Drug: Cardura XL

CARDURA® XL (doxazosin mesylate extended release tablets) contains doxazosin mesylate which is a quinazoline compound with the chemical name 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5 •CH4O3S and the molecular weight is 547.6. It has the following structure: CARDURA XL (doxazosin mesylate extended release tablets) is an extended release tablet for oral use and is designed to deliver 4 or 8 mg of doxazosin as the free base. Each 4 and 8 mg tablet contains 5.1 and 10.2 mg doxazosin mesylate (includes a 5% overage) to provide 4 and 8 mg doxazosin as a free base, respectively. The inactive ingredients for CARDURA XL are: polyethylene oxide, sodium chloride, hypromellose, red ferric oxide, titanium dioxide, magnesium stearate, cellulose acetate, Macrogol®, pharmaceutical glaze, and black iron oxide. CARDURA XL (doxazosin mesylate extended release tablets) System Components and Performance CARDURA XL (doxazosin mesylate extended release tablets) is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet. CARDURA XL (doxazosin mesylate extended release tablets) utilizes GITS (Gastrointestinal Therapeutic System) which is designed to provide a controlled rate of delivery of doxazosin into the gastrointestinal lumen which is independent of pH or gastrointestinal (GI) motility. The function of CARDURA XL (doxazosin mesylate extended release tablets) depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell.

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The incidence of adverse events was derived from two controlled efficacy and safety trials involving 1473 BPH patients. In Study 1, CARDURA XL (doxazosin mesylate extended release tablets) (n=317) was compared to doxazosin IR tablets (n=322) and to placebo (n=156). In Study 2, CARDURA XL (doxazosin mesylate extended release tablets) (n=350) was compared just to doxazosin IR tablets (n=330). In both these studies, CARDURA XL (doxazosin mesylate extended release tablets) was initiated at a dose of 4 mg, which could be increased by the investigator to 8 mg after seven weeks if an adequate response was not seen (see CLINICAL PHARMACOLOGY; Clinical Studies). Similarly, doxazosin IR was begun at a dose of 1 mg, which was increased in all patients to 2 mg after 1 week, followed by the option to increase to 4 mg after 4 weeks, and 8 mg after 7 weeks. In these two studies, 6% of patients receiving CARDURA XL (doxazosin mesylate extended release tablets) withdrew from the study due to adverse events, compared to 7% receiving doxazosin IR, and 3% receiving placebo. The most commonly reported adverse events leading to discontinuation in the CARDURA XL (doxazosin mesylate extended release tablets) group were: dizziness, dyspnea, asthenia, headache, hypotension, postural hypotension, and somnolence. The incidence rates presented below (Table 4) are based on combined data from the two controlled studies (Studies 1 and 2). Adverse events with an incidence in the CARDURA XL (doxazosin mesylate extended release tablets) group of at least 1% and reported more frequently than with placebo are summarized in Table 4. TABLE 4 :Treatment-Emergent Adverse Events Occurring in ≥ 1% of BPH Patients Treated with CARDURA XL (doxazosin mesylate extended release tablets) and Reported More Frequently Than with Placebo in the Two Controlled Clinical Studies
Body System CARDURA XL
(N = 666) Doxazosin IR
(N = 651) Placebo
(N = 156) BODY AS A WHOLE   Abdominal Pain 1.8% 2.3% 0.6%   Asthenia 3.9% 6.9% 1.3%   Back Pain 2.9% 1.7% 2.6%   Headache 6.0% 5.1% 4.5% CARDIOVASCULAR   Hypotension 1.7% 1.8% 0.0%   Postural Hypotension 1.2% 2.2% 0.6% DIGESTIVE   Dyspepsia 1.4% 1.2% 0.0%   Nausea 1.2% 2.3% 0.6% MUSCULOSKELETAL   Myalgia 1.4% 0.5% 0.0% NERVOUS   Dizziness 5.3% 9.1% 1.9%   Somnolence 1.5% 1.2% 0.0%   Vertigo 1.5% 4.1% 0.6% RESPIRATORY   Dyspnea 1.2% 1.2% 0.0%   Respiratory Tract Infection 4.8% 4.5% 1.9% UROGENITAL   Urinary Tract Infection 1.4% 0.8% 0.6% Additional adverse events reported with CARDURA XL (doxazosin mesylate extended release tablets) at an incidence of less than 1% and those of clinical interest include: Cardiovascular System: angina pectoris, syncope, tachycardia, chest pain, palpitations; Digestive System: diarrhea; Musculoskeletal System: arthralgia; Nervous System: libido decreased; Urogenital System: impotence, dysuria. Of these, the following events were reported more frequently with CARDURA XL (doxazosin mesylate extended release tablets) than with placebo: syncope, tachycardia, palpitations, and dysuria. In general, the adverse events reported in the open-label safety extension, in approximately 295 BPH patients treated for up to 37 weeks, were similar in type and frequency to the events described above in the 13-week controlled trials. In post-marketing experience, the following additional adverse reactions have been reported with doxazosin IR: Autonomic Nervous System: priapism; Cardiovascular System: cerebrovascular accidents, dizziness postural, myocardial infarction; Central and Peripheral Nervous System: hypoesthesia, paresthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: fatigue, hot flushes, malaise; Heart Rate/Rhythm: bradycardia, cardiac arrhythmias; Hematopoietic: leukopenia, purpura, thrombocytopenia; Liver/Biliary System: abnormal liver function tests, hepatitis, hepatitis cholestatic, jaundice; Musculoskeletal System: muscle cramps, muscle weakness; Psychiatric: agitation, anorexia, nervousness; Respiratory System: bronchospasm aggravated; Skin Disorders: alopecia, urticaria; Special Senses: blurred vision, Intraoperative Floppy Iris Syndrome (see PRECAUTIONS, Cataract Surgery); Urinary System: hematuria, micturition disorder, micturition frequency, nocturia, polyuria. There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain. Read the Cardura XL (doxazosin mesylate extended release tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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The initial dose of CARDURA XL (doxazosin mesylate extended release tablets) , 4 mg given once daily, should be administered with breakfast. Depending on the patient's symptomatic response and tolerability, the dose may be increased to 8 mg, the maximum recommended dose. The recommended titration interval is 3–4 weeks. If CARDURA XL (doxazosin mesylate extended release tablets) administration is discontinued for several days, therapy should be restarted using the 4 mg once daily dose. Tablets should be swallowed whole, and must not be chewed, divided, cut, or crushed. If switching from CARDURA to CARDURA XL (doxazosin mesylate extended release tablets) , therapy should be initiated with the lowest dose (4 mg once daily). Prior to starting therapy with CARDURA XL (doxazosin mesylate extended release tablets) , the final evening dose of CARDURA should not be taken. Concomitant administration of CARDURA XL (doxazosin mesylate extended release tablets) with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking CARDURA XL.

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No in vivo drug interaction studies were conducted with CARDURA XL (see CLINICAL PHARMACOLOGY; Drug-Drug Interactions). In vitro studies suggest that doxazosin is a substrate of CYP3A4. Caution should be exercised when concomitantly administering a potent 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole with CARDURA XL (doxazosin mesylate extended release tablets) . Pharmacodynamic interactions between CARDURA XL and anti-hypertensive medications or other vasodilating agents have also not been determined. Concomitant administration of CARDURA XL (doxazosin mesylate extended release tablets) with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION). Patients with Coronary Insufficiency Patients with congestive heart failure, angina pectoris, or acute myocardial infarction within the last 6 months were excluded from the Phase 3 studies. If symptoms of angina pectoris should newly appear or worsen, CARDURA XL (doxazosin mesylate extended release tablets) should be discontinued. Drug/Laboratory Test Interactions Doxazosin mesylate does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. No clinically significant abnormalities in white blood cell (WBC) counts were reported in patients treated with CARDURA XL (doxazosin mesylate extended release tablets) in controlled clinical BPH trials. In previous studies of doxazosin IR in BPH patients, the incidence of clinically significant decreases in WBC counts was 0.4% in patients treated with doxazosin IR and 0% in patients treated with placebo. There was no statistically significant difference between these two groups.Read the Cardura XL Drug Interactions Center for a complete guide to possible interactions Learn More »

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CARDURA XL (doxazosin mesylate extended release tablets) is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). CARDURA XL (doxazosin mesylate extended release tablets) is not indicated for the treatment of hypertension.

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CARDURA XL (doxazosin mesylate extended release tablets) is contraindicated in patients with a known sensitivity to doxazosin, other quinazolines (e.g., prazosin, terazosin), or any of the inert ingredients.Last reviewed on RxList: 4/1/2010
This monograph has been modified to include the generic and brand name in many instances.

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There is no experience with CARDURA XL (doxazosin mesylate extended release tablets) overdosage. Overdosage experience with the doxazosin IR is limited. Two adolescents who each intentionally ingested 40 mg doxazosin IR with diclofenac or paracetamol were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidentally ingested 4 mg doxazosin IR was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin IR and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin IR (blood level 0.9 μg/mL; normal values in hypertensives=0.02 μg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg doxazosin IR, alcohol, and Dalmane® (flurazepam) developed hypotension which responded to fluid therapy. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid, keeping the patient in the supine position, and in certain circumstances, the administration of vasopressors. As doxazosin is highly protein bound, dialysis would not be indicated.

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CARDURA® XL (doxazosin mesylate extended release tablets) is available as 4 mg (white, imprinted with CXL 4) and 8 mg (white, imprinted with CXL 8) tablets. Bottle of 30: 4 mg (NDC 0049-2710-30)
Bottle of 30: 8 mg (NDC 0049-2720-30) Recommended Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Distributed by: Roerig, Division of Pfizer Inc, NY, NY 10017. Revised July 2009Last reviewed on RxList: 4/1/2010
This monograph has been modified to include the generic and brand name in many instances.

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General Prostate Cancer Carcinoma of the prostate causes many of the same symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with CARDURA XL. Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery. Gastrointestinal Disorders As with any other non-deformable material, caution should be used when administering CARDURA XL to patients with preexisting severe gastrointestinal 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 extended release formulation. Markedly increased GI retention times, as may occur in patients with chronic constipation, can increase systemic exposure to doxazosin and thereby potentially increase adverse reactions. Patients with Hepatic Impairment CARDURA XL should be administered with caution to patients with evidence of mild or moderate hepatic dysfunction (see CLINICAL PHARMACOLOGY; Pharmacokinetics in Special Populations). Since there is no clinical experience in patients with severe hepatic dysfunction, use in these patients is not recommended. Cardiac Toxicity in Animals Studies in Sprague-Dawley rats after 6, 12, and 18 months, and in CD-1 mice after 18 months of dietary administration, showed an increased incidence of myocardial necrosis or fibrosis at doxazosin base exposure of 26-fold above the human exposure (AUC) at the maximum human recommended dose (MHRD) of 8 mg CARDURA XL. No cardiotoxicity was observed in dogs or Wistar rats after 12 months of oral dosing at doxazosin base exposures of 65- and 85-fold, respectively, above the human exposure (Cmax) at the MHRD of 8 mg CARDURA XL. There is no evidence that similar lesions occur in humans. Carcinogenesis and Mutagenesis Doxazosin mesylate was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 40 mg/kg/day or 120 mg/kg/day, respectively. Systemic drug exposures, as measured by AUC, were approximately 34-fold in rats and 16-fold in mice above the exposures at the MHRD of 8 mg CARDURA XL. Doxazosin base was not mutagenic in the in vitro bacterial Ames assays, the chromosomal aberration assay in human lymphocytes, or the mouse lymphoma assay. Doxazosin was not clastogenic in the in vivo mouse micronucleus assay. Doxazosin mesylate has not been evaluated for genotoxicity. Fertility in Males Studies in rats after oral administration of doxazosin base showed reduced fertility in males, which was reversible after two weeks of treatment termination at doxazosin base exposure of 13fold above the human exposure (AUC) at the MHRD of 8 mg CARDURA XL. There have been no reports of any effects of doxazosin on male fertility in humans. Pregnancy Teratogenic Effects Pregnancy Category C. CARDURA XL is not indicated for use in women. There was no evidence of teratogenicity or embryotoxicity in rat or rabbit fetuses that received up to 20 mg/kg/day or 41 mg/kg/day doxazosin base, respectively, administered during major organ development. Plasma exposure at these doses is approximately 32- and 13-fold, respectively, above the AUC values for doxazosin base in humans given the MHRD of 8 mg CARDURA XL. Embryolethality was observed in rabbits at a dose of 100 mg/kg/day of doxazosin mesylate when administered during major organ development. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CARDURA XL should be used during pregnancy only if clearly needed. Doxazosin base was found to cross the placenta following oral administration to pregnant rats, resulting in fetal exposure. Nonteratogenic Effects In pre- and postnatal development studies in rats, postnatal development was delayed as evidenced by body weight gain suppression and a slight delay in the appearance of developmental anatomical landmarks and reflexes at a doxazosin base exposure of 26-fold above the human exposure (AUC) at the MHRD of 8 mg CARDURA XL. Nursing Mothers CARDURA XL is not indicated for use in women. Doxazosin base was secreted into the milk in lactating rats at concentrations approximately 20-fold above the exposure found in the maternal plasma following an oral dose of 1 mg/kg. It is not known if doxazosin is excreted in human breast milk. Use of CARDURA XL in nursing mothers is not recommended. Pediatric Use The safety and effectiveness of CARDURA XL in pediatric patients have not been established. Geriatric Use Of the 666 patients with BPH who received CARDURA XL in the two controlled clinical efficacy and safety studies, 325 patients (49%) were 65 years of age or older. One hundred thirty-six patients treated with CARDURA XL (20%) were > 70 years of age. In these two studies, the cumulative incidence of hypotension appeared to be age related. The reason for an increased incidence of hypotension in patients older than 70 years of age may be related to a modest increase in systemic exposure to doxazosin (see CLINICAL PHARMACOLOGY; Pharmacokinetics in Special Populations), to an increased propensity to orthostasis in the elderly, or to an enhanced sensitivity to vasodilatory agents in the elderly. The incidence of hypotension reported as an adverse event was higher in patients 70 years of age and older (4/136; 2.9%) as compared to patients < 70 years of age (7/530; 1.3%).Last reviewed on RxList: 4/1/2010
This monograph has been modified to include the generic and brand name in many instances.

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