Xatral

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

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

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

The potential drug interaction of XATRAL with vardenafil was not studied in a clinical trial.

XATRAL should not be used in combination with other alpha1-blockers (see Contraindications).

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

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

XATRAL 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 XATRAL.

Potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and ritonavir, increased XATRAL blood levels and exposure (AUC). Therefore, XATRAL should not be co-administered with potent inhibitors of CYP3A4 (see Contraindications). See Drug-Drug Interactions for details of increased XATRAL 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 XATRAL if other concomitant medications are used as high blood levels of XATRAL 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.

XATRAL should be prescribed carefully in combination with antihypertensive drugs. (see Warnings and Precautions, Cardiovascular and Drug-Drug Interactions, Cardiovascular Drugs).

The effect on QT/QTc interval of the combination of XATRAL 10 mg and sildenafil 100 mg has been studied in an electrophysiology trial (see Action and Clinical Pharmacology, Pharmacodynamics, Electrocardiography).

XATRAL 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 type of medications, therefore, caution should be exercised.

Because of the vasodilatory effects of alpha-blockers and PDE5-inhibitors, patients treated with alpha-blocker therapy should be hemodynamically stable before treatment with PDE5-inhibitors is initiated.

Treatment with XATRAL 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).

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 XATRAL) 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. No changes in blood pressure were observed.

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.

CYP3A4 is the principal hepatic enzyme involved in the metabolism of XATRAL. Ketoconazole is a strong-potency inhibitor of CYP3A4. Repeated 200 mg daily dosing of ketoconazole, for seven days increased XATRAL C_max 2.11-fold and AUC_last 2.46-fold following a single 10 mg dose of XATRAL under fed condition. Other parameters such as t_max and t_1/2 were not modified. The 8-day repeated administration of ketoconazole 400 mg daily increased C_max of XATRAL by 2.3-fold, AUC_last and AUC by 3.2 and 3.0 respectively.

XATRAL should be prescribed carefully in combination with nitrates.

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

The recommended dosage is one 10 mg XATRAL tablet daily to be taken after the same meal each day.

The recommended dosage is one 10 mg XATRAL 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.

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.

Cases of intraoperative floppy iris syndrome have been reported (see Warnings and Precautions, Ophthalmologic).

Cases of priapism have been reported.

The following adverse events have also been reported in postmarketing 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%).

Uncommon: edema, chest pain.

Uncommon: tachycardia. Very Rare: angina pectoris in patients with pre-existing coronary artery disease (see also Warnings and Precautions, 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 XATRAL treatment was not clearly established due to concomitant cardiac disorders, concomitant medications or absence of pre-treatment ECG measurement.

Uncommon: flushing.

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

Uncommon: vertigo.

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

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

XATRAL was not associated with deleterious effects on sexual function.

Uncommon: rhinitis.

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 XATRAL 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 XATRAL group; elderly patients (≥65 years) did not experience more vasodilatory adverse events than the younger patients.

Uncommon: rash, pruritus. Very rare: urticaria, angioedema.

Uncommon: diarrhea.

XATRAL 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.

XATRAL is not indicated for use in children.

XATRAL is not indicated nor recommended for use in women.

The pharmacokinetic parameters (C_max and AUC) are not increased in elderly patients when compared to healthy male volunteers. XATRAL 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.

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 XATRAL to rule out the presence of carcinoma of the prostate.

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

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 Dosage and Administration, Administration).

XATRAL is not indicated for use in children.

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 XATRAL 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.

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

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

XATRAL 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 XATRAL. 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 XATRAL 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 Drug Interactions).

Coronary insufficiency: Specific treatment for coronary insufficiency should be continued; however, if angina pectoris reappears or becomes worse, XATRAL 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 Action and Clinical Pharmacology, Pharmacodynamics, Electrocardiography).

The volume of distribution calculated following intravenous administration is 2.5 L/kg which indicates a distribution into extracellular fluids of the body. XATRAL 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 does not affect the binding of XATRAL to human plasma proteins. Based on in vivo data, it is not likely that XATRAL 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%).

The XATRAL tablet is based on the GEOMATRIX System, a patented prolonged-release technology designed to provide a sustained and continuous delivery of the active ingredient consistent with a once-daily administration. The pharmacokinetic properties of this system have been evaluated in healthy adult volunteers after single and/or multiple administrations 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.

Bioavailability is reduced when XATRAL is administered under fasting conditions. A consistent pharmacokinetic profile is obtained when XATRAL 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 C_max and C_through values are 13.6 (SD=5.6) and 3.1 (SD=1.6) ng/mL respectively. Mean AUC_0-24 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.

Following intravenous or oral administration, the elimination of XATRAL 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 XATRAL is increased to 9.1 hours in healthy middle-aged volunteers and to 10.1 hours in elderly volunteers.

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

XATRAL 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%). XATRAL 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.

In placebo-controlled clinical studies in patients with BPH, XATRAL 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 XATRAL-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.

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.

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. XATRAL 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 Figure 1.

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)

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

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

XATRAL, 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.

Compared to subjects with normal renal function, the mean C_max and AUC values of XATRAL 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. XATRAL has not been evaluated in patients with end-stage renal disease.