24 HR alfuzosin hydrochloride 10 MG Extended Release Oral Tablet [UroXatral]

INDICATIONS AND USAGE Alfuzosin hydrochloride extended-release tablets, USP are indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. Alfuzosin hydrochloride extended-release tablet is an alpha adrenergic antagonist, indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. (1) Important Limitations of Use: Alfuzosin hydrochloride extended-release tablets are not indicated for treatment of hypertension. ( 1.1 ) Alfuzosin hydrochloride extended-release tablets are not indicated for use in the pediatric population. ( 1.1 , 8.4 , 12.3 ) 1.1 Important Limitations of Use Alfuzosin hydrochloride extended-release tablets, USP are not indicated for the treatment of hypertension. Alfuzosin hydrochloride extended-release tablets, USP are not indicated for use in the pediatric population. 1.1 Important Limitations of Use Alfuzosin hydrochloride extended-release tablets, USP are not indicated for the treatment of hypertension. Alfuzosin hydrochloride extended-release tablets, USP are not indicated for use in the pediatric population.

DOSAGE AND ADMINISTRATION The recommended dosage is one 10 mg alfuzosin hydrochloride extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride extended-release tablets 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. ( 2 ) Tablets should not be chewed or crushed ( 2 , 12.3 )

WARNINGS AND PRECAUTIONS Postural hypotension/syncope: Care should be taken in patients with symptomatic hypotension or who have had a hypotensive response to other medications or are concomitantly treated with antihypertensive medication or nitrates ( 5.1 ) Use with caution in patients with severe renal impairment (creatinine clearance <30 mL/min) ( 5.2 , 8.6 , 12.3 ) Use with caution in patients with mild hepatic impairment ( 5.3 , 8.7 , 12.3 ) Should not be used in combination with other alpha adrenergic antagonists ( 5.4 , 7.2 ) Prostate carcinoma should be ruled out prior to treatment ( 5.5 ) Intraoperative Floppy Iris Syndrome (IFIS) during cataract surgery may require modifications to the surgical technique ( 5.6) Discontinue alfuzosin hydrochloride extended-release tablets if symptoms of angina pectoris appear or worsen ( 5.8 ) Use with caution in patients with a history of QT prolongation or who are taking medications which prolong the QT interval ( 5.9 , 12.2 ) 5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of alfuzosin hydrochloride extended-release tablets. As with other alpha-adrenergic antagonists, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin hydrochloride extended-release tablets concomitantly with anti-hypertensive medication and nitrates. Care should be taken when alfuzosin hydrochloride extended-release tablets are administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications. 5.2 Patients with Renal Impairment Caution should be exercised when alfuzosin hydrochloride extended-release tablets are administered in patients with severe renal impairment (creatinine clearance < 30 mL/min) [ see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3) ]. 5.3 Patients with Hepatic Impairment Alfuzosin hydrochloride extended-release tablets are contraindicated for use in patients with moderate or severe hepatic impairment [ see Contraindications ( 4 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3) ]. Although the pharmacokinetics of alfuzosin hydrochloride extended-release tablets have not been studied in patients with mild hepatic impairment, caution should be exercised when alfuzosin hydrochloride extended-release tablets are administered to such patients [ see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3) ]. 5.4 Drug-Drug Interactions Potent CYP3A4 Inhibitors Alfuzosin hydrochloride extended-release tablets are contraindicated for use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood levels are increased [ see Contraindications ( 4 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3) ]. Other alpha-adrenergic antagonists Alfuzosin hydrochloride extended-release tablets are an alpha-adrenergic antagonist and should not be used in combination with other alpha adrenergic antagonist [ see Drug Interactions ( 7.2 ) ]. Phosphodiesterase-5 (PDE5) Inhibitors PDE5-inhibitors are also vasodilators. Caution is advised for concomitant use of PDE5-inhibitors and alfuzosin hydrochloride extended-release tablets, as this combination can potentially cause symptomatic hypotension [ see Drug Interactions ( 7.4) ]. 5.5 Prostatic Carcinoma Carcinoma of the prostate and benign prostatic hyperplasia (BPH) cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined to rule out the presence of carcinoma of the prostate prior to starting treatment with alfuzosin hydrochloride extended-release tablets. 5.6 Intraoperative Floppy Iris Syndrome (IFIS) IFIS has been observed during cataract surgery in some patients on or previously treated with alpha adrenergic 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 modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha adrenergic antagonist therapy prior to cataract surgery. 5.7 Priapism Rarely (probably less than 1 in 50,000), alfuzosin, like other alpha-adrenergic antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients should be advised about the seriousness of the condition [ see Adverse Reactions ( 6.2) and Patient Counseling Information (17.3)] . 5.8 Coronary Insufficiency If symptoms of angina pectoris should appear or worsen, alfuzosin hydrochloride extended-release tablets should be discontinued. 5.9 Patients with Congenital or Acquired QT Prolongation Use with caution in patients with acquired or congenital QT prolongation or who are taking medications that prolong the QT interval [see Clinical Pharmacology ( 12.2 )].

CONTRAINDICATIONS Alfuzosin hydrochloride extended-release tablets are 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 [ see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3) ]. with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased [ see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ) ]. in patients with known hypersensitivity, such as urticaria and angioedema, to alfuzosin hydrochloride or any component of alfuzosin hydrochloride extended-release tablets [ see Adverse Reactions ( 6.2 ) ] Moderate or severe hepatic impairment ( 4 , 8.7 , 12.3 ) Co-administration with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) ( 4 , 5.4 , 7.1 , 12.3 ) Known hypersensitivity (e.g., urticaria or angioedema) to alfuzosin or any of the ingredients ( 4 , 6.2 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alfuzosin is a selective antagonist of post-synaptic alpha 1 -adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. 12.2 Pharmacodynamics Alfuzosin exhibits selectivity for alpha adrenergic receptors in the lower urinary tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of BPH. Cardiac Electrophysiology The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg), 4-way crossover single dose study in 45 healthy white male subjects aged 19 to 45 years. The QT interval was measured at the time of peak alfuzosin plasma concentrations. The 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of alfuzosin hydrochloride extended-release tablets and ketoconazole 400 mg. Table 3 summarizes the effect on uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia, population-specific and subject-specific correction methods) at the time of peak alfuzosin plasma concentrations. No single one of these correction methodologies is known to be more valid. The mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and 5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.8 beats/minute. Table 3. Mean QT and QTc changes in msec (95% CI) from baseline at T m a x (relative to placebo) with different methodologies to correct for effect of heart rate. Drug / Dose QT Fridericia method Population - specific method Subject - specific method Alfuzosin 10 mg -5.8 (-10.2, -1.4) 4.9 (0.9, 8.8) 1.8 (-1.4, 5.0) 1.8 (-1.3, 5.0) Alfuzosin 40 mg -4.2 (-8.5, 0.2) 7.7 (1.9, 13.5) 4.2 (-0.6, 9.0) 4.3 (-0.5, 9.2) Moxifloxacin Active control 400 mg 6.9 (2.3, 11.5) 12.7 (8.6, 16.8) 11.0 (7.0, 15.0) 11.1 (7.2, 15.0) The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (four times the therapeutic dose) studied did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. There has been no signal of Torsade de Pointes in the extensive post-marketing experience with alfuzosin outside the United States. A separate post-marketing QT study evaluated the effect of the co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted QTcF increase of alfuzosin 10 mg alone was 1.9 msec (upperbound 95% CI, 5.5 msec). The concomitant administration of the two drugs showed an increased QT effect when compared with either drug alone. This QTcF increase [5.9 msec (UB 95% CI, 9.4 msec)] was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the QT increase with both drugs given together appeared to be lower than the QTcF increase seen with the positive control moxifloxacin 400 mg [10.2 msec (UB 95% CI, 13.8 msec)]. The clinical impact of these QTc changes is unknown. 12.3 Pharmacokinetics The pharmacokinetics of alfuzosin hydrochloride extended-release tablets have been evaluated in adult healthy male volunteers after single and/or multiple administration with daily doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5 mg to 15 mg. Absorption The absolute bioavailability of alfuzosin hydrochloride extended-release tablets 10 mg under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride extended-release tablets under fed conditions, the time to maximum concentration is 8 hours. C max and AUC 0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ng h/mL, respectively. Alfuzosin hydrochloride extended-release tablets exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of alfuzosin hydrochloride extended-release tablets administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after a single administration. Effect of Food As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride extended-release tablets should be taken with food and with the same meal each day [see Dosage and Administration (2) ] . Figure 1 – Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after a Single Administration of Alfuzosin Hydrochloride Extended-Release tablets 10 mg to 8 Healthy Middle-Aged Male Volunteers in Fed and Fasted States Distribution The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL). Metabolism Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism. Excretion Following oral administration of 14 C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin hydrochloride extended-release tablets 10 mg, the apparent elimination half-life is 10 hours. Specific Populations Geriatric Use : In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. However, trough levels were positively correlated with age. The concentrations in subjects > 75 years of age were approximately 35% greater than in those below 65 years of age. Renal Impairment : The Pharmacokinetic profiles of alfuzosin hydrochloride extended-release tablets 10 mg in subjects with normal renal function (CL CR >80 mL/min), mild impairment (CL CR 60 to 80 mL/min), moderate impairment (CL CR 30 to 59 mL/min), and severe impairment (CL CR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean C max and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] . Hepatic Impairment : The pharmacokinetics of alfuzosin hydrochloride extended-release tablets have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in three to four-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, alfuzosin hydrochloride extended-release tablets are contraindicated in patients with moderate to severe hepatic impairment [see Contraindications (4) , Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] . Pediactric Use: Alfuzosin hydrochloride extended-release tablets are not indicated for use in the pediatric population [see Indication and Usage (1.1) and Use in Specific Population (8.4) ]. Drug-Drug Interactions Metabolic Interactions CYP3A4 is the principal hepatic enzyme is