Uroxatral Tablets (Sanofi-Aventis)

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DESCRIPTION

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 C ₁₉ H ₂₇ N ₅ O ₄ ·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).

CLINICAL PHARMACOLOGY

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 alpha ₁ -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 alpha ₁ -adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

Pharmacokinetics

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.

Absorption:    The absolute bioavailability of UROXATRAL 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg UROXATRAL under fed conditions, the time to maximum concentration is 8 hours. C _max and AUC _0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ng.h/mL, respectively. UROXATRAL exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of UROXATRAL 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, UROXATRAL should be taken immediately following a meal. (See DOSAGE AND ADMINISTRATION .)

Distribution:    The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL).

Metabolism:    Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.

Excretion and Elimination:    Following oral administra- tion of ¹⁴ C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of UROXATRAL 10 mg tablets, the apparent elimination half-life is 10 hours.

Special Populations

Elderly:    In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. However, trough levels were positively correlated with age. The concentrations in subjects >/=75 years of age were approximately 35% greater than in those below 65 years of age.

Patients with Renal Impairment:    The pharmacokinetic profiles of UROXATRAL 10 mg tablets in subjects with normal renal function (CL _CR >80 mL/min), mild impairment (CL _CR 60 to 80 mL/min), moderate impairment (CL _CR 30 to 59 mL/min), and severe impairment (CL _CR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean C _max and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment. (See PRECAUTIONS , Special Populations ).

Patients with Hepatic Insufficiency:    In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in three to four-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, UROXATRAL is contraindicated in patients with moderate to severe hepatic impairment (See CONTRAINDICATIONS ). The pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic insufficiency. (See PRECAUTIONS , Special Populations ).

Drug-Drug Interactions

Metabolic interactions

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

Diltiazem:    Repeated co-administration of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with UROXATRAL) increased the C _max and AUC _0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the C _max and AUC _0-12 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 UROXATRAL and anti-hypertensive medications has the potential to cause hypotension in some patients. (See WARNINGS ).

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 5 mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin.

Digoxin:    Repeated co-administration of UROXATRAL 10 mg tablets and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug.

Cimetidine:    Repeated administration of 1 g/day cimetidine increased both alfuzosin C _max and AUC values by 20%.

Atenolol:    Single administration of 100 mg atenolol with a single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin C _max and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol C _max 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 .)

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 8 patients in this study.

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 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.

Clinical Studies

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).

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).

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.

INDICATIONS AND USAGE

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.

CONTRAINDICATIONS

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.

WARNINGS

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.

PRECAUTIONS

General

Prostatic Carcinoma:    Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined prior to starting therapy with UROXATRAL (alfuzosin HCl extended-release tablets) to rule out the presence of carcinoma of the prostate.

Drug-Drug Interactions:    The pharmacokinetic and pharmacodynamic interactions between UROXATRAL and other alpha-blockers have not been determined. However, interactions may be expected, and UROXATRAL should NOT be used in combination with other alpha-blockers.

Coronary Insufficiency:    If symptoms of angina pectoris should newly appear or worsen, UROXATRAL should be discontinued.

Hepatic Insufficiency:    UROXATRAL should not be given to patients with moderate or severe hepatic insufficiency. (See CONTRAINDICATIONS ). The pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic insufficiency (See CLINICAL PHARMACOLOGY , Patients with Hepatic Insufficiency ).

Renal Insufficiency:    Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal insufficiency (See CLINICAL PHARMACOLOGY , Special Populations ). 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 UROXATRAL is administered in patients with severe renal insufficiency.

Patients with Congenital or Acquired QT Prolongation:    In a study of QT effect in 45 healthy males (See CLINICAL PHARMACOLOGY , Electrophysiology ), the QT effect appeared less with alfuzosin 10 mg than with 40 mg, and the effect of alfuzosin 40 mg did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe UROXATRAL for patients with a known history of QT prolongation or patients who are taking medications known to prolong QT, although there has been no signal of Torsades de Pointe in the extensive post-marketing experience with alfuzosin outside the United States. There are no known PK/PD studies of the effects of other alpha blockers on cardiac repolarization.

Information for Patients

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.

Laboratory Tests

No laboratory test interactions with UROXATRAL tablets are known.

Pediatric Use

UROXATRAL is not indicated for use in children.

Geriatric Use

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.)

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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.

Pregnancy

Teratogenic Effects, Pregnancy and Lactation Category B. UROXATRAL is not indicated for use in women.

There was no evidence of teratogenicity or embryotoxicity in rats at maternal (oral gavage) doses up to 250 mg/kg/day, corresponding to systemic exposure levels 1,200-fold higher than in humans. In rabbits, up to the dose of 100 mg/kg/day (approximately 3 times the clinical dose by body surface area) given orally (via gavage), no evidence of fetal toxicity or teratogenicity was seen.

Gestation was slightly prolonged in rats with a maternal dose >5 mg/kg/day (oral gavage), which corresponds to systemic exposure levels (based on AUC of unbound drug) 12 times higher than human exposure levels, but there were no difficulties with parturition.

Nursing Mothers

UROXATRAL is not indicated for use in women.

ADVERSE REACTIONS

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 listed 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

The following adverse events have also been reported in postmarketing experience: rash, tachycardia, chest pain, priapism.

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.

OVERDOSAGE

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 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.

DOSAGE AND ADMINISTRATION

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.

HOW SUPPLIED

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:

Rx only.

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.

42003790

HPG13824-01

Distributed by:

sanofi-synthelabo

Sanofi-Synthelabo Inc., New York, NY 10016

UROXATRAL® is a registered trademark of Sanofi-Synthelabo.

USS-1      Revised June 2003

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