Document
DailyMed Label: Uroxatral
Title
DailyMed Label: Uroxatral
Date
2009
Document type
DailyMed Prescription
Name
Uroxatral
Generic name
Alfuzosin Hydrochloride
Manufacturer
Stat Rx USA
Product information
NDC: 16590-279
Product information
NDC: 16590-279
Description
11 DESCRIPTION Each UROXATRAL extended-release 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).
Structure Image
Indications
1 INDICATIONS AND USAGE
UROXATRAL is indicated for the treatment of signs and symptoms of
benign prostatic hyperplasia. UROXATRAL is not indicated for the treatment of
hypertension.
2 DOSAGE AND ADMINISTRATION
The recommended dosage is one 10 mg UROXATRAL (alfuzosin HCl)
extended-release tablet once daily. The extent of absorption of Uroxatral is 50%
lower under fasting conditions. Therefore, Uroxatral should be taken immediately
after the same meal each day. The tablets should not be chewed or crushed.
3 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.
4 CONTRAINDICATIONS
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. [see Clinical Pharmacology (12.3) ].
UROXATRAL is contraindicated for use with potent CYP3A4 inhibitors such as
ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are
increased. [see Clinical Pharmacology
(12.3) ] .
UROXATRAL is contraindicated in patients known to be hypersensitive to
alfuzosin hydrochloride or any component of UROXATRAL tablets.
Warnings
5 WARNINGS AND PRECAUTIONS
5.1 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-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. 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.
5.2 Renal Impairment Caution should be exercised when UROXATRAL is administered in
patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical
Pharmacology (12.3) ] .
5.3 Hepatic Impairment UROXATRAL is contraindicated for use in patients with moderate or
severe hepatic impairment [see Use in
Specific Populations (8.7) and Contraindications
(4) ] . The pharmacokinetics of UROXATRAL have not been studied in
patients with mild hepatic impairment [see Clinical Pharmacology (12.3) ] .
5.4 Pharmacodynamic Drug-Drug Interactions UROXATRAL is a selective alpha-blocker and should not be used in
combination with other alpha-blockers [see Drug Interactions (7.2) ] .
Because
of the vasodilatory effects of alpha-blockers and inhibitors of cyclic guanosine
monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5-inhibitors),
patients treated with alpha-blocker therapy should be hemodynamically stable
before treatment with PDE5-inhibitors is initiated. [see Drug Interactions (7.4) ] .
5.5 Pharmacokinetic Drug-Drug Interactions UROXATRAL is contraindicated for use with potent CYP3A4
inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood
levels are increased [see Contraindications
(4) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .
5.6 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 prior to starting
treatment with UROXATRAL to rule out the presence of carcinoma of the
prostate.
5.7 Intraoperative Floppy Iris Syndrome (IFIS) IFIS has been observed during cataract surgery in some patients
on or previously treated with alpha-1 blockers. 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-1 blocker therapy
prior to cataract surgery.
5.8 Coronary Insufficiency If symptoms of angina pectoris should appear or worsen, UROXATRAL
should be discontinued.
5.9 Patients with Congenital or Acquired QT
Prolongation Use with caution in patients with acquired or congenital QT
prolongation or who are taking medications that prolong the QT interval [see Clinical Pharmacology
(12.2) ] .
5.10 Laboratory Test Interactions No laboratory test interactions with UROXATRAL tablets are known.
Adverse reactions
Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies of a drug
cannot be directly compared to rates in the clinical studies of another drug and
may not reflect the rates observed in practice.
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING
UROXATRAL is supplied as follows:
Package
NDC Number
Bottles of 30
0024-4200-30
Bottles of 100
0024-4200-10
Hospital Unit Dose (blister packs containing 10 cards of 10
tablets each)
0024-4200-20
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) [see USP Controlled Room Temperature].
Protect from light and moisture.
Keep UROXATRAL out of reach of children.
Clinical pharmacology
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action Alfuzosin 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.
12.2 Pharmacodynamics 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.
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
T max (relative to placebo) with different methodologies
to correct for effect of heart rate.
Drug/Dose
QT
Fridericia method
Population-specific method
Subject-specific method
Active control
Alfuzosin 10 mg
-5.8 (-10.2, -1.4)
4.9 (0.9, 8.8)
1.8 (-1.4, 5.0)
1.8 (-1.3, 5.0)
Alfuzosin 40 mg
-4.2 (-8.5, 0.2)
7.7 (1.9, 13.5)
4.2 (-0.6, 9.0)
4.3 (-0.5, 9.2)
Moxifloxacin 400 mg
6.9 (2.3, 11.5)
12.7 (8.6, 16.8)
11.0 (7.0, 15.0)
11.1 (7.2, 15.0)
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.
12.3 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
(2) ] .
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 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.
Specific 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.
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 less than 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 Warnings and Precautions
(5.2) and Use in Specific Populations
(8.6) ] .
Hepatic Impairment : The
pharmacokinetics of UROXATRAL have not been studied in patients with mild
hepatic impairment. 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 (4) , Warnings and Precautions
(5.3) and Use in Specific Populations (8.7) ] .
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 max by 2.3-fold
and AUC last 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 Cmax by 2.1-fold and AUC last by 2.5-fold, following a single 10 mg dose of alfusion.
Therefore, UROXATRAL is contraindicated for co-administration with potent
inhibitors of CYP3A4 because exposure is increased, (e.g., ketoconazole,
itraconazole, or ritonavir) [see Contraindications (4) , Warnings and Precautions
(5.5) and Drug Interactions (7.1) ] .
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 antihypertensive medications has the potential to cause
hypotension in some patients [see Warnings
and Precautions (5.1) ] .
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 and Precautions (5.1) ].
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.
Figure 1 Image
Nonclinical toxicology
13 NONCLINICAL TOXICOLOGY
13.1 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 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.
Clinical studies
14 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 4 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 5 and Figures 2, 3, and 4).
Table 4 — Mean Change (SD) from Baseline to week 12 in International
Prostate Symptom Score in Three Randomized, Controlled, Double Blind
Studies
Study 1
Study 2
Study 3
Symptom Score
Placebo (n=167)
UROXATRAL 10 mg (n=170)
Placebo (n=152)
UROXATRAL 10 mg (n=137)
Placebo (n=150)
UROXATRAL 10
mg (n=151)
Difference between baseline and week 12.
Total symptom score
Baseline
18.2 (6.4)
18.2 (6.3)
17.7 (4.1)
17.3 (3.5)
17.7 (5.0)
18.0 (5.4)
Change
-1.6 (5.8)
-3.6 (4.8)
-4.9 (5.9)
-6.9 (4.9)
-4.6 (5.8)
-6.5 (5.2)
p-value
0.001
0.002
0.007
Figure 2 — Mean Change from Baseline in Total Symptom Score: Study 1
Figure 3 — Mean Change from Baseline in Total Symptom Score: Study 2
Figure 4 — Mean Change from Baseline in Total Symptom
Score: 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 5
and Figures 5, 6, and 7).
Table 5 — Mean (SD) Change from Baseline to Week 12 in Peak Urine Flow
Rate (mL/sec) in Three Randomized, Controlled, Double-Blind Studies
Study 1
Study 2
Study 3
Placebo (n=167)
UROXATRAL 10 mg (n=170)
Placebo (n=147)
UROXATRAL 10 mg (n=136)
Placebo (n=150)
UROXATRAL 10
mg (n=151)
Difference between baseline and week 12.
Mean Peak flow rate
Baseline
10.2 (4.0)
9.9 (3.9)
9.2 (2.0)
9.4 (1.9)
9.3 (2.6)
9.5 (3.0)
Change
0.2 (3.5)
1.7 (4.2)
1.4 (3.2)
2.3 (3.6)
0.9 (3.0)
1.5 (3.3)
p-value
0.0004
0.03
0.22
Figure 5 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s): Study 1
Figure 6 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s): Study 2
Figure 7 — Mean Change from Baseline in Peak Urine
Flow Rate (mL/s): 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.
Figure Image 2
Figure Image 3
Figure Image 4
Figure Image 5
Figure Image 6
Figure Image 7
Package label
UROXATRAL LABEL IMAGE
Label Image
2 organizations
1 product
Product
UroxatralOrganization
Concordia Pharmaceuticals Inc.Organization
STAT RX USA LLC