DOSAGE FORMS & STRENGTHS SECTION.

3. DOSAGE FORMS AND STRENGTHS. Extended-release tablet: 10 mg (3). Alfuzosin HCl extended-release tablets 10 mg are available as white and yellow colored bi-layered circular shaped standard convex tablets, debossed with W738 on yellow layer.

ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. Most common adverse reactions in clinical studies (incidence >=2% and at higher incidence than placebo): dizziness, upper respiratory tract infection, headache, fatigue. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC. at 1-800-346-6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 placebo-controlled clinical trials involving 1,608 men where daily doses of 10 and 15 mg alfuzosin were evaluated. In these trials, 473 men received alfuzosin HCl extended-release tablets 10 mg. In these trials, 4% of patients taking alfuzosin HCl extended-release tablets 10 mg withdrew from the trial due to adverse reactions, compared with 3% in the placebo group. Table summarizes adverse reactions that occurred in >=2% of patients receiving alfuzosin HCl extended-release tablets, and at 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 - Adverse Reactions Occurring in >= 2% of Alfuzosin HCl Extended-Release Tablets-Treated Patients and More Frequently than with Placebo in 3-Month Placebo-Controlled Clinical TrialsAdverse ReactionPlaceboAlfuzosin HCl Extended-Release Tablets(n=678)(n=473)Dizziness 19 (2.8%) 27 (5.7%) Upper respiratory tract infection (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 alfuzosin HCl extended-release tablets and occurring more frequently than with placebo, are listed alphabetically by body system and by decreasing frequency within body system: Body as 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 trials with alfuzosin 10 mg are summarized in Table 2. Approximately 20% to 30% of patients in these trials were taking antihypertensive medication. Table - Number (%) of Patients with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Trials SymptomsPlaceboAlfuzosin HCl Extended-Release Tablets(n=678)(n=473)Dizziness 19 (2.8%) 27 (5.7%) Hypotension or posturalhypotension 2 (0.4%) Syncope 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 decrease >=20 mm Hg from baseline) was observed in none of the 674 placebo patients and (0.2%) of the 469 alfuzosin HCl extended-release tablets patients. Decreased diastolic blood pressure (<= 50 mm Hg, with decrease >= 15 mm Hg from baseline) was observed in (0.4%) of the placebo patients and in (0.9%) of the alfuzosin HCl extended-release tablets patients. 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 alfuzosin HCl extended-release tablets patients. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post approval use of alfuzosin HCl extended-release tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.General disorders: edema Cardiac disorders: tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillationGastrointestinal disorders: diarrhea 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 Vascular disorders: flushingDuring cataract surgery, 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 [see Warnings and Precautions (5.6)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility. There was no evidence of drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose [MRHD] of 10 mg based on AUC of unbound drug), in females and males, respectively. The highest dose tested in female mice may not have constituted maximally tolerated dose. Likewise, there was no evidence of drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively). Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in human cell line. There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Alfuzosin is selective antagonist of post-synaptic alpha1-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 reduction in symptoms of BPH.Cardiac Electrophysiology The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in 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 HCl extended-release tablets and ketoconazole 400 mg. Table 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 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 Tm x (relative to placebo) with different methodologies to correct for effect of heart rate. Active controlDrug /DoseQTFridericia methodPopulation- specific methodSubject-specific methodAlfuzosin10 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 400 mg6.9(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 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 HCl 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. AbsorptionThe absolute bioavailability of alfuzosin HCl extended-release tablets 10 mg under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin HCl extended-release tablets under fed conditions, the time to maximum concentration is hours. Cmax and AUC0-24 are 13.6 (SD 5.6) ng/mL and 194 (SD 75) ng.h/mL, respectively. Alfuzosin HCl 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 HCl extended-release tablets administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after single administration.Effect of Food As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin HCl extended-release tablets should be taken with food and with the same meal each day [see Dosage and Administration (2)]. Figure - Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after Single Administration of Alfuzosin HCl Extended-Release Tablets 10 mg to Healthy Middle-Aged Male Volunteers in Fed and Fasted StatesDistributionThe 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 wide concentration range (5 to 5,000 ng/mL).MetabolismAlfuzosin 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.ExcretionFollowing oral administration of 14C-labeled alfuzosin solution, the recovery of radioactivity after days (expressed as percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin HCl extended-release tablets 10 mg, the apparent elimination half-life is 10 hours.Specific PopulationsGeriatric Use: In pharmacokinetic assessment during phase 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 HCl extended-release tablets 10 mg in subjects with normal renal function (CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean Cmax 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 HCl extended-release tablets have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories 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 HCl 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)].Pediatric Use: Alfuzosin HCl extended-release tablets are not indicated for use in the pediatric population [see Indications and Usage (1.1) and Use in Specific Populations (8.4)] Drug-Drug InteractionsMetabolic InteractionsCYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. Potent CYP3A4 InhibitorsRepeated oral administration of 400 mg/day of ketoconazole, potent inhibitor of CYP3A4, increased alfuzosin Cmax by 2.3-fold and AUClast by 3.2-fold, following single 10 mg dose of alfuzosin.In another study, repeated oral administration of lower (200 mg/day) dose of ketoconazole increased alfuzosin Cmax by 2.1-fold and AUClast by 2.5-fold, following single 10 mg dose of alfuzosin.Therefore, alfuzosin HCl extended-release tablets are contraindicated for co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure [see Contraindications (4), Warnings and Precautions (5.4) and Drug Interactions (7.1)]. Moderate CYP3A4 Inhibitors Diltiazem: Repeated co-administration of 240 mg/day of diltiazem, moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with alfuzosin HCl extended-release tablets) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of alfuzosin HCl extended-release tablets and antihypertensive medications has the potential to cause hypotension in some patients [see Warnings and Precautions (5.1)]. In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes. Other Interactions Warfarin: Multiple dose administration of an immediate release tablet formulation of alfuzosin mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to single 25 mg oral dose of warfarin.Digoxin: Repeated co-administration of alfuzosin HCl extended-release tablets 10 mg and digoxin 0.25 mg/day for days did not influence the steady-state pharmacokinetics of either drug. Cimetidine: Repeated administration of 1g/day cimetidine increased both alfuzosin Cmax and AUC values by 20%.Atenolol: Single administration of 100 mg atenolol with single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. [see Warnings and Precautions (5.1)]. Hydrochlorothiazide: Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the patients in this study.. Figure 1.

CLINICAL STUDIES SECTION.

14. CLINICAL STUDIES.

CONTRAINDICATIONS SECTION.

4. CONTRAINDICATIONS. 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). 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). Alfuzosin HCl extended-release tablets are contraindicated for use: in patients with moderate or severe hepatic impairment (Childs-Pugh categories 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 HCl extended-release tablets [see Adverse Reactions (6.2)] in patients with moderate or severe hepatic impairment (Childs-Pugh categories 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 HCl extended-release tablets [see Adverse Reactions (6.2)].

DESCRIPTION SECTION.

11. DESCRIPTION.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. 10 mg once daily with food and with the same meal each day. (2) Tablets should not be chewed or crushed (2, 12.3). The recommended dosage is one 10 mg alfuzosin HCl extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, alfuzosin HCl extended-release tablets should be taken with food and with the same meal each day. The tablets should not be chewed or crushed.

DRUG INTERACTIONS SECTION.

7. DRUG INTERACTIONS. Concomitant use of PDE5 inhibitors with alpha adrenergic antagonists, including alfuzosin HCl extended-release tablets, can potentially cause symptomatic hypotension (5.4, 7.4) Concomitant use of PDE5 inhibitors with alpha adrenergic antagonists, including alfuzosin HCl extended-release tablets, can potentially cause symptomatic hypotension (5.4, 7.4) 7.1 CYP3A4 Inhibitors. Alfuzosin HCl extended-release tablets are contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased [see Contraindications (4), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 7.2 Alpha Adrenergic Antagonists. The pharmacokinetic and pharmacodynamic interactions between alfuzosin HCl extended-release tablets and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and alfuzosin HCl extended-release tablets should not be used in combination with other alpha adrenergic antagonists [see Warnings and Precautions (5.4)]. 7.3 Antihypertensive Medication and Nitrates. There may be an increased risk of hypotension/postural hypotension and syncope when taking alfuzosin HCl extended-release tablets concomitantly with anti-hypertensive medication and nitrates [see Warnings and Precautions (5.1)]. 7.4 PDE5 Inhibitors. Caution is advised when alpha adrenergic antagonists, including alfuzosin HCl extended-release tablets, are coadministered 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 [see Warnings and Precautions (5.4)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in clinical studies of alfuzosin HCl extended-release tablets, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling.. 17.1 Hypotension/Syncope:. Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning alfuzosin HCl extended-release tablets, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period. This is important for those with low blood pressure or who are taking antihypertensive medications or nitrates [see Warnings and Precautions (5.1)]. 17.2 Intraoperative Floppy Iris Syndrome. Patients should be instructed to tell their ophthalmologist about their use of alfuzosin HCl extended-release tablets before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking alfuzosin HCl extended-release tablets [see Warnings and Precautions (5.6)]. 17.3 Priapism. Patients should be advised about the possibility of priapism resulting from treatment with alfuzosin HCl extended-release tablets and medications in the same class. Although this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence) [see Warnings and Precautions (5.7)]. 17.4 Instructions of Use. Alfuzosin HCl extended-release tablets should be taken with food and with the same meal each day. Patients should be advised not to crush or chew alfuzosin HCl extended-release tablets.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Alfuzosin is selective antagonist of post-synaptic alpha1-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

NONCLINICAL TOXICOLOGY SECTION.

13. NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility. There was no evidence of drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose [MRHD] of 10 mg based on AUC of unbound drug), in females and males, respectively. The highest dose tested in female mice may not have constituted maximally tolerated dose. Likewise, there was no evidence of drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively). Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in human cell line. There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats.

OVERDOSAGE SECTION.

10. OVERDOSAGE.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Label. Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Alfuzosin HCl extended-release tablet is not indicated for use in the pediatric population. Additional information regarding clinical study in which efficacy was not demonstrated in pediatric patients ages to 16 years is approved for Sanofi-Aventis U.S. LLCs alfuzosin hydrochloride extended-release tablets. However, due to Sanofi-Aventis U.S. LLCs marketing exclusivity rights, this drug is not labeled with that pediatric information.

PHARMACODYNAMICS SECTION.

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 reduction in symptoms of BPH.Cardiac Electrophysiology The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in 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 HCl extended-release tablets and ketoconazole 400 mg. Table 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 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 Tm x (relative to placebo) with different methodologies to correct for effect of heart rate. Active controlDrug /DoseQTFridericia methodPopulation- specific methodSubject-specific methodAlfuzosin10 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 400 mg6.9(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 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of alfuzosin HCl 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. AbsorptionThe absolute bioavailability of alfuzosin HCl extended-release tablets 10 mg under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin HCl extended-release tablets under fed conditions, the time to maximum concentration is hours. Cmax and AUC0-24 are 13.6 (SD 5.6) ng/mL and 194 (SD 75) ng.h/mL, respectively. Alfuzosin HCl 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 HCl extended-release tablets administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after single administration.Effect of Food As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin HCl extended-release tablets should be taken with food and with the same meal each day [see Dosage and Administration (2)]. Figure - Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after Single Administration of Alfuzosin HCl Extended-Release Tablets 10 mg to Healthy Middle-Aged Male Volunteers in Fed and Fasted StatesDistributionThe 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 wide concentration range (5 to 5,000 ng/mL).MetabolismAlfuzosin 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.ExcretionFollowing oral administration of 14C-labeled alfuzosin solution, the recovery of radioactivity after days (expressed as percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of alfuzosin HCl extended-release tablets 10 mg, the apparent elimination half-life is 10 hours.Specific PopulationsGeriatric Use: In pharmacokinetic assessment during phase 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 HCl extended-release tablets 10 mg in subjects with normal renal function (CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean Cmax 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 HCl extended-release tablets have not been studied in patients with mild hepatic impairment. In patients with moderate or severe hepatic insufficiency (Child-Pugh categories 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 HCl 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)].Pediatric Use: Alfuzosin HCl extended-release tablets are not indicated for use in the pediatric population [see Indications and Usage (1.1) and Use in Specific Populations (8.4)] Drug-Drug InteractionsMetabolic InteractionsCYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. Potent CYP3A4 InhibitorsRepeated oral administration of 400 mg/day of ketoconazole, potent inhibitor of CYP3A4, increased alfuzosin Cmax by 2.3-fold and AUClast by 3.2-fold, following single 10 mg dose of alfuzosin.In another study, repeated oral administration of lower (200 mg/day) dose of ketoconazole increased alfuzosin Cmax by 2.1-fold and AUClast by 2.5-fold, following single 10 mg dose of alfuzosin.Therefore, alfuzosin HCl extended-release tablets are contraindicated for co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure [see Contraindications (4), Warnings and Precautions (5.4) and Drug Interactions (7.1)]. Moderate CYP3A4 Inhibitors Diltiazem: Repeated co-administration of 240 mg/day of diltiazem, moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with alfuzosin HCl extended-release tablets) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of alfuzosin HCl extended-release tablets and antihypertensive medications has the potential to cause hypotension in some patients [see Warnings and Precautions (5.1)]. In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes. Other Interactions Warfarin: Multiple dose administration of an immediate release tablet formulation of alfuzosin mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to single 25 mg oral dose of warfarin.Digoxin: Repeated co-administration of alfuzosin HCl extended-release tablets 10 mg and digoxin 0.25 mg/day for days did not influence the steady-state pharmacokinetics of either drug. Cimetidine: Repeated administration of 1g/day cimetidine increased both alfuzosin Cmax and AUC values by 20%.Atenolol: Single administration of 100 mg atenolol with single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. [see Warnings and Precautions (5.1)]. Hydrochlorothiazide: Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the patients in this study.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category B. Alfuzosin HCl extended-release tablets are not indicated for use in women, and there are no studies of alfuzosin in pregnant womenAlfuzosin 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 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 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1) 12/2010Warnings and Precautions, PDE5 inhibitors (5.4) 04/2010Warnings and Precautions, Priapism (5.7) 12/2010.

SPL UNCLASSIFIED SECTION.

Alfuzosin HCl extended-release tablets are indicated for the treatment of signs and symptoms of benign prostatic hyperplasia.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category B. Alfuzosin HCl extended-release tablets are not indicated for use in women, and there are no studies of alfuzosin in pregnant womenAlfuzosin 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 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 mg/kg/day oral maternal dose) the MRHD, but difficulties with parturition were not observed.. 8.4 Pediatric Use. Alfuzosin HCl extended-release tablet is not indicated for use in the pediatric population. Additional information regarding clinical study in which efficacy was not demonstrated in pediatric patients ages to 16 years is approved for Sanofi-Aventis U.S. LLCs alfuzosin hydrochloride extended-release tablets. However, due to Sanofi-Aventis U.S. LLCs marketing exclusivity rights, this drug is not labeled with that pediatric information.. 8.5 Geriatric Use. Of the total number of subjects in clinical studies of alfuzosin HCl extended-release tablets, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)] 8.6 Renal Impairment. Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)]. In phase studies, the safety profile of patients with mild (n=172) or moderate (n=56) renal impairment was similar to the patients with normal renal function in those studies. Safety data are available in only limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when alfuzosin HCl extended-release tablets are administered in patients with severe renal impairment [see Warnings and Precautions (5.2)]. 8.7 Hepatic Impairment. The pharmacokinetics of alfuzosin HCl extended-release tablets have not been studied in patients with mild hepatic impairment. Alfuzosin HCl extended-release tablets are contraindicated for use in patients with moderate or severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Postural hypotension/syncope: Care should be taken in patients with symptomatic hypotension or who have had 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 HCl extended-release tablets if symptoms of angina pectoris appear or worsen (5.8) Use with caution in patients with history of QT prolongation or who are taking medications which prolong the QT interval (5.9, 12.2). Postural hypotension/syncope: Care should be taken in patients with symptomatic hypotension or who have had 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 HCl extended-release tablets if symptoms of angina pectoris appear or worsen (5.8) Use with caution in patients with 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 few hours following administration of alfuzosin HCl extended-release tablets. As with other alpha adrenergic antagonists, there is 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 HCl extended-release tablets concomitantly with anti-hypertensive medication and nitrates. Care should be taken when alfuzosin HCl extended-release tablets are administered to patients with symptomatic hypotension or patients who have had hypotensive response to other medications. 5.2 Patients with Renal Impairment. Caution should be exercised when alfuzosin HCl 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 HCl 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 HCl extended-release tablets have not been studied in patients with mild hepatic impairment, caution should be exercised when alfuzosin HCl 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 HCl 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 HCl 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 HCl 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 HCl 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 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 patients 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 benefit of stopping alpha adrenergic antagonist therapy prior to cataract surgery. 5.7 Priapism. Rarely (probably less than 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 HCl 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)].