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Overview
What is Uroxatral?
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 CHNO•HCl. The
molecular weight of alfuzosin hydrochloride is 425.9. Its structural formula is:
What does Uroxatral look like?
What are the available doses of Uroxatral?
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What should I talk to my health care provider before I take Uroxatral?
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How should I use Uroxatral?
UROXATRAL is indicated for the treatment of signs and symptoms of
benign prostatic hyperplasia. UROXATRAL is not indicated for the treatment of
hypertension.
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.
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.
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.
UROXATRAL is contraindicated for use with potent CYP3A4 inhibitors such as
ketoconazole, itraconazole, and ritonavir, since alfuzosin blood levels are
increased. .
UROXATRAL is contraindicated in patients known to be hypersensitive to
alfuzosin hydrochloride or any component of UROXATRAL tablets.
What interacts with Uroxatral?
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What are the warnings of Uroxatral?
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What are the precautions of Uroxatral?
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What are the side effects of Uroxatral?
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What should I look out for while using Uroxatral?
What might happen if I take too much Uroxatral?
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.
How should I store and handle Uroxatral?
Store bottles of 1000 SINGULAIR 5-mg chewable tablets and 8000 SINGULAIR 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light resistant container. UROXATRAL is supplied as follows: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.UROXATRAL is supplied as follows: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.UROXATRAL is supplied as follows: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.UROXATRAL is supplied as follows: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.UROXATRAL is supplied as follows: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.
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Clinical Information
Chemical Structure
No Image found
Clinical Pharmacology
Alfuzosin is a selective antagonist of post-synaptic alpha-adrenoreceptors, which are located in the prostate, bladder
base, bladder neck, prostatic capsule, and prostatic urethra.
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-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.
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. C and
AUC 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 .
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 studies indicate that alfuzosin is moderately bound to human plasma
proteins (82% to 90%), with linear binding over a wide concentration range (5 to
5,000 ng/mL).
Metabolism
Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the
administered dose excreted unchanged in the urine. Alfuzosin is metabolized by
three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The
metabolites are not pharmacologically active. CYP3A4 is the principal hepatic
enzyme isoform involved in its metabolism.
Excretion
Following oral administration of C-labeled alfuzosin
solution, the recovery of radioactivity after 7 days (expressed as a percentage
of the administered dose) was 69% in feces and 24% in urine. Following oral
administration of UROXATRAL 10 mg tablets, the apparent elimination half-life is
10 hours.
Specific Populations
Elderly
Renal Impairment
[see and ]
Hepatic Impairment
[see , and ]
Drug-Drug Interactions
Metabolic Interactions
CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of
alfuzosin.
Potent CYP3A4 Inhibitors
Repeated oral administration of 400 mg/day of ketoconazole, a potent
inhibitor of CYP3A4, increased alfuzosin C by 2.3-fold
and AUC by 3.2-fold, following a single 10 mg dose of
alfuzosin.
In another study, repeated oral administration of a lower (200 mg/day) dose
of ketoconazole increased alfuzosin Cmax by 2.1-fold and AUC 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) .
Moderate CYP3A4 Inhibitors
Diltiazem:
[see ]
In human liver microsomes, at concentrations that are achieved at the
therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4
isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce
CYP1A, 2A6 or 3A4 isoenzymes.
Other Interactions
Warfarin:
Digoxin:
Cimetidine:
Atenolol:
[see ].
Hydrochlorothiazide:
Non-Clinical Toxicology
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.
Caution should be exercised when UROXATRAL is administered in
patients with severe renal impairment .
UROXATRAL is contraindicated for use in patients with moderate or
severe hepatic impairment . The pharmacokinetics of UROXATRAL have not been studied in
patients with mild hepatic impairment .
UROXATRAL is a selective alpha-blocker and should not be used in
combination with other alpha-blockers .
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. .
UROXATRAL is contraindicated for use with potent CYP3A4
inhibitors (e.g. ketoconazole, itraconazole, ritonavir) since alfuzosin blood
levels are increased .
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.
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.
If symptoms of angina pectoris should appear or worsen, UROXATRAL
should be discontinued.
Use with caution in patients with acquired or congenital QT
prolongation or who are taking medications that prolong the QT interval .
No laboratory test interactions with UROXATRAL tablets are known.
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.
The incidence of treatment-emergent adverse events 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 studies, 4%
of patients taking UROXATRAL (alfuzosin HCl) 10 mg extended-release tablets
withdrew from the study due to adverse events, compared with 3% in the placebo
group.
Table 1 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:
Gastrointestinal system:
Reproductive system:
Respiratory system:
Signs and Symptoms of Orthostasis in Clinical Studies: The
adverse reactions related to orthostasis that occurred in the double-blind phase
3 studies with alfuzosin 10 mg are summarized in Table 2. Approximately 20% to
30% of patients in these studies were taking antihypertensive medication.
Testing for blood pressure changes or orthostatic hypotension was conducted
in three controlled studies. Decreased systolic blood pressure (≤90 mm Hg, with
a decrease ≥20 mm Hg from baseline) was observed in none of the 674 placebo
patients and 1 (0.2%) of the 469 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.
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.
General disorders:
Cardiac disorders:
Gastrointestinal disorders:
Hepatobiliary disorders:
Respiratory system disorders:
Reproductive system disorders:
Skin and subcutaneous tissue disorders:
Vascular disorders:
During cataract surgery, a variant of small pupil syndrome known as
Intraoperative Floppy Iris Syndrome (IFIS) has been reported in some patients on
or previously treated with alpha-1 blockers .
UROXATRAL is contraindicated for use with potent CYP3A4
inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin
blood levels are increased. .
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 .
There may be an increased risk of hypotension/postural
hypotension and syncope when taking UROXATRAL concomitantly with
anti-hypertensive medication and nitrates .
Alpha-adrenergic blockers and PDE5 inhibitors are both
vasodilators that can lower blood pressure. Patients treated with alpha-blockers
should be hemodynamically stable before treatment with PDE5 inhibitors
initiation .
Pregnancy 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.
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
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 .
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 .
