Alfadil XL

Each Alfadil XL 4 mg Controlled-Release Tablet contains Doxazosin mesilate equivalent to 4 mg doxazosin.
Doxazosin, as mesilate (Alfadil XL) utilizes GITS (Gastrointestinal Therapeutic System) which is designed to provide a controlled rate of delivery of doxazosin into the gastrointestinal lumen.
Doxazosin, as mesilate (Alfadil XL) controlled release tablets contain doxazosin mesilate, which is a quinazoline compound with the chemical name I-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesilate is C₂₃H₂₅N₅O₅·CH₄O₃S and the molecular weight is 547.6.

Pharmacological Category: Alpha-1 Adrenoreceptor Antagonist.
Pharmacology: Pharmacodynamics: Benign Prostatic Hyperplasia: Administration of Doxazosin, as mesilate (Alfadil XL) to patients with symptomatic BPH results in a significant improvement in urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoceptors located in the muscular stroma and capsule of the prostate and in the bladder neck.
Doxazosin has been shown to be an effective blocker of the 1A subtype of the alpha-1-adrenoceptor, which accounts for over 70% of the subtypes in the prostate. This accounts for the action in BPH patients.
Doxazosin mesilate, as (Alfadil XL) has demonstrated sustained efficacy and safety in the long-term treatment of BPH.
Doxazosin mesilate, as (Alfadil XL) given in the recommended dosage regimen has little or no effect on blood pressure in normotensive patients.
In a controlled clinical BPH trial, treatment with doxazosin in patients with sexual dysfunction was associated with improvement in sexual function.
Pharmacokinetics: Absorption: After oral administration of therapeutic doses, Doxazosin, as mesilate (Alfadil XL) is well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one-third of those of the same dose of standard doxazosin tablets. Trough levels at 24 hours are, however, similar.
The pharmacokinetic characteristics of Doxazosin, as mesilate (Alfadil XL) will lead to a smoother plasma profile.
Peak/trough ratio of Doxazosin, as mesilate (Alfadil XL) is less than half that of standard doxazosin tablets.
At steady state, the relative bioavailability of doxazosin from doxazosin GITS compared to the standard form was 54% at the 4 mg dose and 59% at the 8 mg dose.
Pharmacokinetic studies with Doxazosin, as mesilate (Alfadil XL) in the elderly have shown no significant alterations compared to younger patients.
Biotransformation/Elimination: The plasma elimination is biphasic, with the terminal elimination half-life being 22 hours. This provides the basis for once-daily dosing. Doxazosin is extensively metabolized, with <5% excreted as unchanged drug.
Pharmacokinetic studies with standard doxazosin in patients with renal impairment have shown no significant alterations compared to patients with normal renal function.
There are only limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g., cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single-dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 40%. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution (see Precautions).
Approximately 98% of doxazosin is protein-bound in plasma.
Doxazosin is primarily metabolized by O-demethylation and hydroxylation.
Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.
Toxicology: Preclinical Safety Data: Carcinogenesis: Chronic dietary administration (up to 24 months) of doxazosin at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times the human AUC at a dose of 16 mg/day, respectively.
Mutagenesis: Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
Impairment of Fertility: Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 mg/kg/day (but not 5 or 10 mg/kg/day), about 4 times the human AUC at a dose of 12 mg/day. This effect was reversible within 2 weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Lactation: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-¹⁴C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.

Benign Prostatic Hyperplasia: Doxazosin, as mesilate (Alfadil XL) is indicated for the treatment of clinical symptoms in benign prostatic hyperplasia (BPH) and for reduced urinary flow associated with BPH. Doxazosin GITS may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are clinically insignificant, patients with hypertension and BPH have had both the conditions effectively treated with Doxazosin, as mesilate (Alfadil XL) monotherapy.

Doxazosin, as mesilate (Alfadil XL) can be taken with or without food.
Doxazosin, as mesilate (Alfadil XL) tablets should be swallowed whole with a sufficient amount of liquid. Patients should not chew, divide or crush the tablets (see Information for Patients under Precautions).
The optimal effect of doxazosin may take up to 4 weeks. If necessary, the dosage may be increased following this period to 8 mg once daily according to patient response.
The maximum recommended dose is 8 mg once daily.
Use in Elderly: Normal adult dosage is recommended.
Use in Renally Impaired Patients: Since the pharmacokinetics of doxazosin are unchanged in patients with renal insufficiency, and there is no evidence that doxazosin aggravates existing renal dysfunction, the usual dosages may be used in these patients.
Use in Hepatically Impaired Patients: See Precautions.
Use in Children: The safety and efficacy of doxazosin in children have not been established.

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head-down position. Other supportive measures should be performed if thought appropriate in individual cases. Since doxazosin is highly protein bound, dialysis is not indicated.

Doxazosin, as mesilate (Alfadil XL) is contraindicated in patients with a known hypersensitivity to quinazolines, doxazosin, or any of the inert ingredients such as polyethylene oxide, hypromellose, ferric oxide, magnesium stearate, sodium chloride, cellulose acetate, polyethylene glycol, Opadry white, and Opacode Black Ink.

Postural Hypotension/Syncope: As with all alpha-blockers, a very small percentage of patients have experienced postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope), particularly with the commencement of therapy. When instituting therapy with any effective alpha-blocker, the patient should be advised how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of doxazosin therapy.
Use with Phosphodiesterase Type-5 Inhibitors: Concomitant administration of doxazosin with a phosphodiesterase type-5 (PDE-5) inhibitor should be used with caution as it may lead to symptomatic hypotension in some patients. No studies have been conducted with Doxazosin, as mesilate (Alfadil XL).
Impaired Hepatic Function: As with any drug wholly metabolized by the liver, doxazosin should be administered with caution to patients with evidence of impaired hepatic function (see Pharmacology: Pharmacokinetics under Actions).
Gastrointestinal Disorders: Markedly reduced gastrointestinal (GI) retention times of doxazosin GITS may influence the pharmacokinetic profile and hence the clinical efficacy of the drug. As with any other non-deformable material, caution should be used when administering doxazosin, as mesilate (Alfadil XL) in patients with pre-existing severe GI narrowing (pathologic or iatrogenic).
There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained-release formulation.
Intraoperative Floppy Iris Syndrome: The 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 alpha-1 blockers. As IFIS may lead to increased procedural complications during the operation, current or past use of alpha-blockers should be made known to the ophthalmologic surgeon in advance of surgery.
Priapism: Prolonged erections and priapism have been reported with alpha-1 blockers including doxazosin in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
Information for Patients: Patients should be informed that Doxazosin, as mesilate (Alfadil XL) should be swallowed whole. Patients should not chew, divide or crush the tablets. Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. In Doxazosin, as mesilate (Alfadil XL), the medication is contained within a non-absorbable shell that has been specially designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Effects on Ability to Drive and Use Machines: The ability to engage in activities, such as operating machinery or operating a motor vehicle may be impaired, especially when initiating Doxazosin, as mesilate (Alfadil XL) therapy.

Although no teratogenic effects were seen in animal testing with doxazosin, reduced fetal survival was observed in animals at extremely high doses. These doses were approximately 300 times the maximum human recommended dose.
A single case report demonstrated transfer of doxazosin into human breast milk and animal studies have shown that doxazosin accumulates in breast milk (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
As there are no adequate and well-controlled studies in pregnant or nursing women, the safety of Doxazosin, as mesilate (Alfadil XL) during pregnancy or lactation has not yet been established. Accordingly, during pregnancy or lactation, doxazosin GITS should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.

The following lists the common (>1%) adverse events reported in pre-marketing placebo-controlled clinical trials with Doxazosin, as mesilate (Alfadil XL). It is important to emphasize that events reported during therapy may not necessarily be caused by the therapy.
Benign Prostatic Hyperplasia: Ear and Labyrinth Disorders: Vertigo.
General Disorders and Administration Site Conditions: Asthenia, peripheral edema.
Gastrointestinal Disorders: Abdominal pain, dyspepsia, nausea.
Infection and Infestations: Influenza-like symptoms, respiratory tract infection, urinary tract infection.
Musculoskeletal and Connective Tissue Disorders: Back pain, myalgia.
Nervous System Disorders: Dizziness, headache, somnolence.
Respiratory, Thoracic and Mediastinal Disorders: Bronchitis, dyspnea, rhinitis.
Vascular Disorders: Hypotension, postural hypotension.
The incidence of adverse events following treatment with Doxazosin, as mesilate (Alfadil XL) (41%) in clinical studies of patients with BPH was broadly similar to that following placebo (39%) and less than that following standard doxazosin (54%).
The adverse event profile in elderly (>65 years) BPH patients showed no difference from the profile in the younger population.
In post-marketing experience, the following additional adverse events have been reported: Blood and Lymphatic Disorders: Leukopenia, thrombocytopenia.
Ear and Labyrinth Disorders: Tinnitus.
Eye Disorders: Blurred vision, IFIS (Intraoperative Floppy Iris Syndrome) (see Precautions).
Gastrointestinal Disorders: Gastrointestinal obstruction, constipation, diarrhea, dyspepsia, flatulence, mouth dry, vomiting.
General Disorders and Administration Site Conditions: Fatigue, malaise, pain.
Hepatobiliary Disorders: Cholestasis, hepatitis, jaundice.
Immune System Disorders: Allergic reaction.
Investigations: Abnormal liver function tests, weight increase.
Metabolism and Nutrition: Anorexia.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle cramps, muscle weakness.
Nervous System Disorders: Dizziness postural, hypoesthesia, paresthesia, syncope, tremor.
Psychiatric Disorders: Agitation, anxiety, depression, insomnia, nervousness.
Renal and Urinary Disorders: Dysuria, hematuria, micturition disorder, micturition frequency, nocturia, polyuria, urinary incontinence.
Reproductive System and Breast Disorder: Gynecomastia, impotence, priapism, retrograde ejaculation.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm aggravated, coughing, dyspnea, epistaxis.
Skin/Appendages: Alopecia, pruritus, purpura, skin rash, urticaria.
Vascular Disorders: Hot flushes, hypotension.
The following additional adverse events have been reported in marketing experience among patients treated for hypertension but these, in general, are not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin: bradycardia, tachycardia, palpitation, chest pain, angina pectoris, myocardial infarction, cerebrovascular accidents, and cardiac arrhythmias.

Use with PDE-5 inhibitors: See Use with Phosphodiesterase Type-5 Inhibitors under Precautions.
CYP3A4 Inhibitors: In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering doxazosin with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole (see Pharmacology: Pharmacokinetics under Actions).
Other: Most (98%) of the plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. Doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs, uricosuric agents, or anticoagulants.

Store at temperatures not exceeding 30°C. Protect from moisture.

Drugs for Bladder & Prostate Disorders

G04CA - Alpha-adrenoreceptor antagonists ; Used in the treatment of benign prostatic hypertrophy.

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