Xatral XL 10mg

Xatral XL 10mg hydrochloride extended-release tablets are indicated for the treatment of signs and symptoms of benign prostatic hyperplasia.

Important Limitations of Use

Xatral XL 10mg hydrochloride extended-release tablets are not indicated for the treatment of hypertension.

Xatral XL 10mg hydrochloride extended-release tablets are not indicated for use in the pediatric population.

Xatral XL 10mg is used to treat the signs and symptoms of benign enlargement of the prostate (benign prostatic hyperplasia or BPH). Benign enlargement of the prostate is a problem that can occur in men as they get older. The prostate gland is located below the bladder. As the prostate gland enlarges, certain muscles in the gland may become tight and get in the way of the tube that drains urine from the bladder. This can cause problems with urinating, such as a need to urinate often, a weak stream when urinating, or a feeling of not being able to empty the bladder completely.

Xatral XL 10mg helps relax the muscles in the prostate and the opening of the bladder. This may help increase the flow of urine or decrease the symptoms. However, Xatral XL 10mg will not shrink the prostate. The prostate may continue to get larger. This may cause the symptoms to become worse over time. Therefore, even though Xatral XL 10mg may lessen the problems caused by enlarged prostate now, surgery still may be needed in the future.

Xatral XL 10mg is usually given only to men. It is not normally given to women or children.

Xatral XL 10mg is available only with your doctor's prescription.

The recommended dosage is one 10 mg Xatral XL 10mg (Xatral XL 10mg HCl) extended-release tablet once daily. The extent of absorption of Xatral XL 10mg is 50% lower under fasting conditions. Therefore, Xatral XL 10mg should be taken with food and with the same meal each day. The tablets should not be chewed or crushed.

How supplied

Dosage Forms And Strengths

Xatral XL 10mg (Xatral XL 10mg HCl) extended-release tablet 10 mg is available as a round, three-layer tablet: one white layer between two yellow layers, debossed with X10.

Storage And Handling

Xatral XL 10mg is supplied as follows:

Package NDC Number

Bottles of 100 24987-200-10 & 24987-200-20

Xatral XL 10mg (Xatral XL 10mg 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).

Protect from light and moisture.

Keep Xatral XL 10mg out of reach of children.

Distributed by Covis Pharmaceuticals, Inc. Cary, NC 27511. Revised: Sep 2013

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What is the most important information I should know about Xatral XL 10mg?

Hypersensitivity to Xatral XL 10mg hydrochloride or any component of Xatral XL 10mg.

Moderate or severe hepatic insufficiency (Child-Pugh categories B and C), since Xatral XL 10mg blood levels are increased in these patients.

Co-administration with potent CYP3A4 inhibitors eg, ketoconazole, itraconazole and ritonavir, since Xatral XL 10mg blood levels are increased.

Use in pregnancy: Xatral XL 10mg 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.

Use in lactation: Xatral XL 10mg is not indicated for use in women.

Use Xatral XL 10mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Xatral XL 10mg. Talk to your pharmacist if you have questions about this information.
• Take Xatral XL 10mg by mouth with food. Take with the same meal every day.
• Swallow Xatral XL 10mg whole. Do not break, crush, split, or chew before swallowing.
• Taking Xatral XL 10mg at the same time each day will help you remember to take it.
• Take Xatral XL 10mg on a regular schedule to get the most benefit from it.
• If you miss a dose of Xatral XL 10mg, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Xatral XL 10mg.

Use: Labeled Indications

Benign prostatic hyperplasia: Treatment of signs and symptoms of benign prostatic hyperplasia (BPH)

Off Label Uses

Facilitation of expulsion of ureteral stones

Data from two randomized unblinded active-controlled studies and one randomized placebo-controlled study in patients with symptomatic, uncomplicated distal ureteral stones ≤1 cm size supports the use of Xatral XL 10mg in the facilitation of ureteral stone expulsion. Additional trials may be necessary to further define the role of Xatral XL 10mg in the management of distal ureteral stones.

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What other drugs will affect Xatral XL 10mg?

Metabolic Interactions: CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of Xatral XL 10mg.

Potent CYP3A4 Inhibitors: Repeated administration of ketoconazole 400 mg, a potent inhibitor of CYP3A4, increased Xatral XL 10mg C_max 2.3-fold and AUC 3.2-fold following a single 10-mg dose of Xatral XL 10mg. Therefore, Xatral XL 10mg should not be co-administered with potent inhibitors of CYP3A4 because exposure is increased (eg, ketoconazole, itraconazole or ritonavir).

Moderate CYP3A4 Inhibitors: Diltiazem: Repeated co-administration of diltiazem 240 mg/day, a moderately potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg 3 times daily) Xatral XL 10mg (equivalent to the exposure with Xatral XL 10mg 10 mg) increased the C_max and AUC_0-24 of Xatral XL 10mg 1.5- and 1.3-fold, respectively. Xatral XL 10mg increased the C_max and AUC_0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of Xatral XL 10mg and antihypertensive medications has the potential to cause hypotension in some patients.

In human liver microsomes, at concentrations that are achieved at the therapeutic dose, Xatral XL 10mg did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, Xatral XL 10mg did not induce CYP1A, 2A6 or 3A4 isoenzymes.

Other Interactions: Warfarin: Multiple dose administration of an immediate-release tablet formulation of Xatral XL 10mg 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 co-administration of Xatral XL 10mg 10 mg and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug.

Cimetidine: Repeated administration of cimetidine 1 g/day increased both Xatral XL 10mg C_max and AUC values by 20%.

Atenolol: Single administration of atenolol 100 mg with a single 2.5-mg dose of an immediate-release Xatral XL 10mg tablet in 8 healthy young male volunteers increased Xatral XL 10mg C_max and AUC values by 28% and 21%, respectively. Xatral XL 10mg increased atenolol C_max and AUC values by 26% and 14%, respectively. In this study, the combination of Xatral XL 10mg with atenolol caused significant reductions in mean blood pressure and in mean heart rate.

Hydrochlorothiazide: Single administration of hydrochlorothiazide 25 mg did not modify the pharmacokinetic parameters of Xatral XL 10mg. There was no evidence of pharmacodynamic interaction between Xatral XL 10mg and hydrochlorothiazide in the 8 patients in this study.

Electrophysiology: The effect of Xatral XL 10mg 10 and 40 mg 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 19-45 years. The QT interval was measured at the time of peak Xatral XL 10mg plasma concentrations. Xatral XL 10mg 40-mg dose was chosen because this dose achieves higher blood levels than those achieved with the co-administration of Xatral XL 10mg and ketoconazole 400 mg. The mean change of heart rate associated with Xatral XL 10mg 10-mg dose in this study was 5.2 beats/min and 5.8 beats/min with Xatral XL 10mg 40 mg. The change in heart rate with moxifloxacin was 2.8 beats/min. Mean QT and QTc changes in msec (95% CI) from baseline at T_max (relative to placebo) with different methodologies to correct for effect of heart rate. The QT effect appeared greater for 40 mg compared to Xatral XL 10mg 10 mg. The effect of the highest Xatral XL 10mg 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 post-marketing experience with Xatral XL 10mg.

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What are the possible side effects of Xatral XL 10mg?

The incidence of treatment-emergent adverse events has been ascertained from 3 placebo-controlled clinical trials involving 1608 men in which daily doses of Xatral XL 10mg 10 and 15 mg were evaluated. In these 3 trials, 473 men received Xatral XL 10mg hydrochloride 10 mg extended-release tablets. In these studies, 4% of patients taking Xatral XL 10mg hydrochloride 10-mg extended-release tablets withdrew from the study due to adverse events, compared with 3% in the placebo group. The following treatment-emergent adverse events were reported in 2% of patients receiving Xatral XL 10mg.

The following adverse events, reported by between 1% and 2% of patients receiving Xatral XL 10mg 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 and nausea.

Reproductive System: Impotence.

Respiratory System: Bronchitis, sinusitis and pharyngitis.

The following adverse events have also been reported in post-marketing experience: Rash, tachycardia, chest pain and priapism.

Signs and Symptoms of Orthostasis in Clinical Studies: The adverse events related to orthostasis that occurred in the double-blind phase 3 studies with Xatral XL 10mg 10 mg are given in Table 2. Approximately 20-30% of patients in these studies were taking antihypertensive medication.

Multiple testing for blood pressure changes or orthostatic hypotension was conducted in the 3 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 min standing following being supine were excluded from the 3 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 Xatral XL 10mg 10 mg patients. Decreased diastolic blood pressure was observed in 3 (0.4%) of the placebo patients and 4 (0.9%) of the Xatral XL 10mg 10 mg patients. A positive orthostatic test was seen in 52 (7.7%) of placebo patients and in 31 (6.6%) of the Xatral XL 10mg 10 mg patients.

No vital sign measurements were obtained following the 1st dose administration in the phase 3 studies, except for a subset of patients in study 1 who had blood pressure measurements 12-16 hrs after the 1st dose to assess the potential to produce orthostatic hypotension. None of these 35 Xatral XL 10mg 10 mg treated patients showed a positive test for systolic, diastolic or orthostatic blood pressure change.

Xatral XL 10mg is a selective antagonist of post-synaptic α₁-adrenoreceptors which are located in the prostate, bladder base and neck, prostatic capsule and urethra.

Xatral XL 10mg hydrochloride is (RS)-N-[3-[(4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]propyl]tetrahydrofuran-2-carboxamide hydrochloride. The empirical formula is C₁₉H₂₈ClN₅O₄ and its molecular weight is 425.9.