UroXatral

Dosage Forms And Strengths

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

Storage And Handling

UROXATRAL is supplied as follows:

Package NDC Number

Bottles of 100 24987-200-10 & 24987-200-20

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

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Protect from light and moisture.

Keep UROXATRAL out of reach of children.

Distributed by Covis Pharmaceuticals, Inc. Cary, NC 27511. Revised: Sep 2013

UROXATRAL is indicated for the treatment of signs and symptoms of benign prostatic hyperplasia.

Important Limitations Of Use

UROXATRAL is not indicated for the treatment of hypertension. UROXATRAL is not indicated for use in the pediatric population.

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

UROXATRAL is contraindicated for use:

• in patients with moderate or severe hepatic impairment (Childs-Pugh categories B and C), since alfuzosin blood levels are increased in these patients.
• with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are increased.
• in patients with known hypersensitivity, such as urticaria and angioedema, to alfuzosin hydrochloride or any component of UROXATRAL tablets

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of UROXATRAL. As with other alpha adrenergic antagonists, 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. There may be an increased risk of hypotension/postural hypotension and syncope when taking UROXATRAL concomitantly with anti-hypertensive medication and nitrates. 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 With Renal Impairment

Caution should be exercised when UROXATRAL is administered in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Patients With Hepatic Impairment

UROXATRAL is contraindicated for use in patients with moderate or severe hepatic impairment. Although the pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic impairment, caution should be exercised when UROXATRAL is administered to such patients.

Drug-Drug Interactions

Potent CYP3A4 Inhibitors

UROXATRAL is contraindicated for use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood levels are increased.

Other alpha adrenergic antagonists

UROXATRAL is an alpha adrenergic antagonist and should not be used in combination with other alpha adrenergic antagonist.

Phosphodiesterase-5 (PDE5) Inhibitors

PDE5-inhibitors are also vasodilators. Caution is advised for concomitant use of PDE5-inhibitors and UROXATRAL, as this combination can potentially cause symptomatic hypotension.

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 UROXATRAL.

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 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.

Priapism

Rarely (probably less than 1 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.

Patient Counseling Information

See FDA-approved patient labeling.

Hypotension/Syncope

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. This is important for those with low blood pressure or who are taking antihypertensive medications or nitrates.

Intraoperative Floppy Iris Syndrome

Patients should be instructed to tell their ophthalmologist about their use of UROXATRAL before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking UROXATRAL.

Priapism

Patients should be advised about the possibility of priapism resulting from treatment with UROXATRAL 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).

Instructions Of Use

UROXATRAL should be taken with food and with the same meal each day. Patients should be advised not to crush or chew UROXATRAL tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 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 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 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 a 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.

Use In Specific Populations

Pregnancy

Pregnancy Category B

UROXATRAL is 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.

Pediatric Use

UROXATRAL is 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 H2O) 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 cmH20 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.

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, but greater sensitivity of some older individuals cannot be ruled out

Renal Impairment

Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal impairment. 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 impairment.

Hepatic Impairment

The pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic impairment. UROXATRAL is contraindicated for use in patients with moderate or severe hepatic impairment.

SIDE EFFECTS

Clinical Trials Experience

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 UROXATRAL (alfuzosin HCl) 10 mg extended-release tablets. In these trials, 4% of patients taking UROXATRAL (alfuzosin HCl) 10 mg extended-release 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 UROXATRAL, 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.

Table 1 : Adverse Reactions Occurring in ≥2% of UROXATRAL-Treated Patients and More Frequently than with Placebo in 3-Month Placebo-Controlled Clinical Trials

The following adverse reactions, 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

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.

Table 2: Number (%) of Patients with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Trials

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 UROXATRAL 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 UROXATRAL 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 UROXATRAL patients.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of UROXATRAL. 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

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.

DRUG INTERACTIONS

CYP3A4 Inhibitors

UROXATRAL is contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased.

Alpha Adrenergic Antagonists

The pharmacokinetic and pharmacodynamic interactions between UROXATRAL and other alpha adrenergic antagonists have not been determined. However, interactions may be expected, and UROXATRAL should not be used in combination with other alpha adrenergic antagonists.

Antihypertensive Medication And Nitrates

There may be an increased risk of hypotension/postural hypotension and syncope when taking UROXATRAL concomitantly with anti-hypertensive medication and nitrates.

PDE5 Inhibitors

Caution is advised when alpha adrenergic antagonists, including UROXATRAL, 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.

Pregnancy Category B

UROXATRAL is 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.

Clinical Trials Experience

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 UROXATRAL (alfuzosin HCl) 10 mg extended-release tablets. In these trials, 4% of patients taking UROXATRAL (alfuzosin HCl) 10 mg extended-release 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 UROXATRAL, 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.

Table 1 : Adverse Reactions Occurring in ≥2% of UROXATRAL-Treated Patients and More Frequently than with Placebo in 3-Month Placebo-Controlled Clinical Trials

The following adverse reactions, 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

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.

Table 2: Number (%) of Patients with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Trials

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 UROXATRAL 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 UROXATRAL 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 UROXATRAL patients.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of UROXATRAL. 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

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.

Should overdose of UROXATRAL 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.

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 UROXATRAL 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.

Table 3: Mean QT and QTc changes in msec (95% CI) from baseline at Tmax (relative to placebo) with different methodologies to correct for effect of heart rate.

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 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. Cmax and AUC0-24 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 with food and with the same meal each day.

Figure 1 :Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after a Single Administration of UROXATRAL 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 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

Following oral administration of ¹⁴C-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.