APO-ALFUZOSIN (alfuzosin hydrochloride) is indicated for:

• Benign Prostatic Hyperplasia

APO-ALFUZOSIN is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

• Acute Urinary Retention

APO-ALFUZOSIN is indicated as adjunctive therapy with urethral catheterization for Acute Urinary Retention related to BPH and management following catheter removal.

Geriatrics (>65 years of age):

Alfuzosin hydrochloride has been found to be safe and effective when administered at the therapeutic dose (10 mg once-daily) to patients over the age of 65 years.

Women:

APO-ALFUZOSIN is not indicated nor recommended for use in women.

Pediatrics (<18 years):

APO-ALFUZOSIN is not indicated for use in children.

Recommended Dose and Dosage Adjustment

Benign Prostatic Hyperplasia: The recommended dosage is one 10 mg APO-ALFUZOSIN (alfuzosin hydrochloride) tablet daily to be taken after the same meal each day.

Acute Urinary Retention: The recommended dosage is one 10 mg APO-ALFUZOSIN tablet daily after a meal to be taken from the first day of catheterization and continued beyond catheter removal unless there is a relapse of acute urinary retention or disease progression.

Administration

The tablet should be swallowed whole. Any other mode of administration, such as crunching, crushing, chewing, grinding or pounding to powder should be prohibited. These actions may lead to an inappropriate release and absorption of the drug and therefore possible early adverse reactions.

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 APO-ALFUZOSIN (alfuzosin hydrochloride) to rule out the presence of carcinoma of the prostate.

Patients with known hypersensitivity to alpha1-blockers should be closely monitored while on APO-ALFUZOSIN.

There are no data available on the effect on driving vehicles. Adverse reactions such as vertigo, dizziness and asthenia may occur essentially at the beginning of treatment. This has to be taken into consideration when driving vehicles and operating machines.

Patient should be warned that the tablet should be swallowed whole. Any other mode of administration, such as crunching, crushing, chewing, grinding or pounding to powder should be prohibited. These actions may lead to inappropriate release and absorption of the drug and therefore possible early adverse reactions (see 4.2, Administration).

Cardiovascular

APO-ALFUZOSIN is not indicated for the treatment of hypertension.

As with all alpha1-blockers in some patients, in particular, patients receiving antihypertensive medications, postural hypotension with or without dizziness or other symptoms may develop within a few hours following administration of APO-ALFUZOSIN. However, these effects are usually transient, occur at the beginning of treatment and do not usually prevent the continuation of treatment. In such cases, the patients should lie down until the symptoms have completely disappeared. As with other alpha1-blockers (alpha1-adrenergic blocking agents), there is a potential for syncope. Patients beginning treatment should be warned of the possible occurrence of such events.

Care should be taken when APO-ALFUZOSIN is administered to patients with symptomatic orthostatic hypotension or patients who have had a pronounced hypotensive response to another alpha1-blocker.

As with all alpha1-blockers, alfuzosin has been observed to increase heart rate. Caution should be taken in patients with histories of tachyarrhythmia or with certain cardiovascular conditions, such as myocardial ischemia. The heart rate increasing effects of alfuzosin are additive to those of other heart rate increasing drugs (see 4.5).

Coronary insufficiency:

Specific treatment for coronary insufficiency should be continued; however, if angina pectoris reappears or becomes worse, APO-ALFUZOSIN should be discontinued.

Patients with congenital QTc prolongation, with a known history of acquired QTc prolongation or who are taking drugs known to increase the QTc interval should be evaluated before and during the administration of alfuzosin.

Co-administration of alfuzosin with a drug known to be a QTc prolonging drug should be evaluated by the physician based on individual patient’s condition (See 5.1, Pharmacodynamics, Electrocardiography).

Ophthalmologic

Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with some alpha-1-blockers.

Cases of IFIS have been observed with alfuzosin hydrochloride use.  Ophthalmic surgeons should be informed in advance of cataract surgery of current or past use of alpha-1-blockers, as IFIS may lead to increased procedural complications.  The ophthalmologists should be prepared for possible modifications to their surgical technique.

Special Populations

Pregnant Women:

APO-ALFUZOSIN is not indicated nor recommended for use in women. No embryotoxic and/or teratogenic effects in the rat and rabbit were observed with alfuzosin hydrochloride. Parameters of male and female fertility, parturition, lactation and pup development were not modified by alfuzosin hydrochloride.

Nursing Women:

APO-ALFUZOSIN is not indicated nor recommended for use in women. It is unknown if the drug is excreted in human milk.

Pediatrics (<18 years):

APO-ALFUZOSIN is not indicated for use in children.

Geriatrics (>65 years of age):

The pharmacokinetics parameters (Cmax and AUC) are not increased in elderly patients when compared to healthy male volunteers. Alfuzosin hydrochloride has been found to be a safe and effective  alpha1-blockers when administered at the therapeutic dose (10 mg once-daily) to patients over the age of 65 years.

Overview

APO-ALFUZOSIN (alfuzosin hydrochloride) is not an inducer or an inhibitor of any of the principal hepatic enzymes involved in the metabolism of other drugs.

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of APO- ALFUZOSIN.

Potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and ritonavir, increased alfuzosin hydrochloride blood levels and exposure (AUC).  Therefore, APO-ALFUZOSIN should not be co-administered with potent inhibitors of CYP3A4 (See CONTRAINDICATIONS). See Drug- Drug Interactions for details of increased alfuzosin hydrochloride blood levels. As this is only a partial list, the physician is advised to consult current scientific literature regarding other CYP 3A4 competitive inhibitors prior to prescribing APO-ALFUZOSIN if other concomitant medications are used as high blood levels of APO-ALFUZOSIN can result.

It is not known how combined exposure of any medications metabolized by the CYP3A4 hepatic enzyme isoform (such as modern alpha1-blockers), herbal remedies (particularly St. John’s Wort, Milk thistle) and grapefruit juice may influence the overall efficacy and unwanted side effects of these medications, therefore, caution should be exercised.

APO-ALFUZOSIN should be prescribed carefully in combination with antihypertensive drugs (see 4.4, Cardiovascular and Drug-Drug Interactions, Cardiovascular Drugs).

Drug-Drug Interactions

Anti-Infectious Drugs

Imidazole

Ketoconazole

CYP3A4 is the principal hepatic enzyme involved in the metabolism of APO-ALFUZOSIN. Ketoconazole is a strong-potency inhibitor of CYP3A4. Repeated 200 mg daily dosing of ketoconazole, for seven days increased alfuzosin hydrochloride Cmax 2.11-fold and AUClast 2.46-fold following a single 10 mg dose of alfuzosin hydrochloride under fed condition. Other parameters such as tmax and t1/2 were not modified. The 8-day repeated administration of ketoconazole 400 mg daily increased Cmax of alfuzosin hydrochloride by 2.3-fold, AUClast and AUC by 3.2 and 3.0 respectively.

Cardiovascular Drugs

Alpha1-Blocker

APO-ALFUZOSIN should not be used in combination with other alpha1-blockers (see 4.3). Anticoagulant

Warfarin

The potential drug interactions of alfuzosin hydrochloride with warfarin were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with warfarin.

Beta-Blocker

Atenolol

The potential drug interactions of alfuzosin hydrochloride with atenolol were studied in clinical trials. The results showed that alfuzosin hydrochloride may be used with atenolol taking into account the hypotensive effects specific to drugs in this group.

Calcium Channel Blocker

Diltiazem

Repeated coadministration of 240 mg/day of diltiazem, a moderate-potency inhibitor of CYP3A4, with 7.5 mg/day alfuzosin (equivalent to the exposure with alfuzosin hydrochloride prolonged-release tablets) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. No changes in blood pressure were observed.

Cardiotonic Glycoside

Digoxin

Repeated coadministration of alfuzosin hydrochloride and digoxin for 7 days did not influence the steady-state pharmacokinetics of either drug.

Diuretic

Hydrochlorothiazide

The potential drug interactions of alfuzosin hydrochloride with hydrochlorothiazide were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with hydrochlorothiazide.

Nitrates

APO-ALFUZOSIN should be prescribed carefully in combination with nitrates.

Gastrointestinal Drugs

Histamine H2 Receptor Antagonist

Cimetidine

The potential drug interactions of alfuzosin hydrochloride with cimetidine were studied in clinical trials. The results showed that alfuzosin hydrochloride can be prescribed without risk of interactions in combination with cimetidine.

Sexual Function Drugs

Inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5)

Tadalafil

The potential drug interaction of alfuzosin hydrochloride with tadalafil was studied in a clinical trial. The results showed that there is no clinically significant hemodynamic interaction between alfuzosin hydrochloride 10 mg once daily and tadalafil 20 mg. APO-ALFUZOSIN can be prescribed in combination with tadalafil.

Sildenafil

The effect on QT/QTc interval of the combination of alfuzosin 10 mg and sildenafil 100 mg has been studied in an electrophysiology trial (See 5.1, Pharmacodynamics, Electrocardiography).

Drug-Food Interactions

APO-ALFUZOSIN should be taken after a meal.

It is not known how combined exposure of grapefruit juice may influence the overall efficacy and unwanted side effects of these types of medications, therefore, caution should be exercised.

Drug-Herb Interactions

Interactions with herbal products have not been established. It is not known how combined exposure of herbal remedies (particularly St. John’s Wort, Milk thistle) may influence the overall efficacy and unwanted side effects of these medications, therefore, caution should be exercised when taking herbal remedies with these types of medications.

Drug-Laboratory Interactions

Treatment with alfuzosin hydrochloride for up to 12 months produced no clinically significant changes in urinalysis, the routine biochemical and hematologic tests as well as in prostate specific antigen (PSA).

Alfuzosin is not indicated for women. For more details concerning fertility, see Toxicology under 5.4

Pregnancy Category: B

Patients may experience dizziness or fainting caused by a decrease in blood pressure after taking APO-ALFUZOSIN.  However, these effects are usually transient, occur at the beginning of treatment and do not usually prevent the continuation of treatment.  In such cases, patients should lie down until the symptoms have completely disappeared.  Although these symptoms are unlikely, patients should not drive, operate machinery or perform hazardous tasks for 12 hours after the initial dose.

Adverse Drug Reaction Overview

Dizziness and headache are the most frequent adverse drug reactions with alfuzosin hydrochloride.

Alfuzosin hydrochloride was associated with a low incidence of postural symptoms. As with all alpha1-blockers, there is also a potential for syncope.

Alfuzosin hydrochloride was not associated with deleterious effects on sexual function.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.  Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Safety information was derived from placebo-controlled clinical trials involving 1,608 men with BPH. The safety profile of alfuzosin hydrochloride in the ALFAUR study which included 363 patients with Acute Urinary Retention due to BPH was similar to the safety profile reported in previous BPH studies.

In the BPH studies, 4% of patients taking alfuzosin hydrochloride 10 mg prolonged release tablets withdrew from the study due to adverse events, compared with 3% in the placebo group. Dizziness and headache were the most frequent cause in each of the groups, although no single symptom was predominant. The withdrawal rate was similar in the alfuzosin hydrochloride group following long-term use in open-label extension studies for up to 1 year.

Table 1 summarizes the treatment-emergent adverse events that occurred in ≥2% of patients receiving alfuzosin hydrochloride prolonged-release tablets and placebo, in three 3-month trials. 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.

Table 1 – Treatment-Emergent Adverse Events Occurring in ≥2% of Patients with BPH treated with Alfuzosin Hydrochloride and with Placebo in 3-Month Placebo-Controlled Clinical Studies

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following adverse events, reported by between 1% and 2% of patients receiving alfuzosin hydrochloride prolonged-release tablets and placebo are listed and are as follows:

Table 2 – Treatment-Emergent Adverse Events Occurring Between 1% and 2% of Patients with BPH treated with Alfuzosin Hydrochloride Prolonged-release Tablets and Placebo in 3-Month Placebo-Controlled Clinical Studie

Reproductive System and Breast Disorders

Impotence and other events related to sexual function are commonly associated with other alpha1-blockers, however, with alfuzosin hydrochloride, there were minimal effects regarding sexual function and ejaculatory disorders/abnormalities with no reports of priapism. Also, no patient discontinued treatment with alfuzosin hydrochloride due to ejaculation disorders. The reported incidence of ejaculation disorders was not associated with the study drug and is consistent with that reported in the untreated population.

Vascular Disorders

Signs and Symptoms of Orthostasis in Clinical Studies

The number of patients with symptoms of orthostasis are summarized in Table 3.

Table 3 – Number (%) of Patients with BPH with Symptoms Possibly Associated with Orthostasis in 3-Month Placebo-Controlled Clinical Studies

Multiple testing for blood pressure changes or orthostatic hypotension was conducted in the three controlled studies. These tests were considered positive for blood pressure decrease if (1) supine systolic blood pressure was ≤ 90 mmHg, with a decrease ≥ 20 mmHg versus baseline, and/or (2) supine diastolic blood pressure was ≤ 50 mmHg, with a decrease ≥ 15 mmHg versus baseline.

The tests were considered positive for orthostatic hypotension if there was a decrease in systolic blood pressure of ≥ 20 mmHg upon standing from the supine position during the orthostatic tests. The percentage of patients with a positive test at any visit was 7.7% for placebo and 6.6% for alfuzosin hydrochloride prolonged-release tablets, as shown in Table 4.

Table 4 – Number (%) of Patients with BPH with Clinically Meaningful Decreases in Blood Pressure at Any Visit in 3-Month Placebo-Controlled Clinical Studies

*N = 471

A subset of patients from Study 1 had blood pressure measurements 12 to 16 hours after the first dose to assess the potential to produce orthostatic hypotension. None of the 35 alfuzosin hydrochloride prolonged release tablet-treated patients showed a positive test for systolic, diastolic, or orthostatic blood pressure change.

No age effect on the overall incidence of patients reporting adverse events was observed in the alfuzosin hydrochloride prolonged-release tablet group; elderly patients (≥ 65 years) did not experience more vasodilatory adverse events than the younger patients.

Post-Market Adverse Drug Reactions

The following adverse events have also been reported in post-marketing experience:

The following frequency rating is used; very common (≥ 10%), Common (≥ 1% and < 10%), Uncommon (≥ 0.1% and < 1%), Rare (≥ 0.01% and < 0.1%), Very rare (< 0.01%)

Cardiac Disorders:

Uncommon: tachycardia

Very Rare: angina pectoris in patients with pre-existing coronary artery disease (see also 4.4, Cardiovascular).  Isolated spontaneous cases of QT interval prolongation, ventricular arrhythmias, including Torsade de Pointes, ventricular tachycardia and fibrillation have been reported particularly in patients with preexisting cardiovascular diseases; however, a relationship between these adverse events and the alfuzosin hydrochloride treatment was not clearly established due to concomitant cardiac disorders, concomitant medications or absence of pre- treatment ECG measurement.

Vascular Disorders:

Uncommon: flushing

Gastrointestinal disorders:

Uncommon: diarrhea

General Disorders and Administration Site Conditions:

Uncommon: edema, chest pain

Ear and Labyrinth Disorders:

Uncommon: vertigo

Eye disorders:

Cases of intraoperative floppy iris syndrome have been reported (see 4.4, Ophthalmologic).

Hepato-biliary disorders:

Cases of hepatocellular injury and cholestatic liver disease have been reported.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Rhinitis.

Skin and Subcutaneous Tissue Disorders:

Uncommon: rash, pruritus

Very rare: urticaria, angioedema

- To report any side effects:

Should overdose of APO-ALFUZOSIN (alfuzosin hydrochloride) 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, vasopressor should then be used and the renal function should be monitored and supported as needed. Alfuzosin hydrochloride is 87% (82 - 90%) protein-bound, therefore, dialysis may not be of benefit.

Mechanism of Action

APO-ALFUZOSIN (alfuzosin hydrochloride), indicated for the treatment of benign prostatic hyperplasia (BPH) and as adjunctive therapy with urethral catheterization for acute urinary retention related to BPH and management following catheter removal, is a uroselective antagonist of post-synaptic α1-adrenoceptors located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

Pharmacodynamics

The clinical manifestations of benign prostatic hyperplasia are due to bladder outlet obstruction caused by anatomical (static) and functional (dynamic) factors. The static component is related to an increase in prostate size which may not cause symptoms. The dynamic component is related primarily to an increase in smooth muscle tone in the prostate, prostatic capsule, bladder base, bladder neck, and prostatic urethra. This increased tone is mediated by the activation of α1- adrenoceptors and leads to an increased resistance to urinary voiding and the symptoms of BPH such as a hesitant, interrupted, weak stream; urgency and leaking or dribbling; and/or more frequent urination, especially at night. Alfuzosin hydrochloride blocks α1-adrenoceptors leading to a relaxation of the smooth muscle in the bladder neck and prostate.

In animal studies, alfuzosin was shown to be functionally uroselective by preferentially decreasing urethral blood pressure over arterial blood pressure. In human tissue, in vitro, alfuzosin has induced preferential α1-adrenoceptor antagonist activity on prostatic cells relative to renal artery cells. This is illustrated in the figure below:

Figure 1: Prostatic Selectivity Score

In placebo-controlled clinical studies in patients with BPH, alfuzosin hydrochloride was shown to:

• significantly increase urine peak flow rate (Qmax) by 30% which is observed after the first dose
• significantly reduce detrusor pressure and increase bladder capacity
• significantly reduce residual urine volume

These favourable urodynamic effects lead to an improvement of lower tract irritative and obstructive symptoms without any deleterious effect on sexual function. The Quality of Life Index was also significantly improved by 33% in the alfuzosin hydrochloride prolonged-release tablet - treated patients.

In addition, the efficacy of alfuzosin 10 mg OD on peak flow rate and the limited effect on blood pressure have been demonstrated to be related to its pharmacokinetic profile. Moreover, the efficacy on peak flow rate is maintained up to 24 hours after intake.

A lower frequency of acute urinary retention was observed in the alfuzosin treated patient than in the untreated patient.

Electrocardiography:

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 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co- administration of alfuzosin hydrochloride and ketoconazole 400 mg (CYP3A4 inhibitor).  QT interval, obtained with 12-lead ECGs, was measured from 2h to 12h post treatment administration.  Table 5 summarizes the mean effect and the maximum mean effect on heart rate (HR) and corrected QT interval (QTc) with different methods of correction [Bazett (QTcB), Fridericia (QTcF) and population-specific (QTcN) correction methods].  There is a trend to lower values for QTc interval changes from QTcBà QTcF à QTcN, demonstrating the critical role of the correction formula used to minimize the biased overestimation linked to the heart rate increase.  The maximum mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 3.69 beats/minute and 5.45 beats/minute with 40 mg alfuzosin.  The change in heart rate with moxifloxacin was 2.85 beats/minute.

Table 5: 12-lead ECG – Mean change in HR and QTc data from T7 – T11h and maximum mean baseline- and placebo-adjusted HR and QTc interval changes over the observation period T2-T12h

*Active control

The maximum mean effect on QTcN 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.

A separate post-marketing study evaluated the effect of the co-administration of 10 mg alfuzosin and a drug with similar QT effect size.  It was a double-blind, randomized, placebo and active- controlled (moxifloxacin 400 mg), 5-way crossover study conducted in 39 healthy white male subjects aged 19 to 46 years.  QT interval, obtained with 12-lead ECGs, was measured from 4h to 12h post treatment administration. Maximum mean effect on HR and QT interval were extracted from a time-matched placebo adjusted analysis.  In this study, the maximum mean placebo-substracted QTcN increase of alfuzosin 10 mg alone was 4.41 msec (upperbound 95% CI, 7.09 msec), shown in Table 6 below. The concomitant administration of the two drugs (alfuzosin and sildenafil) showed an increased QT effect when compared with either drug alone. This maximum mean QTcN increase [8.27 msec (UB 95% CI, 10.90 msec)] was not more than additive.  Although this study was not designed to make direct statistical comparisons between drugs, the maximum mean QTcN increase with both drugs given together appeared to be lower than the maximum mean QTcN increase seen with the positive control moxifloxacin 400 mg [11.44 msec (UB 95% CI, 14.01 msec)]. The combination of alfuzosin + sildenafil produced a statistically significant increase in the mean heart rate [+ 4 bpm, p<0.0001].

Table 6: 12-lead ECG – Mean change in HR and QTc data from T7 – T10h and maximum mean baseline- and placebo-adjusted HR and QT interval changes over the observation period T4-T12h

*Active control

**For the analysis of the mean difference, only QTcNi data are available (QT interval corrected by a subject specific formula)

QT interval prolongation has not been studied in patients with BPH, therefore similar data is not available.  This population may suffer from other conditions and have a higher risk to develop QT interval prolongation due to concomitant risk factors or pre-existing cardiovascular disorders. Based on individual patient’s condition, monitoring for ECG abnormalities should be considered by the physician during treatment.

Absorption:

Bioavailability is reduced when alfuzosin hydrochloride is administered under fasting conditions. A consistent pharmacokinetic profile is obtained when alfuzosin hydrochloride is administered following a meal. A mean peak plasma concentration of 12.3 ± 6.6 ng/mL is reached in 6 to 14 hours after a single dose.

Under fed conditions and after repeated doses, mean Cmax and Cthrough values are 13.6 (SD = 5.6) and 3.1 (SD = 1.6) ng/mL respectively. Mean AUC0-24 is 194 (SD = 75) mg.h/mL. A plateau of concentration is observed from 3 to 14 hours with concentrations above 8.1 ng/mL (Cav) for 11 hours.

Figure 2: Mean (SEM) alfuzosin plasma concentration-time profiles after a repeated administration of alfuzosin 10 mg OD tablet in healthy middle-aged male volunteers (N=42)

Distribution:

The volume of distribution calculated following intravenous administration is 2.5 L/kg which indicates a distribution into extracellular fluids of the body. Alfuzosin hydrochloride is moderately bound to plasma proteins with the free fraction accounting for 13.3% in healthy volunteers. Fractions bound to serum albumin and α1-glycoproteins are 68.2 and 52.5%, respectively. Salicylic acid, hydrochlorothiazide, diltiazem, digoxin and indomethacin do not affect the binding of alfuzosin hydrochloride to human plasma proteins. Based on in vivo data, it is not likely that alfuzosin hydrochloride will affect the extent of binding of these drugs to human plasma proteins. There is an increase in free fraction in renal insufficiency patients (16.8%) and in patients with hepatic disease (20.8%).

Metabolism:

Alfuzosin hydrochloride undergoes metabolism by the liver, with only 11% of the parent compound being excreted as unchanged in the urine. The metabolites which are all inactive are eliminated in the urine (15-30%) and feces (75-91%). Alfuzosin hydrochloride is metabolized by three metabolic pathways (oxidation, O-demethylation, N–dealkylation) which are qualitatively identical to those observed in the animal (rat and dog).

CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.

Excretion:

Following intravenous or oral administration, the elimination of alfuzosin hydrochloride is characterized, in healthy young subjects and in the target population, by a terminal half-life of about 4.8 hours and a total clearance of 0.3 L/h/kg.

The apparent half-life of alfuzosin hydrochloride is increased to 9.1 hours in healthy middle-aged volunteers and to 10.1 hours in elderly volunteers.

Special Populations and Conditions

 Geriatrics:

 Compared to healthy middle-aged volunteers, the pharmacokinetic parameters of alfuzosin hydrochloride (Cmax and AUC) are not increased in elderly patients.

Renal Insufficiency:

Compared to subjects with normal renal function, the mean Cmax and AUC values of alfuzosin hydrochloride are moderately increased (1.5 to 1.6 fold) in patients with various stages of renal impairment, with no change in the apparent elimination half-life. This change in the pharmacokinetic profile is not considered clinically relevant; and therefore, does not necessitate a dosing adjustment.  Alfuzosin hydrochloride prolonged-release tablet has not been evaluated in patients with end-stage renal disease.

Hepatic Insufficiency:

After a single oral administration of alfuzosin hydrochloride in patients with severe hepatic insufficiency, the elimination half-life is prolonged. A two-fold increase in Cmax values and a three-fold increase in the AUC is observed. Bioavailability is increased in comparison with that in healthy volunteers (See 4.3).

Chronic Cardiac Insufficiency:

The pharmacokinetic profile of alfuzosin hydrochloride administered intravenously is not affected by chronic cardiac insufficiency.

Acute toxicity

The results of single dose toxicity studies in mice and rats after oral and intraperitoneal administration are summarized in the table 12 below.

Table 12 - Single dose toxicity studies in mice and rats after oral and intraperitoneal administration

Clinical symptoms included palpebral ptosis, motor disturbances, sedation, prostration, cyanosis and clonic convulsions. Symptoms disappeared within 4 to 5 days after administration.

After intravenous administration in mice and rats, no deaths were observed as the maximum deliverable dose under experimental conditions was 40 mg/kg for both mice and rats.

Chronic toxicity

The chronic toxicity of orally administered alfuzosin was studied in rats and dogs in 1 month and 3 month toxicity studies. In addition, chronic oral toxicity was evaluated in rats up to 6 months. The dosages administered in these studies are given in the following table.

Table 13 - Chronic 1-month and 3-month toxicity studies in rats and dogs.

In the 1 week intravenous studies in rats, 3 animals died on days 1, 3 and 5 as a result of severe cardiac depression. Survivors exhibited prostration, dyspnea, sialorrhea, peripheral vasodilation and palpebral ptosis. No lesions were observed at injection sites. When dogs were administered alfuzosin intravenously for one week, no deaths occurred and clinical symptoms consisted of peripheral vasodilation, nasal dryness, diarrhea, hypotonia, tremor, protrusion of the nictitating membrane and hyperdacryorrhea. Palpebral ptosis was observed at 15 and 30 mg/kg bid with vomiting and salivation occurring at 30 mg/kg bid. In a one month intravenous study in dogs, no deaths occurred and no lesions were evident at injection sites. However clinical symptoms such as peripheral vasodilation, palpebral ptosis, nasal dryness, tachypnea, tachycardia and some hypotonia, vomiting, and ptyalism were recorded.

In one month oral studies in rats, clinical signs began to appear at 100 mg/kg/day for males and 200 mg/kg/day for females and consisted mainly of sedation, hypersalivation, slight changes in haematology as well as increased triglycerides. When rats where treated by i.v. route with 2, 10 or 50 mg/kg/day alfuzosin three deaths occurred in the first week. Clinical symptoms included palpebral ptosis, hypotonia, ocular secretions, peripheral vasodilation, respiratory difficulties and vaginal dilation.

Beagle dogs treated with 200 mg/kg/day for 4 weeks demonstrated motor incoordination and loss of appetite accompanied by a reduction in water intake. A dose of 200 mg/kg/day also produced an increase in SGPT, proteinuria, haematuria and renal lesions. When dogs were treated with 60 mg/kg/day for one week followed by 100 mg/kg/day for 3 weeks, clinical symptoms were mild and consisted of vomiting and diarrhea, tremor, sedation, vasodilation, palpebral ptosis and abnormal gait. Similar symptoms were observed in dogs treated for 3 months with 80 mg/kg/day. When dogs were treated with the 5 mg SR formulation for one month (20 mg/animal/day) no clinical signs and no deaths were observed. Body weight and food consumption were normal. In addition, dogs treated with 2, 5 or 20 mg/kg bid by IV route demonstrated typical clinical symptoms but no deaths were observed.

In 3 month toxicity studies in rats, 200 mg/kg /day caused transient hypersalivation, mild anaemia, increased urine output and weight changes of adrenal glands and spleen in males. When dogs were treated with alfuzosin 5, 20 or 80 mg/kg/day for 3 months, no deaths occurred and clinical symptoms included soft feces, vomiting, tremor, peripheral vasodilation and hyper salivation at 20 and 80 mg/kg/day. In addition, abnormal quietness was observed at all doses.

Rats treated with alfuzosin for 6 months demonstrated marked accumulation of the compound in blood and histopathological changes in adrenal tissue at 50 mg/kg/day in males and 250 mg/kg/day in females as well as liver cell changes such as necrosis of cells around acinus and cytoplasmic eosinophilia. In a this 6 month toxicity study, rats of both sexes were divided into four groups and administered 10, 50 or 250 mg/kg/day alfuzosin or control. Twenty-two animals died out of which 4 cases were considered not related to treatment. The deaths were dose-related (2 males at 50 mg/kg/day, 7 males and 9 females at 250 mg/kg/day). Rats administered 250 mg/kg/day and 2 males at 50 mg/kg/day died within 30 minutes after oral gavage and exhibited respiratory difficulties, hypersalivation and peripheral vasodilation prior to death. The other animals died between 2 and 22 hours following administration of alfuzosin. Alfuzosin also caused ptosis and peripheral vasodilation from Week 1 and peripheral redness of the eyes and vaginal dilation from Week 2. Rats receiving 50 and 250 mg/kg/day showed a dose-related frequency of salivation (from Week 2) and urogenital wetness (from Week 7). Food consumption slightly increased in all animals with the exception of males receiving 250 mg/kg/day who lost all appetite from Week 9.

When rats were treated with alfuzosin 1, 5 or 20 mg/kg/day for one year clinical symptoms were ptosis at 5 and 25 mg/kg/day and scrotal reddening and vaginal dilation in all treatment groups. Increased weight gain was observed in females at 25 mg/kg/day after Month 1. Food consumption was increased in males at the two higher doses and females at 25 mg/kg/day. Water consumption was normal. Twelve animals died or were sacrificed, however 8 cases were not treatment related. Organ weight examination revealed increases in the pituitary gland in females, the kidney and thyroid in males and the liver and spleen in both sexes.

Oral administration of alfuzosin to dogs for 53 weeks is characterized by a fairly wide range of clinical symptoms such as photophobia, tremor, palbebral ptosis, nasal dryness and soft feces. However laboratory and physiological tests did not show any treatment related effects.

Macroscopic and microscopic examinations revealed impairment of the female reproductive cycle.

Carcinogenicity Studies

Carcinogenicity studies were carried out in the mouse and rat. Alfuzosin was shown to have no carcinogenic effect. In a 98-week oral carcinogenicity study in mice, alfuzosin was administered at doses with vehicle control to groups of 51 males and 51 females in 2 sub-groups. Mortality was increased in males at 100 mg/kg/day (53% in controls, 78% in the 100 mg/kg/day group).

There were very slight increases in the relative weight of the liver in a few males who received 100 mg/kg/day of alfuzosin. No tumoral or other types of lesions were observed. At doses up to 100 mg/kg/day, alfuzosin had no carcinogenic potential in mice.

In a 104-weeks oral carcinogenicity study in rats, alfuzosin was administered at doses of 10, 30 and 100 mg/kg/day, with vehicle control, to groups of 50 males and 50 females in 2 sub-groups. Mortality was comparable in all doses. No oncogenic effect was noted.

Mutagenicity Studies

Alfuzosin did not show any mutagenic potential in the AMES test, mouse lymphoma test, chromosomal aberrations test in Chinese hamster ovary cells, unscheduled DNA repair test and mouse micronucleus test.

Reproduction and Teratogenicity Studies

Studies were carried out in the Sprague Dawley rat and the New Zealand rabbit. Alfuzosin was not embryotoxic, produced no teratogenic effects and did not affect fertility, parturition or lactation at dose levels many-fold greater than therapeutic levels in man.

A preliminary fertility study in Sprague Dawley rats established that the maximum dose to be used in the principal fertility study should be < 200 mg/kg/day. The principal study utilized groups of 26 male and female animals who received alfuzosin by gavage at doses of 5, 25 and 125 mg/kg/day, with vehicle control. Males were treated from Day 71 prior to mating to the end of gestation of the female. Females were treated from Day 15 prior to mating to Day 21 post- coitum and half of the females to Day 25 post-partum. The vaginal cytological cycle was altered at doses of 25 and 125 mg/kg/day of alfuzosin, but alfuzosin had not effect on mating, ovulation or pre- and post-natal development. The “No Adverse Effect Level” for the F0 generation was 5 mg/kg/day. The viability of the offspring was reduced at a dose of 125 mg/kg/day but the reproductive behaviour of the F1 generation was not changed following treatment of the parents. Consequently, the “No Adverse Effect Level” for the F1 and F2 generations was considered to be 25 mg/kg/day.

In a peri- and post-natal study in the rat, alfuzosin was administered from Day 15 post-coitum to Day 21 post-partum at doses of 5, 25 and 125 mg/kg/day, with vehicle control, to groups of 20 females. Alfuzosin at these doses caused no abnormalities in parents or pups. The “No Adverse Effect Level” for the F0 generation was 5 mg/kg/day and for the F1 generation was 125 mg/kg/day.

Teratogenicity studies were carried out in the rat and rabbit. Alfuzosin produced no teratogenic effects.

Alfuzosin was administered by gavage to three groups of females rats at various dose levels, with vehicle control, from Day 6 to Day 15 of gestation. In a preliminary study, 15 animals received 100 or 200 mg/kg/day. In the main study, 20 animals received 10, 50 or 250 mg/kg/day. These studies showed no effect of alfuzosin on organogenesis up to a dose of 250 mg/kg/day. The “No Adverse Effect Level” for the F0 and F1 generations was 250 mg/kg/day.

Alfuzosin was administered by gavage to two groups of females rabbits at various dose levels, with vehicle control from Day 6 to Day 18 of gestation. In a preliminary study, 4 animals received 50, 100 or 250 mg/kg/day. In the main study, 14 animals received 10, 30 or 100 mg/kg/day. These studies showed no effect of alfuzosin on organogenesis up to a dose of 100 mg/kg/day. The “No Adverse Effect Level” for the F0 generation was 10 mg/kg/day and for the F1 generation was 30 mg/kg/day.

Cytotoxicity Studies

Alfuzosin was administered in vitro to cultures of hepatocytes from males Sprague Dawley rats and male Beagle dogs at concentration from 1.25 to 100 μM. Findings were similar in both species: Alfuzosin induced gradual membrane and metabolic damage. However the IC50 was >100 μM. Alfuzosin was otherwise well tolerated by hepatocytes at these concentrations.

Immunotoxicity Studies

Sensitization studies carried out in male and female Dunkin Hartley albino guinea pigs showed that alfuzosin had a mild sensitizing capacity at oral doses of 6-10 mg/kg.

In addition to the active ingredient, alfuzosin hydrochloride, each tablet also contains the non- medicinal ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyvinyl acetate phthalate, and yellow ferric oxide.

For a complete quantitative listing, see Section 2.

Not applicable

Store below 30° C. Keep in a safe place out of the reach of children. No special precautions applicable.

Secondary packaging: Carton

Not applicable.