on body surface area) (maternal oral dose of 100 mg/kg/day) no embryofetal toxicity or teratogenicity was observed.

Gestation was slightly prolonged in rats at exposure levels (based on AUC of unbound drug) approximately 12 times (greater than 5 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed.

Pediatric Use UROXATRAL is not indicated for use in the pediatric population. Efficacy of alfuzosin hydrochloride was not demonstrated in a randomized, double-blind, placebo-controlled, efficacy and safety trial conducted in 172 patients ages 2 to 16 years with elevated detrusor leak point pressure (LPP≥40 cm H 2 O) of neurologic origin treated with alfuzosin hydrochloride using pediatric formulations. The trial included a 12-week efficacy phase followed by a 40-week safety extension period.

No statistically significant difference in the proportion of patients achieving a detrusor leak point pressure of <40 cm H 2 0 was observed between the alfuzosin and placebo groups. During the placebo-controlled trial, the adverse reactions reported in ≥2% of patients treated with alfuzosin and at a higher incidence than in the placebo group were: pyrexia, headache, respiratory tract infection, cough, epistaxis and diarrhea. The adverse reactions reported for the whole 12-month trial period, which included the open-label extension, were similar in type and frequency to the reactions observed during the 12-week period.

Alfuzosin hydrochloride was not studied in patients below the age of 2.

is contraindicated for use: in patients with moderate or severe hepatic impairment (Childs-Pugh categories B and C), since alfuzosin blood levels are increased in these patients. with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased . in patients with known hypersensitivity, such as urticaria and angioedema, to alfuzosin hydrochloride or any component of UROXATRAL tablets Moderate or severe hepatic impairment Co-administration with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) Known hypersensitivity (e.g., urticaria or angioedema) to alfuzosin or any of the ingredients

Should overdose of UROXATRAL lead to hypotension, support of the cardiovascular system is of first importance. 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, then the administration of intravenous fluids should be considered.

If necessary, vasopressors should then be used, and the renal function should be monitored and supported as needed. Alfuzosin is 82% to 90% protein bound; therefore, dialysis may not be of benefit.