Alfuzosin Hydrochloride (4012)
| Ingredients: |
Alfuzosin Hydrochloride |
| Indications: |
Hyperplasia, benign prostatic |
| Pregnancy Category: |
B |
| FDA Approved: |
2003- 06- 01 |
| Classes: |
Antiadrenergics, alpha blocking; Antiadrenergics, peripheral |
| Brand Names: |
Alfetim
-
Hungary
;
Dalfaz
-
Argentina, Poland, Spain
;
Flotral
-
India
;
Uroxatral
-
US; Chile
;
Uroxatral OD
-
Argentina, Uruguay
;
Uroxatral uno
-
Germany
;
Xatral
-
AFRICA; Austria, Belgium, Canada, China, Czech-republic, Denmark, England, France, Ireland, Israel, Italy, Netherlands, Sweden, Switzerland
;
Xatral LP
-
Ecuador, France, Hong-kong
;
Xatral OD
-
Brazil, Colombia, Costa-rica, Dominican-republic, El-salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Philippines, Venezuela
;
Xatral SR
-
Austria, Bulgaria, Egypt, Israel, Malaysia, Singapore
;
Xatral XL
-
Indonesia, Israel, Korea, Singapore, Thailand
;
Xatral XR 10
-
Singapore
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$55.88
(
Benign Prostatic Hyperplasia ;
Uroxatral ;
10 mg ;
1 tablet(s)/day ;
30 day supply
)
|
DESCRIPTION
|
| |
Each Uroxatral 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 C19 H27 N5 O4 ·HCl. The molecular weight of alfuzosin hydrochloride is 425.9.
The tablet also contains the following inactive ingredients: Colloidal silicon dioxide, ethylcellulose, hydrogenated castor oil, hydroxypropyl methylcellulose, magnesium stearate, mannitol,
microcrystalline cellulose, povidone, and yellow ferric oxide.
|
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 α- adrenergic receptors. Alfuzosin exhibits selectivity for α1- 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.
Alfuzosin HCl extended- release tablets are a selective antagonist of post- synaptic α1 - adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.
Pharmacokinetics
|
| |
The pharmacokinetics of alfuzosin HCl have been evaluated in adult healthy male volunteers after single and/ or multiple administration
with daily doses ranging from 7.5- 30 mg, and in patients with BPH at doses from 7.5- 15 mg.
Absorption
|
| |
The absolute bioavailability of alfuzosin HCl 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg
alfuzosin HCl under fed conditions, the time to maximum concentration is 8 hours. Cmax and AUC(0- 24) are 13.6 (SD = 5.6) ng/ ml and 194 (SD = 75) ng·h/ ml, respectively. Alfuzosin HCl exhibits linear kinetics
following single and multiple dosing up to 30 mg. Steady- state plasma levels are reached with the second dose of alfuzosin
HCl administration. Steady- state alfuzosin plasma concentrations are 1.2- to 1.6- fold higher than those observed after a
single administration.
|
Effect of Food
|
| |
The extent of absorption is 50% lower under fasting conditions. Therefore, alfuzosin HCl should be taken immediately following
a meal. (See DOSAGE AND ADMINISTRATION .)
|
Distribution
|
| |
The volume of distribution following IV 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- 90%), with linear binding over a wide concentration
range (5- 5000 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 administration of14C- 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 alfuzosin HCl 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 alfuzosin HCl 10 mg tablets in subjects with normal renal function (CLCR >80 ml/ min), mild
impairment (CLCR 60- 80 ml/ min), moderate impairment (CLCR 30- 59 ml/ min), and severe impairment (CLCR <30 ml/ min) were
compared. These clearances were calculated by the Cockcroft- Gault formula. Relative to subjects with normal renal function,
the mean Cmax and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment. (See PRECAUTIONS, General, Renal Insufficiency .)
|
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 3- to 4- fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore,
alfuzosin HCl is contraindicated in patients with moderate to severe hepatic impairment (see CONTRAINDICATIONS ). The pharmacokinetics of alfuzosin HCl have not been studied in patients with mild hepatic insufficiency. (See PRECAUTIONS, General, Hepatic Insufficiency .)
|
|
Electrophysiology
|
| |
The effect of 10 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- 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 coadministration of alfuzosin HCl 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 per minute and 5.8 beats per minute with 40 mg alfuzosin. The change in heart rate
with moxifloxacin was 2.8 beats per minute.
| TABLE 1
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
|
| Drug/ Dose |
QT |
Fridericia Method |
Population- Specific Method |
Subject- Specific Method |
| 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 (4 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 postmarketing experience with alfuzosin outside the US.
|
|
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, 1608 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 alfuzosin HCl 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 7 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- 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 ).
| TABLE 2
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 |
| |
|
Placebo |
Uroxatral 10 mg |
Placebo |
Uroxatral 10 mg |
Placebo |
Uroxatral 10 mg |
| Symptom Score |
(n=167) |
(n=170) |
(n=152) |
(n=137) |
(n=150) |
(n=151) |
| Total symptom score |
| |
Baseline |
18.2 (6.4) |
18.2 (6.8) |
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 |
|
| *
|
Difference between baseline value and last value. |
|
Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo
in Studies 1 and 2 ( TABLE 3 ).
| TABLE 3
Mean (SD) From Baseline in Peak Urine Flow Rate (ml/ sec) in Three Randomized, Controlled, Double- Blind Studies
|
| |
|
Study 1 |
Study 2 |
Study 3 |
| |
|
Placebo |
Uroxatral 10 mg |
Placebo |
Uroxatral 10 mg |
Placebo |
Uroxatral 10 mg |
| |
|
(n=167) |
(n=170) |
(n=147) |
(n=136) |
(n=150) |
(n=136) |
| 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 |
|
| *
|
Difference between baseline value and last value. |
|
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
|
| |
Alfuzosin HCl extended- release tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia.
Alfuzosin HCl is not indicated for the treatment of hypertension.
|
CONTRAINDICATIONS
|
| |
Alfuzosin HCl 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, Special Populations, Patients With Hepatic Insufficiency .)
Alfuzosin HCl should not be coadministered with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir,
since alfuzosin blood levels are increased. (See CLINICAL PHARMACOLOGY .)
Alfuzosin HCl extended- release tablets are contraindicated in patients known to be hypersensitive to alfuzosin HCl 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 alfuzosin HCl extended- release tablets. As with other
α- 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 alfuzosin HCl 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 alfuzosin HCl extended- release tablets to rule out
the presence of carcinoma of the prostate.
|
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 mydriatric 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 utilization of iris hooks, iris dilator rings, or viscoelastic sunstances.
There does not appear to be a benefit of stopping alpha- 1 blocker therapy prior to cataract surgery.
|
Coronary Insufficiency
|
| |
If symptoms of angina pectoris should newly appear or worsen, alfuzosin HCl should be discontinued.
|
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, Patients With 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 alfuzosin HCl 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 alfuzosin HCl 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 postmarketing experience with alfuzosin
outside the US. There are no known PK/ PD studies of the effects of other α- blockers on cardiac repolarization.
|
|
Information for the Patient
|
| |
Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when
beginning alfuzosin HCl, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during
this period.
Alfuzosin HCl should be taken with food and with the same meal each day.
Patients should be advised not to crush or chew alfuzosin HCl tablets.
|
Laboratory Tests
|
| |
No laboratory test interactions with alfuzosin HCl tablets are known.
|
Pediatric Use
|
| |
Alfuzosin HCl is not indicated for use in children.
|
Geriatric Use
|
| |
Of the total number of subjects in clinical studies of alfuzosin HCl, 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, Special Populations, Elderly .)
|
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
|
| |
Alfuzosin HCl 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 1200- 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
|
| |
Alfuzosin HCl is not indicated for use in women.
|
|
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 Cmax 2.3- fold and AUC(last) 3.2- fold following a single 10 mg dose of alfuzosin. Therefore, alfuzosin HCl should not be coadministered
with potent inhibitors of CYP3A4 because exposure is increased, ( e.g., ketoconazole, itraconazole, or ritonavir). (See CONTRAINDICATIONS .)
|
Moderate CYP3A4 Inhibitors
|
| |
Diltiazem
|
| |
Repeated coadministration 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 alfuzosin HCl) increased the Cmax and AUC(0- 24) of alfuzosin 1.5- and 1.3- fold, respectively. Alfuzosin increased the Cmax 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 alfuzosin HCl and antihypertensive 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 6 days to 6 healthy
male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin.
|
Digoxin
|
| |
Repeated coadministration of alfuzosin HCl 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 Cmax 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 8 healthy
young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax 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.
|
α-Blockers
|
| |
The pharmacokinetic and pharmacodynamic interactions between alfuzosin HCl and other α- blockers have not been determined.
However, interactions may be expected, and alfuzosin HCl should NOT be used in combination with other α- blockers.
|
|
|
ADVERSE REACTIONS
|
| |
The incidence of treatment- emergent adverse events has been ascertained from 3 placebo- controlled clinical trials involving
1608 men in which daily doses of 10 and 15 mg alfuzosin were evaluated. In these 3 trials, 473 men received alfuzosin HCl
10 mg extended- release tablets. In these studies, 4% of patients taking 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 alfuzosin HCl, 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 in TABLE 4 for the 3 month trials.
| TABLE 4
Treatment- Emergent Adverse Events Occurring in ≥2% of Uroxatral- Treated Patients and More Frequently Than With Placebo in
3 Month Placebo- Controlled Clinical Studies
|
| |
Placebo |
Uroxatral |
| Adverse Event |
(n=678) |
(n=473) |
| Dizziness |
19 (2.8%) |
27 (5.7%) |
| Upper respiratory tract infection |
4 (0.6%) |
14 (3.0%) |
| Headache |
12 (1.8%) |
14 (3.0%) |
| Fatigue |
12 (1.8%) |
13 (2.7%) |
|
The following adverse events, reported by between 1 and 2% of patients receiving alfuzosin HCl 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 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- 30% of patients in these studies were taking antihypertensive medication.
| TABLE 5
Number (%) of Patients With Symptoms Possibly Associated With Orthostasis in 3 Month Placebo- Controlled Clinical Studies
|
| |
Placebo |
Uroxatral |
| Symptoms |
(n=678) |
(n=473) |
| Dizziness |
19 (2.8%) |
27 (5.7%) |
| Hypotension or postural hypotension |
0 |
2 (0.4%) |
| Syncope |
0 |
1 (0.2%) |
|
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 alfuzosin HCl patients. Decreased diastolic blood pressure was observed
in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the alfuzosin HCl patients. A positive orthostatic test was seen in
52 (7.7%) of placebo patients and in 31 (6.6%) of the alfuzosin HCl 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- 16 hours after the first dose to assess the potential to produce
orthostatic hypotension. None of these 35 alfuzosin HCl treated patients showed a positive test for systolic, diastolic or
orthostatic blood pressure change.
|
Postmarketing Adverse Event Reports
|
| |
In addition to adverse events reported from clinical trials, the following events have been reported from worldwide postmarketing
experience with alfuzosin HCL:
| • |
Rash
|
| • |
Tachycardia
|
| • |
Chest pain
|
| • |
Priapism
|
During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported
in some patients on or previously treated with alpha- 1 blockers (see PRECAUTIONS ).
|
|
OVERDOSAGE
|
| |
Should overdose of 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 IV 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- 90%
protein- bound; therefore, dialysis may not be of benefit.
|
DOSAGE AND ADMINISTRATION
|
| |
The recommended dosage is one 10 mg alfuzosin HCl extended- release tablet daily to be taken immediately after the same meal
each day. The tablets should not be chewed or crushed.
|
HOW SUPPLIED
|
| |
Uroxatral 10 mg is available as a round, three- layer tablet: one white layer between two yellow layers, debossed with "X10".
Storage
|
| |
Store at 25°C (77°F); excursions permitted to 15- 30°C (59- 86°F).
Protect from light and moisture.
Keep Uroxatral out of reach of children.
|
|
PRODUCT IDENTIFICATION
|
| |
None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| tablet, extended release - oral - 10 mg -
|
| 100.0 |
$186.25 |
Uroxatral
Sanofi- Synthelabo Inc
|
00024420010 |
|
|