UROXATRAL®
(alfuzosin HCl extended-release tablets)

Each UROXATRAL (alfuzosin HCl extended-release tablets) tablet contains 10 mg alfuzosin hydrochloride as the active ingredient. Alfuzosin hydrochloride 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 is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of alfuzosin hydrochloride is C₁₉H₂₇N₅O₄•HCl. The molecular weight of alfuzosin hydrochloride is 425.9. Its structural formula is:

The tablet also contains the following inactive ingredients: colloidal silicon dioxide (NF), ethylcellulose (NF), hydrogenated castor oil (NF), hydroxypropyl methylcellulose (USP), magnesium stearate (NF), mannitol (USP), microcrystalline cellulose (NF), povidone (USP), and yellow ferric oxide (NF).

The symptoms associated with benign prostatic hyperplasia (BPH) such as urinary frequency, nocturia, weak stream, hesitancy and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to the prostate size. Prostate size alone does not correlate with symptom severity. The dynamic component is a function of the smooth muscle tone in the prostate and its capsule, the bladder neck, and the bladder base as well as the prostatic urethra. The smooth muscle tone is regulated by alpha-adrenergic receptors. Alfuzosin exhibits selectivity for alpha₁-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.

UROXATRAL (alfuzosin HCl extended-release) is a selective antagonist of post-synaptic alpha₁-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

The pharmacokinetics of UROXATRAL 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.

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

Potent CYP3A4 inhibitors

Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin C_max 2.3-fold and AUC_last 3.2-fold following a single 10 mg dose of alfuzosin. Therefore, UROXATRAL should not be co-administered with potent inhibitors of CYP3A4 because exposure is increased, (e.g., ketoconazole, itraconazole, or ritonavir). (See CONTRAINDICATIONS).

Moderate CYP3A4 inhibitors

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 UROXATRAL and ketoconazole 400 mg. Table 1 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-substracted 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.

Three randomized placebo-controlled, double-blind, parallel-arm, 12-week studies were conducted with the 10 mg daily dose of alfuzosin. In these three studies, 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 UROXATRAL 10 mg daily. Table 1 provides the results of the three studies 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. 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 studies 1 and 3.

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

Figure 2 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 1

Figure 3 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 2

Figure 4 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 3

Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo in studies 1 and 2 (Table 3 and Figures 5, 6, and 7).

Figure 5 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 1

Figure 6 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 2

Figure 7 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 3

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 studies 2 and 3 and Day 28 in study 1.

UROXATRAL (alfuzosin HCl extended-release tablets) is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. UROXATRAL is not indicated for the treatment of hypertension.

UROXATRAL should not be used in patients with moderate or severe hepatic insufficiency, (Childs-Pugh categories B and C) since alfuzosin blood levels are increased in these patients. (See CLINICAL PHARMACOLOGY, Patients with Hepatic Insufficiency subsection.)

UROXATRAL should not be co-administered with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased. (See CLINICAL PHARMACOLOGY).

UROXATRAL (alfuzosin HCl extended-release tablets) is contraindicated in patients known to be hypersensitive to alfuzosin hydrochloride or any component of UROXATRAL tablets.

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of UROXATRAL (alfuzosin HCl extended-release tablets). As with other alpha-blockers, 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. Care should be taken when UROXATRAL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning UROXATRAL, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period.

UROXATRAL should be taken with food and with the same meal each day.

Patients should be advised not to crush or chew UROXATRAL tablets.

No laboratory test interactions with UROXATRAL tablets are known.

UROXATRAL is not indicated for use in children.

Of the total number of subjects in clinical studies of UROXATRAL, 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. (See CLINICAL PHARMACOLOGY, Elderly subsection.)

There was no evidence of a 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 level of exposure to humans based on AUC of unbound drug) in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a 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 level of exposure to humans based on AUC of unbound drug) 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 a human cell line.

There was no evidence of reproductive organ toxicity when male rats were given alfuzosin at daily oral (gavage) doses of up to 250 mg/kg/day for 26 weeks, which corresponds to levels of exposure several hundred times that in humans. 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 doses of 25 mg/kg and 20 mg/kg, respectively, corresponding to levels of systemic exposure (based on AUC of unbound drug) 12- and 18-fold higher, respectively, than in humans, although this did not result in impaired fertility in rats.

UROXATRAL is not indicated for use in women.

The incidence of treatment-emergent adverse events has been ascertained from 3 placebo-controlled clinical trials involving 1,608 men in which 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 studies, 4% of patients taking UROXATRAL (alfuzosin HCl extended-release tablets) 10 mg tablets withdrew from the study due to adverse events, compared with 3% in the placebo group.

Table 4 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving UROXATRAL, and at an incidence numerically higher than that of the placebo group. In general, the adverse events seen in long-term use were similar in type and frequency to the events described below for the 3-month trials.

The following adverse events, reported by between 1% and 2% of patients receiving UROXATRAL and occurring more frequently than with placebo, are uled 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 Studies: The adverse events related to orthostasis that occurred in the double-blind phase 3 studies with alfuzosin 10 mg are summarized in Table 5. Approximately 20% to 30% of patients in these studies were taking antihypertensive medication.

Multiple testing for blood pressure changes or orthostatic hypotension was conducted in the three controlled studies at each scheduled clinic visit (Days 14, 28, 56, and 84). Patients with a decrease in systolic blood pressure of >20 mm Hg after 2 minutes standing following being supine were excluded from the three trials. These tests were considered positive for blood pressure decrease if (1) supine systolic blood pressure was ≤90 mm Hg, with a decrease ≥20 mm Hg versus baseline, and/or (2) supine diastolic blood pressure was ≤50 mm Hg, with a decrease≥15 mm Hg versus baseline. The tests were considered positive for orthostatic hypotension if there was a decrease in systolic blood pressure of ≥20 mm Hg upon standing from the supine position during the orthostatic tests. According to these definitions, decreased systolic blood pressure was observed in none of the 674 placebo patients and 1 (0.2%) of the 469 UROXATRAL patients. Decreased diastolic blood pressure was observed in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the UROXATRAL patients. A positive orthostatic test was seen in 52 (7.7%) of placebo patients and in 31 (6.6%) of the UROXATRAL patients.

No vital sign measurements were obtained following first dose administration in the phase 3 studies, except for a subset of patients in study 1 who had blood pressure measurements 12 to 16 hours after the first dose to assess the potential to produce orthostatic hypotension. None of these 35 UROXATRAL treated patients showed a positive test for systolic, diastolic or orthostatic blood pressure change.

In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with UROXATRAL: rash, urticaria, angioedema, pruritis, rhinitis, tachycardia, chest pain, priapism, diarrhea, flushing, edema, angina pectoris in patients with pre-existing coronary artery disease.

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-1 blockers (see PRECAUTIONS).

Should overdose of UROXATRAL (alfuzosin HCl 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 accomplishedby 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% proteinbound; therefore, dialysis may not be of benefit.

The recommended dosage is one 10 mg UROXATRAL (alfuzosin HCl extended-release tablets) tablet daily to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

UROXATRAL (alfuzosin HCl extended-release tablets) 10 mg is available as a round, three-layer tablet: one white layer between two yellow layers, debossed with X10. UROXATRAL is supplied as follows:

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

Protect from light and moisture.

Keep UROXATRAL out of reach of children.

Read the Patient Information that comes with UROXATRAL before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or your treatment. You and your doctor should talk about all your medicines, including UROXATRAL, now and at your regular checkups.

What is the most important information I should know about UROXATRAL?

UROXATRAL can cause:

• a sudden drop in blood pressure, especially when you start treatment. This may lead to fainting, dizziness, or lightheadedness. Do not drive, operate machinery, or do any dangerous activities until you know how UROXATRAL affects you. This is especially important if you already have a problem with low blood pressure or take medicines to treat high blood pressure. If you begin to feel dizzy or lightheaded, lie down with your legs and feet up, and if your symptoms do not improve call your doctor.

What is UROXATRAL?

UROXATRAL is a prescription medicine that is called an "alpha-blocker". UROXATRAL is used in adult men to treat the symptoms of benign prostatic hyperplasia (BPH). UROXATRAL may help to relax the muscles in the prostate and the bladder which may lessen the symptoms of BPH and improve urine flow.

Before prescribing UROXATRAL, your doctor may examine your prostate gland and do a blood test called a prostate specific antigen (PSA) test to check for prostate cancer. Prostate cancer and BPH can cause the same symptoms. Prostate cancer needs a different treatment.

UROXATRAL is not for use in women or children.

Some medicines called "alpha-blockers" are used to treat high blood pressure. UROXATRAL has not been studied for the treatment of high blood pressure.

Who should not take UROXATRAL?

Do not take UROXATRAL if you:

• have liver problems
• are taking antifungal drugs like ketoconazole or HIV drugs called protease inhibitors
• are already taking an alpha-blocker for either high blood pressure or prostate problems
• are a woman
• are a child under the age of 18
• are allergic to UROXATRAL The active ingredient is alfuzosin hydrochloride. See the end of this leaflet for a complete ul of ingredients in UROXATRAL.

Before taking UROXATRAL, tell your doctor:

• if you have liver problems
• if you have kidney problems
• if you or any family members have a rare heart condition known as congenital prolongation of the QT interval.
• about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some of your other medicines may affect the way you respond or react to UROXATRAL.
• if you have had low blood pressure, especially after taking another medicine. Signs of low blood pressure are fainting, dizziness, and lightheadedness.
• if you have a heart problem called angina (pain in your chest, jaw, or arm).

What you need to know while taking UROXATRAL (alfuzosin HCl) tablets

• If you have an eye surgery for cataract (clouding of the eye) planned, tell your ophthalmologist that you are using UROXATRAL or have previously been treated with an alpha-blocker.

How do I take UROXATRAL?

• Take UROXATRAL exactly as your doctor prescribes it.
• Take one UROXATRAL tablet after the same meal each day. UROXATRAL should be taken just after eating food. Do not take it on an empty stomach.
• Swallow the UROXATRAL tablet whole. Do not crush, split, or chew UROXATRAL tablets.
• If you take too much UROXATRAL call your local poison control center or emergency room right away.

What are the possible side effects of UROXATRAL?

The most common side effects with UROXATRAL are:

• dizziness
• headache
• tiredness

Call your doctor if you get any side effect that bothers you.

These are not all the side effects of UROXATRAL. For more information ask your doctor or pharmacist.

How do I store UROXATRAL?

Store UROXATRAL between 59°F and 86°F (15°C and 30°C).

Protect from light and moisture.

Keep UROXATRAL and all medicines out of the reach of children.

General information about UROXATRAL:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use UROXATRAL for a condition for which it was not prescribed. Do not give UROXATRAL to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about UROXATRAL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about UROXATRAL that is written for health professionals.

You may also visit our website at www.UROXATRAL.com or call 1-800-446-6267.

What are the ingredients of UROXATRAL?

Active Ingredient: alfuzosin hydrochloride

Inactive Ingredients: colloidal silicon dioxide (NF), ethylcellulose (NF), hydrogenated castor oil (NF), hydroxypropyl methylcellulose (USP), magnesium stearate (NF), mannitol (USP), microcrystalline cellulose (NF), povidone (USP), and yellow ferric oxide (NF).