Xatral: Medical Uses, Administration, Mechanism of Action, Side Effects, Contraindications, Interactions and Precautions

It is a drug in the α1 blocker class. It is used to treat benign prostatic hyperplasia (BPH).

As an α1 adrenergic receptor antagonist, it works by relaxing the muscles of the prostate and bladder neck, which facilitates urination .

Alfuzosin was approved by the US Food and Drug Administration for the treatment of benign prostatic hyperplasia in June 2003.

It is marketed by Sanofi Aventis in the United States under the brand name Xatral and elsewhere under the brand names Xat, Xatral, Prostetrol and Alfural.

Each xatral prolonged-release tablet contains 10 mg of 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, slightly soluble in alcohol, and practically insoluble in dichloromethane.

Medical uses

Benign prostatic hyperplasia

Benign prostatic hyperplasia is an enlarged prostate gland. Xatral is the most widely used drug to treat benign prostatic hyperplasia.

Xatral blockers are the first-line treatment for symptoms of benign prostatic hyperplasia in men.

Xatral, terazosin, alfuzosin, and tamsulosin have been well established in the treatment to reduce lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia.

All of them are believed to be equally effective for this purpose. The first generation of Xatral, like prazosin, is not recommended for treating lower urinary tract symptoms due to its blood pressure lowering effect.

However, the second and third generation is recommended. In some cases, Xatral has been used in combination therapy with 5-alpha reductase blockers.

Dutasteride and tamsulosin are on the market as combination therapy and results have shown that they improve symptoms significantly compared to monotherapy.

Hypertension

Xatral is used as a second-line treatment for high blood pressure. They are not believed to be good as a first-line treatment because there are other more selective ones, although they may be good for treating men with hypertension and benign prostatic hyperplasia.

Xatral has been shown to improve the symptoms of benign prostatic hyperplasia in the elderly and at the same time reduce blood pressure. Benign prostatic hyperplasia is very common in men over 60 years old and hypertension as well.

Terazosin is also safe and effective to use against hypertension and benign prostatic hyperplasia, but it is first generation, while doxazosin is second generation Xatral.

Post-traumatic stress disorder (PTSD) and nightmares

Post-traumatic stress disorder is a disabling condition that can be caused by some type of life-threatening trauma. It is common in veteran soldiers who have experienced some type of trauma.

Xatral, which is commonly used as antihypertension, but due to Xatral’s alpha-1 adrenergic activity, that activity has been linked to fear and startle responses.

Xatral has been established as an active and safe alpha-1 adrenergic receptor antagonist for the brain. It can be used against traumatic nightmares, sleep disorders, and chronic post-traumatic stress disorder.

Pediatric use

These medications treat benign prostatic hyperplasia, or an enlarged prostate, by relaxing the muscles of the bladder and prostate to make urination easier. They do not shrink the prostate. They usually work immediately.

If you have high blood pressure and benign prostatic hyperplasia, alpha blockers may be a good option for you because they treat both conditions. But these medications can cause problems if you plan to have cataract surgery.

Xatral is not indicated for use in the pediatric population.

The efficacy of alfuzosin hydrochloride was not demonstrated in a randomized, double-blind, placebo-controlled, efficacy and safety trial conducted in 172 patients aged 2 to 16 years with elevated pressure at the detrusor leak point (LPP≥40 cm H2O ) of neurological origin treated with alfuzosin hydrochloride using pediatric formulations.

The trial included a 12-week efficacy phase followed by a 40-week safety extension period.

No statistically significant difference was observed in the proportion of patients who achieved a detrusor leak point pressure of <40 cmH20 between the alfuzosin and placebo groups.

During the placebo-controlled trial, adverse reactions reported in ≥2% of alfuzosin-treated patients and at a higher incidence than in the placebo group were: pyrexia, headache, respiratory tract infection, cough, epistaxis, and diarrhea.

The adverse reactions reported throughout the 12-month trial period, which included the open-label extension, were similar in type and frequency to the reactions observed during the 12-week period.

Alfuzosin hydrochloride has not been studied in patients younger than 2 years of age.

Geriatric use

Of the total subjects in Xatral clinical studies, 48% were 65 years or older, while 11% were 75 and older.

No overall differences in safety or efficacy were seen between these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out.

Dosage and administration

The recommended dose is one Xatral (alfuzosin HCl) 10 mg extended-release tablet once a day.

The degree of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, Xatral should be taken with food and with the same food every day. The tablets should not be chewed or crushed.

Xatral (alfuzosin HCl) 10 mg prolonged-release tablet is available as a three-layer round tablet: a white layer between two yellow layers, marked with X10. Store at 25 ° C (77 ° F); excursions allowed at 15 ° to 30 ° C (59 ° to 86 ° F).

How Xatral works as an α1 blocker class drug

Acute urinary retention is a life-threatening consequence of benign prostatic hypertrophy. The initial treatment for acute urinary retention is to temporarily insert an indwelling urinary catheter.

The catheter is usually removed in a few days to attempt a voiding test without a catheter.

A randomized, placebo-controlled study has shown that Xatral increases the likelihood of successful catheter removal, while reducing the risk of a subsequent episode of acute urinary retention.

An episode of acute urinary retention is no longer an absolute indication for surgical intervention. Alpha blockers are a very reasonable initial option for managing acute urinary retention.

Mechanism of action

Xatral inhibits norepinephrine, which inhibits the contraction of blood vessels. It occurs because Xatral inhibits the activation of post-synaptic alpha-1 receptors by releasing catecholamines and / or circulation that is neural. Xatral has no effect on renin release or cardio output.

Benign prostatic hyperplasia

Xatral blocks alpha receptors and relaxes the smooth muscles of the bladder. Helps urine flow smoothly and can decrease pain. From the bladder pressing on the prostate.

Selective alpha-1 blockers are better tolerated than non-selective alpha blockers in the body and therefore work better in benign prostatic hyperplasia.

Xatral, tamsulosin, and doxazosin are the main drug for benign prostatic hyperplasia because they have a long half-life and a modified-release formulation.

Tamsulosin is used primarily because it does not affect blood pressure and the side effects of vasodilation are minimal.

Hypertension

Xatral lowers blood pressure by blocking alpha-1 receptors, so norepinephrine cannot bind to the receptor and causes blood vessels to dilate.

Without resistance in the blood vessels, the blood flows more freely. Xatral has a good effect on plasma lipoproteins, insulin resistance and lowers blood glucose levels.

Xatral side effects

As Alpha-1-a blockers affect the symptoms of benign prostatic hypertrophy more specifically than Alpha-1 blockers, the adverse effects appear to be more linked to the reproductive system and minimize the effect on the blood pressure system.

However, hypotension and its complications (such as weakness and dizziness) are a constant risk, even when a selective alpha-1a blocker is being used.

Therefore, when starting treatment with an alpha-1 blocker, it is important to control blood pressure to minimize the risk of adverse effects related to low blood pressure.

The most common side effects are dizziness (due to postural hypotension), upper respiratory infection, headache, fatigue, and abdominal disorders.

Side effects include stomach pain, heartburn, and a stuffy nose. The adverse effects of alfuzosin are similar to those of tamsulosin, with the exception of retrograde ejaculation.

By reducing the alpha-1-adrenergic activity of blood vessels, these drugs can cause hypotension (low blood pressure) and disrupt the baroreflex response.

By doing so, they can cause dizziness, lightheadedness, or fainting when rising from a lying or sitting posture (known as orthostatic hypotension or postural hypotension).

For this reason, it is generally recommended to take Xatral at bedtime. The risk of a first dose phenomenon can be reduced or eliminated by gradual titration of the dose, since the adverse effects of Xatral are dose related.

This is also the case for others. Alpha-1 blockers work in a similar way, as tamsulosin is an alpha-1-blocker and prazosin is an alpha-1 blocker.

The risk of floppy iris syndrome during cataract surgery is high when the patient is using Xatral.

This is especially the case with Xatral and other alpha-1-a blockers, as alpha-1-a receptors are also present in the iris dilator muscle, allowing unopposed action of the parasympathetic innervated iris constrictor muscle and loss of iris tone.

However, this can be treated if the eye surgeon is experienced and knowledgeable in the use of alpha-1 blocker.

Clinical trial experience

Because clinical trials are conducted under widely varying conditions, the rates of adverse reactions seen in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates seen in clinical practice.

The incidence of adverse reactions was determined in 3 placebo-controlled clinical trials involving 1,608 men evaluating daily doses of 10 and 15 mg of alfuzosin.

In these 3 trials, 473 men received Xatral (alfuzosin HCl) 10 mg prolonged-release tablets.

In these trials, 4% of patients taking Xatral (alfuzosin HCl) 10 mg prolonged-release tablets withdrew from the trial due to adverse reactions, compared with 3% in the placebo group.

Adverse reactions that occurred in ≥2% of patients receiving xatral, and at a higher incidence than in the placebo group.

In general, the adverse reactions observed in long-term use were similar in type and frequency to the events described below for the 3-month trials.

The following adverse reactions, reported by 1% to 2% of patients receiving xatral and occurring more frequently than placebo, are listed alphabetically by body system and by decreasing frequency within the 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 trials: Adverse reactions related to orthostasis that occurred in phase 3 double-blind trials with 10 mg alfuzosin.

Approximately 20% to 30% of the patients in these trials were taking antihypertensive medication.

Contraindications of Xatral

It should be used with caution in patients with severe renal impairment, and should not be prescribed to patients with a known history of QT prolongation taking medications that prolong the QT interval.

Renal insufficiency

Systemic exposure increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate and severe renal impairment.

In phase 3 studies, the safety profile of patients with mild (n = 172) or moderate (n = 56) renal impairment was similar to that of patients with normal renal function in those studies.

Safety data are available only in a limited number of patients (n = 6) with creatinine clearance below 30 ml / min; therefore, caution should be exercised when Xatral is administered in patients with severe renal impairment.

Hepatic impairment

The pharmacokinetics of Xatral have not been studied in patients with mild hepatic impairment. Xatral is contraindicated for use in patients with moderate or severe hepatic impairment.

Chemistry of the Xatral

The Xatral contains a stereocenter and is therefore chiral. There are two enantiomeric forms, (R) -alfuzosin and (S) -alfuzosin. The drug is used as a racemate, (RS) -alfuzosin, a 1: 1 mixture of the (R) and (S) forms. It is provided as the hydrochloride salt.

Alfuzosin hydrochloride is (R, S) -N- [3 – [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula for alfuzosin hydrochloride is C19H27N5O4 • HCl. The molecular weight of alfuzosin hydrochloride is 425.9.

The tablet also contains the following inactive ingredients : colloidal silicon dioxide (NF), ethylcellulose (NF), hydrogenated castor oil (NF), hydroxypropyl methylcellulose (USP), magnesium stearate (NF), mannitol (USP), microcrystalline cellulose (NF), povidone (USP) and yellow ferric oxide (NF).

Tests for changes in blood pressure or orthostatic hypotension were performed in three controlled studies.

A decrease in systolic blood pressure (≤90 mmHg, with a decrease of ≥20 mmHg from baseline) was not observed in any of the 674 placebo-treated patients and in 1 (0.2%) of the 469 Xatral-treated patients .

A decrease in diastolic blood pressure (≤50 mmHg, with a decrease of ≥15 mmHg from baseline) was observed in 3 (0.4%) of the placebo patients and in 4 (0.9%) of the patients with placebo. Xatral.

A positive orthostatic test (decrease in systolic blood pressure of ≥20 mm Hg when standing from the supine position) was observed in 52 (7.7%) placebo patients and 31 (6.6%) of Xatral patients .

The following adverse reactions have been identified during post-approval use of Xatral.

Because these reactions are reported voluntarily in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship with drug exposure.

  • General disorders : edema.
  • Cardiac disorders : tachycardia, chest pain, angina pectoris in patients with pre-existing coronary artery disease, atrial fibrillation
  • Gastrointestinal disorders : diarrhea.
  • Hepatobiliary disorders : hepatocellular and cholestatic damage to the liver (including jaundice leading to drug discontinuation).
  • Respiratory system disorders : rhinitis
  • Reproductive system disorders : priapism.
  • Skin and subcutaneous tissue disorders : rash, pruritus, urticaria, angioedema, toxic epidermal necrolysis.
  • Vascular disorders : redness.
  • Blood and lymphatic system disorders : thrombocytopenia

During cataract surgery, a variant of the small pupil syndrome known as intraoperative floppy iris syndrome (IFIS) has been reported in some patients or previously treated with alpha adrenergic antagonists.

Interactions with other medications

CYP3A4 inhibitors

Xatral is contraindicated for use with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, as blood levels of alfuzosin increase.

Alpha adrenergic antagonists

The pharmacokinetic and pharmacodynamic interactions between Xatral and other alpha adrenergic antagonists have not been determined. However, interactions can be expected, and Xatral should not be used in combination with other alpha adrenergic antagonists.

Antihypertensive drugs and nitrates

There may be an increased risk of hypotension / postural hypotension and syncope when taking Xatral concomitantly with antihypertensive drugs and nitrates.

PDE5 inhibitors

Caution is advised when alpha adrenergic antagonists, including Xatral, are co-administered with PDE5 inhibitors.

Alpha adrenergic antagonists and PDE5 inhibitors are vasodilators that can lower blood pressure. Concomitant use of these two classes of drugs can cause symptomatic hypotension.

Precautions

Postural hypotension

Postural hypotension with or without symptoms (eg dizziness) may appear within a few hours after Xatral administration. As with other alpha adrenergic antagonists, there is a potential for syncope.

Patients should be warned of the possible occurrence of such events and avoid situations where injury occurs in the event of syncope.

There may be an increased risk of hypotension / postural hypotension and syncope when taking Xatral concomitantly with antihypertensive drugs and nitrates.

Caution should be exercised when Xatral is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medicinal products.

Patients with kidney failure

Caution should be exercised when Xatral is administered in patients with severe renal impairment (creatinine clearance <30 ml / min).

Patients with liver failure

Xatral is contraindicated for use in patients with moderate or severe hepatic impairment. Although the pharmacokinetics of Xatral have not been studied in patients with mild hepatic impairment, caution should be exercised when Xatral is administered to such patients.

Pharmacokinetics

Absorption : the bioavailability of Xatral is around 90% during oral administration in the fasted state. Food may have an effect on absorption if eaten shortly before, the Tmax for the fasted state is 2.9-5.6 hours compared to 5.2-7 hours in the fed state.

Food has no effect on the absorption of Xatral, but it can delay the plasma concentration for 1 hour, the maximum plasma level is 1 to 2 hours. The bioavailability of Xatral in the fed state is around 49%.

Tmax is 8 hours in the fed state. The Cmax range was 13.9-18.6 ng / mL faster and 7.2-15.6 ng / mL in the fed state.

Distribution : it is 90% bound to plasma and the volume of distribution is 2.5 l / kg.

Elimination : the elimination half-life of Xatral is approximately 8 hours, it is metabolized mainly through the liver. 75-91% is excreted in the faeces and 35% in unchanged form.

The volume of distribution and excretion increase with renal impairment due to decreased protein binding, but the elimination rate of the half-life is unchanged, therefore no dose adjustment is necessary for low to moderate renal impairment. .

The delay in the elimination half-life, the maximum concentration in plasma is doubled and the bioavailability is modified in patients with hepatic insufficiency. Xatral should not be used in patients with renal impairment.

It is excreted through the urine and 9% of that amount is not modified in its active form, the elimination half-life is 9 to 13 hours for healthy volunteers. The elimination half-life for target patients is around 14-15 hours.

No dose adjustment is necessary in patients with renal impairment and moderate hepatic impairment. 10-20% of Xatral is excreted unchanged in the urine and feces during oral administration.