Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are not indicated for the treatment of hypertension.

Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are not indicated for use in the pediatric population.

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.

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 Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release 10 mg tablets. In these trials, 4% of patients taking Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release 10 mg 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 Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets, 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.

The following adverse reactions, reported by between 1% and 2% of patients receiving Alfuzosin hydrochloride (Alfuzosin hydrochloride) 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 a whole:
Gastrointestinal system:
Reproductive system:
Respiratory system:
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.

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 Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablet 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 Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablet 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 Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablet patients.

The following adverse reactions have been identified during post approval use of Alfuzosin hydrochloride (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:
Hepatobiliary disorders:
Respiratory system disorders:
Reproductive system disorders:
Skin and subcutaneous tissue disorders:
Vascular disorders:
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

Pregnancy Category BAlfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are not indicated for use in women, and there are no studies of alfuzosin in pregnant women.

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.

Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are not indicated for use in the pediatric population.

Additional information regarding a clinical study in which efficacy was not demonstrated in pediatric patients ages 2 to 16 years is approved for Sanofi-Aventis U.S. LLC’s Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets. However, due to Sanofi-Aventis U.S. LLC’s marketing exclusivity rights, this drug is not labeled with that pediatric information.

Should overdose of Alfuzosin hydrochloride (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.

Each Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablet contains 10 mg Alfuzosin hydrochloride (Alfuzosin hydrochloride) , USP as the active ingredient. Alfuzosin hydrochloride (Alfuzosin hydrochloride) , USP is a white to off-white crystalline powder that melts at approximately 240°C. It is freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane.

Alfuzosin hydrochloride (Alfuzosin hydrochloride) , USP is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of Alfuzosin hydrochloride (Alfuzosin hydrochloride) , USP is CHNO•HC1. The molecular weight of Alfuzosin hydrochloride (Alfuzosin hydrochloride) , USP is 425.9Its structural formula is:

The tablet also contains the following inactive ingredients: colloidal silicon dioxide (NF), hypromellose (USP), lactose anhydrous (NF), magnesium stearate (NF), povidone (USP), and talc (USP).     

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 (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.

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.

The pharmacokinetics of Alfuzosin hydrochloride (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 (Alfuzosin hydrochloride) extended-release 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets under fed conditions, the time to maximum concentration is 8 hours. C and AUCare 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ngh/mL, respectively. Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets exhibit linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of Alfuzosin hydrochloride (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 (Alfuzosin hydrochloride) extended-release tablets should be taken with food and with the same meal each day

Figure 1 – Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after a Single Administration of Alfuzosin hydrochloride (Alfuzosin hydrochloride) Extended-Release 10 mg Tablets 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 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 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 (Alfuzosin hydrochloride) extended-release 10 mg tablets, the apparent elimination half-life is 10 hours.

Specific Populations

Geriatric Use
Drug-Drug Interactions

Metabolic Interactions

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin.

Potent CYP3A4 Inhibitors

Repeated oral administration of 400 mg/day of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin C by 2.3-fold and AUC by 3.2-fold, following a single 10 mg dose of alfuzosin.

In another study, repeated oral administration of a lower (200 mg/day) dose of ketoconazole increased alfuzosin C by 2.1-fold and AUC by 2.5-fold, following a single 10 mg dose of alfuzosin.

Therefore, Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are contraindicated for co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, or ritonavir) because of increased alfuzosin exposure

Moderate CYP3A4 Inhibitors

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:
Digoxin:
Cimetidine:
max
Hydrochlorothiazide:
Moderate CYP3A4 Inhibitors

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:
Digoxin:
Cimetidine:
max
Hydrochlorothiazide:

Three randomized placebo-controlled, double-blind, parallel-arm, 12-week trials were conducted with the 10 mg daily dose of alfuzosin. In these three trials, 1,608 patients [mean age 64.2 years, range 49-92 years; Caucasian (96.1%), Black (1.6%), Asian (1.1%), other (1.2%)] were randomized and 473 patients received Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release 10 mg tablets daily. Table 4 provides the results of the three trials that evaluated the 10 mg dose.

There were two primary efficacy variables in these three studies. The International Prostate Symptom Score (IPSS, or AUA Symptom Score) consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible scores ranging from 0 to 35 with higher numerical scores on the IPSS total symptom score representing greater severity of symptoms. The second efficacy variable was peak urinary flow rate. The peak flow rate was measured just prior to the next dose in study 2 and on average at 16 hours post-dosing in trials 1 and 3.

There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS total symptom score versus placebo in all three studies, indicating a reduction in symptom severity (Table 5 and Figures 2, 3, and 4).

Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo in trials 1 and 2 (Table 5 and Figures 5, 6, and 7).

Mean total IPSS decreased at the first scheduled observation at Day 28 and mean peak flow rate increased starting at the first scheduled observation at Day 14 in trials 2 and 3 and Day 28 in trial 1.

Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets 10 mg are white to off white, round shape, flat face beveled edge tablets debossed with ‘1021’on one side and ‘10’ on other side. Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets are supplied as follows:

       

       Bottles of 30                                                                         13668 - 021 - 30

       Bottles of 100                                                                       13668 - 021 - 01

       Bottles of 500                                                                       13668 - 021 - 05

       90 Unit Dose Tablets                                                          13668 - 021 - 64

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). [see USP   Controlled Room Temperature].

Protect from light and moisture.

Dispense in a tight, light-resistant container.

Keep Alfuzosin hydrochloride (Alfuzosin hydrochloride) extended-release tablets out of the reach of children.

See FDA-approved patient labeling.

Alfuzosin hydrochloride (Alfuzosin hydrochloride) Extended-Release Tablets, 10 mg