ALFUZOSIN HYDROCHLORIDE (Page 2 of 6)

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of alfuzosin hydrochloride extended-release tablets. 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 [see Warnings and Precautions ( 5.6)].

7 DRUG INTERACTIONS

7.1 CYP3A4 inhibitors

Alfuzosin hydrochloride 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 hydrochloride extended-release tablets and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and alfuzosin hydrochloride extended-release tablet 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 hydrochloride 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 hydrochloride extended-release tablets, 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 [see Warnings and Precautions ( 5.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Alfuzosin hydrochloride extended-release tablets are not indicated for use in women.

There are no adequate data on the developmental risk associated with use of alfuzosin hydrochloride extended-release tablets in pregnant women.

Based on findings from animal studies, alfuzosin administered during the period of organogenesis was not teratogenic, embryotoxic or fetotoxic at up to 1,200 times the MRHD of 10 mg via AUC in rats and 3 times in rabbits, via body surface area.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancy 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 1,200 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.

8.2 Lactation

Risk Summary

Alfuzosin hydrochloride extended-release tablets are not indicated for use in women. There are no data on the presence of alfuzosin hydrochloride extended-release tablets in human milk, the effect on the breastfed child, or effect on milk production.

8.3 Females and Males of Reproductive Potentials

8.4 Pediatric Use

Alfuzosin hydrochloride extended-release tablets are 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 cmH 2 O 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.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of alfuzosin hydrochloride 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 3 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 a limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when alfuzosin hydrochloride 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 hydrochloride extended-release tablets have not been studied in patients with mild hepatic impairment. Alfuzosin hydrochloride 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)].

10 OVERDOSAGE

Should overdose of alfuzosin hydrochloride extended-release tablets 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.

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