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| Product NDC Code | 62135-053 | ||||
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| Drug Name | Doxazosin mesylate |
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| Type | Generic | ||||
| Pharm Class | Adrenergic alpha-Antagonists [MoA], alpha-Adrenergic Blocker [EPC] |
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| Route | ORAL | ||||
| Dosage Form | TABLET | ||||
| RxCUI drug identifier | 197625, 197626, 197627, 197628 |
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| Application Number | ANDA075646 | ||||
| Labeler Name | Chartwell RX, LLC | ||||
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Overdosage of Doxazosin mesylate
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Experience with doxazosin mesylate overdosage is limited. Two adolescents, who each intentionally ingested 40 mg doxazosin mesylate with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidently ingested 4 mg doxazosin mesylate 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 mesylate and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin mesylate (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg doxazosin mesylate, alcohol, and Dalmane ® (flurazepam) developed hypotension which responded to fluid therapy. The oral LD 50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The most commonly reported adverse reactions from clinical trials are Fatigue, malaise, hypotension, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Doxazosin mesylate Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension. ( 7.1 ) Concomitant administration of doxazosin mesylate with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. ( 7.2 )
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow. Hypertension The mechanism of action of doxazosin mesylate is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of doxazosin mesylate results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro .
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Benign Prostatic Hyperplasia (BPH) Administration of doxazosin mesylate to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate [ see Clinical Studies (14.1) ]. Effect on Normotensive Patients with Benign Prostatic Hyperplasia (BPH) Although blockade of alpha 1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin mesylate treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect (Table 4). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic blood pressure less than 60 mmHg at any time during treatment with doxazosin mesylate 1–8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%). Hypertension Administration of doxazosin mesylate results in a reduction in systemic vascular resistance. In patients with hypertension, there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2–6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha 1 -adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate occur at about 2–3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin mesylate was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration (C max ) and 12% in the area under the concentration-time curve (AUC) occurred when doxazosin mesylate was administered with food. Neither of these differences is clinically significant. In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The AUC after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 vs. 3.5 hours). Distribution At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins. Metabolism Doxazosin mesylate is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. 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 to a lesser extent. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. Excretion Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2 to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. Specific Populations Geriatric The pharmacokinetics of doxazosin mesylate in young (< 65 years) and elderly (≥65 years) subjects were similar for plasma half-life values and oral clearance. Renal Impairment Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Hepatic Impairment Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment on the pharmacokinetics of doxazosin is not known [ see Use in Specific Populations (8.6) ]. Drug Interactions There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine). Cimetidine: In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in mean C max and mean half-life of doxazosin. In vitro data in human plasma indicate that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS The use of doxazosin mesylate is contraindicated in patients with a hypersensitivity to doxazosin, other quinazolines (e.g., prazosin, terazosin), or any of its components. Hypersensitivity to doxazosin, other quinazolines, or any other ingredient in doxazosin mesylate tablets. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha-adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C 23 H 25 N 5 O 5 · CH 4 O 3 S and the molecular weight is 547.6. It has the following structure: Doxazosin mesylate is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. Doxazosin mesylate is available as colored tablets for oral use and contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg, and 8 mg of doxazosin as the free base. The inactive ingredients for all tablets are lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, and magnesium stearate. "Image Description"
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose may be titrated at 1 to 2-week intervals, up to 8 mg once daily. ( 2.2 ) For the treatment hypertension: Initiate therapy at 1 mg once daily. Dose may be titrated as needed, up to 16 mg once daily. ( 2.3 )
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Doxazosin Tablets, USP: 1 mg, 2 mg, 4 mg, or 8 mg. Each tablet contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg or 8 mg doxazosin (free base). Tablets: 1 mg, 2 mg, 4 mg, 8 mg.
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Doxazosin mesylate tablets are an alpha 1 adrenergic antagonist indicated for: ( 1 ) Signs and symptoms of Benign Prostatic Hyperplasia (BPH) Treatment of Hypertension
Spl product data elements
Usually a list of ingredients in a drug product.Doxazosin mesylate Doxazosin mesylate LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE DOXAZOSIN MESYLATE DOXAZOSIN white to off white C;E;105 Doxazosin mesylate Doxazosin mesylate LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE DOXAZOSIN MESYLATE DOXAZOSIN white to off white C;E;106 Doxazosin mesylate Doxazosin mesylate LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE DOXAZOSIN MESYLATE DOXAZOSIN white to off white C;E;107 Doxazosin mesylate Doxazosin mesylate LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE DOXAZOSIN MESYLATE DOXAZOSIN white to off white C;E;108
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and Pharmacology An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6–12 months) studies in rats and mice (exposure 8 times human AUC exposure in rats and somewhat equivalent to human C max exposure in mice). Findings were not seen at lower doses. In dogs no cardiotoxicity was observed following 12 months of oral dosing at doses that resulted in maximum plasma concentrations (C max ) 14 times the C max exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar rats at C max exposures 15 times human C max exposure. There is no evidence that similar lesions occur in humans.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis: Chronic dietary administration (up to 24 months) of doxazosin mesylate 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, respectively, the human AUC at a dose of 16 mg/day. Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels. Fertility in Males : Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Doxazosin Tablets, USP 1 mg - NDC 62135-051-90 - 90's Bottle Label Doxazosin Tablets, USP 2 mg - NDC 62135-052-90 - 90's Bottle Label Doxazosin Tablets, USP 4 mg - NDC 62135-053-90 - 90's Bottle Label Doxazosin Tablets, USP 8 mg - NDC 62135-054-90 - 90's Bottle Label Doxazosin Tablets, USP 1 mg - NDC 62135-051-90 - 90's Bottle Label Doxazosin Tablets, USP 2 mg - NDC 62135-052-90 - 90's Bottle Label Doxazosin Tablets, USP 4 mg - NDC 62135-053-90 - 90's Bottle Label Doxazosin Tablets, USP 8 mg - NDC 62135-054-90 - 90's Bottle Label
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.1.1 Benign Prostatic Hyperplasia (BPH) Doxazosin mesylate tablets are indicated for the treatment of the signs and symptoms of BPH.
1.2 Hypertension Doxazosin mesylate tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Doxazosin mesylate tablets may be used alone or in combination with other antihypertensives.
2.1 Dosing Information Following the initial dose and with each dose increase of doxazosin mesylate, monitor blood pressure for at least 6 hours following administration. If doxazosin mesylate administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.
2.2 Benign Prostatic Hyperplasia The recommended initial dosage of doxazosin mesylate is 1 mg given once daily either in the morning or evening. Depending on the individual patient's urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose for BPH is 8 mg once daily. Routinely monitor blood pressure in these patients.
2.3 Hypertension The initial dosage of doxazosin mesylate is 1 mg given once daily. Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.
5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin mesylate. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. Concomitant administration of doxazosin mesylate with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.
5.2 Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha 1 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 alpha 1 blocker therapy prior to cataract surgery.
5.3 Prostate Cancer Carcinoma of the prostate causes many of the 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 doxazosin mesylate for the treatment of BPH.
5.4 Priapism Alpha 1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). This condition can lead to permanent impotence if not promptly treated.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Benign Prostatic Hyperplasia (BPH) The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below (Table 2) are based on combined data from seven placebo-controlled trials involving once-daily administration of doxazosin mesylate in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. Adverse reactions occurring more than 1% more frequently in BPH patients treated with doxazosin mesylate vs placebo are summarized in Table 1. Table 1. Adverse Reactions Occurring more than 1% More Frequently in BPH Patients Treated with Doxazosin Mesylate Versus Placebo BODY SYSTEM Doxazosin Mesylate N=665 Placebo N=300 NERVOUS SYSTEM DISORDERS Dizziness* 15.6% 9.0% Somnolence 3.0% 1.0% CARDIAC DISORDERS Hypotension 1.7% 0% RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnoea 2.6% 0.3% GASTROINTESTINAL DISORDERS Dry Mouth 1.4% 0.3% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 8.0% 1.7% Oedema 2.7% 0.7% *Includes vertigo Other adverse reactions occurring less than 1% more frequently in BPH patients treated with doxazosin mesylate vs placebo but plausibly related to doxazosin mesylate include: palpitations. Hypertension Doxazosin mesylate has been administered to approximately 4000 hypertensive patients in clinical trials, of whom 1679 were included in the hypertension clinical development program. In placebo-controlled studies, adverse events occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. Adverse reactions occurring more than 1% more frequently in hypertensive patients treated with doxazosin mesylate vs placebo are summarized in Table 1. Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once-daily administration of doxazosin at doses ranging from 1 to 16 mg. Table 2. Adverse Reactions Occurring more than 1% More Frequently in Hypertensive Patients Treated with Doxazosin Mesylate versus Placebo BODY SYSTEM Doxazosin Mesylate N=339 Placebo N=336 NERVOUS SYSTEM DISORDERS Dizziness 19% 9% Somnolence 5% 1% RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Rhinitis 3% 1% RENAL AND URINARY DISORDERS Polyuria 2% 0% REPRODUCTIVE SYSTEM AND BREAST DISORDERS GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue / Malaise 12% 6% Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with doxazosin mesylate vs placebo but plausibly related to doxazosin mesylate use include vertigo, hypotension, hot flushes, epistaxis and oedema. Doxazosin mesylate has been associated with decreases in white blood cell counts Laboratory changes observed in clinical studies Leukopenia/Neutropenia: Decreases in mean white blood cell (WBC) and mean neutrophil count were observed in controlled clinical trials of hypertensive patients receiving doxazosin mesylate. In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of doxazosin mesylate. No patients became symptomatic as a result of the low WBC or neutrophil counts.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxazosin mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In post-marketing experience, the following additional adverse reactions have been reported: Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia; Immune System Disorders: allergic reaction; Nervous System Disorders: hypoesthesia; Eye Disorders: Intraoperative Floppy Iris Syndrome [ see Warnings and precautions (5.4) ]; Cardiac Disorders: bradycardia; Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated; Gastrointestinal Disorders: vomiting; Hepatobiliary Disorders: cholestasis, hepatitis cholestatic; Skin and Subcutaneous Tissue Disorders: urticaria; Musculoskeletal and Connective Tissue Disorders: muscle cramps, muscle weakness; Renal and Urinary Disorders: hematuria, micturition disorder, micturition frequency, nocturia; Reproductive System and Breast Disorders: gynecomastia, priapism.
7.1. CYP 3A Inhibitors In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Strong CYP3A inhibitors may increase exposure to doxazosin. Monitor blood pressure and for symptoms of hypotension when doxazosin mesylate is used concomitantly with strong CYP3A inhibitors [ see Clinical Pharmacology (12.3) ].
7.2 Phosphodiesterase-5 (PDE-5) inhibitors Concomitant administration of doxazosin mesylate with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Monitor blood pressure and for symptoms of hypotension [ see Warnings and Precautions (5.1) ].
8.2 Lactation Risk Summary There is limited information on the presence of doxazosin mesylate in human milk [see Data ]. There is no information on the effects of doxazosin mesylate on the breastfeed infant or the effects on milk production. Data A single case study reports that doxazosin mesylate is present in human milk, which resulted in an infant dose of less than 1% of the maternal weight-adjusted dosage and a milk/plasma ratio of 0.1. However, these data are insufficient to confirm the presence of doxazosin mesylate in human milk.
8.6 Hepatic Impairment Doxazosin mesylate is extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to doxazosin. Use of doxazosin mesylate in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Monitor blood pressure and for symptoms of hypotension in patients with lesser degrees of hepatic impairment (Child-Pugh Class A and B) [ see Clinical Pharmacology (12.3) ].
14.1 Benign Prostatic Hyperplasia (BPH) The efficacy of doxazosin mesylate was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin mesylate treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosin mesylate was seen as early as one week into the treatment regimen, with doxazosin mesylate-treated patients (N=173) showing a significant (p<0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N=41). In long-term studies, improvement was maintained for up to 2 years of treatment. In 66–71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate. In three placebo-controlled studies of 14–16 weeks' duration, obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2–6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin mesylate. The results from the three placebo-controlled studies (N=609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in Table 3. In all three studies, doxazosin mesylate resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3–3.3 mL/sec in maximum flow rate were seen with doxazosin mesylate in Studies 1 and 2, compared to 0.1–0.7 mL/sec with placebo. Table 3 In one fixed-dose study (Study 2), doxazosin mesylate therapy (4 to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3–3.3 mL/sec (Table 3) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin mesylate vs. placebo was seen after one week. The proportion of patients who responded with a maximum flow rate improvement of ≥3 mL/sec was significantly larger with doxazosin mesylate (34–42%) than placebo (13–17%). A significantly greater improvement was also seen in average flow rate with doxazosin mesylate (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated in Figure 1. Figure 1 – Study 1 "Image Description" "Image Description"
14.2 Hypertension In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1–6 hours) were larger by about 50–75% (i.e., trough values were about 55–70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65. In the same patient population, patients receiving doxazosin mesylate gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients. TABLE 4 Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensives (Diastolic BP < 90 mmHg) in Two Double-blind, Placebo-controlled U.S. Studies with Doxazosin Mesylate 1 to 8 mg once daily. PLACEBO (N=85) Doxazosin Mesylate (N=183) Sitting BP (mmHg) Baseline Change Baseline Change Systolic 128.4 –1.4 128.8 –4.9* Diastolic 79.2 –1.2 79.6 –2.4* Standing BP (mmHg) Baseline Change Baseline Change Systolic 128.5 –0.6 128.5 –5.3* Diastolic 80.5 –0.7 80.4 –2.6* *p ≤0.05 compared to placebo
Doxazosin mesylate: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Postural Hypotension Advise patients of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. Advise patients to report symptoms to their healthcare provider. Priapism Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur. This product's label may have been updated. For full prescribing information, please visit www.chartwellpharma.com. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Chartwell RX, LLC. Manufactured for: Chartwell RX, LLC. Congers, NY 10920 L71479 Revised 05/2023 Print Patient Information at: www.chartwellpharma.com/our-products/
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.PATIENT INFORMATION Doxazosin Tablets, USP (dox-AY-zoe-sin) What are Doxazosin Tablets? Doxazosin tablets are a prescription medicine that contain doxazosin mesylate and is called an "alpha-blocker". Doxazosin tablets are used to treat: the symptoms of benign prostatic hyperplasia (BPH) high blood pressure (hypertension) It is not known if doxazosin tablets is safe and effective in children. Who should not take doxazosin tablets? Do not take doxazosin mesylate if you : are allergic to doxazosin, other quinazolines, or any of the ingredients in doxazosin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in doxazosin tablets. What should I tell my healthcare provider before taking doxazosin tablets? Before taking doxazosin tablets, tell your healthcare provider about all of your medical conditions, including if you : have had low blood pressure, especially after taking other medicine. Signs of low blood pressure include fainting, dizziness, and lightheadedness. have any planned eye surgery have prostate cancer or a history of prostate cancer. Your healthcare provider may have you checked for prostate cancer before you start taking and while you take doxazosin tablets. have liver problems are pregnant or plan to become pregnant. It is not known if doxazosin tablets will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if doxazosin tablets passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby if you take doxazosin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Doxazosin tablets may affect the way other medicines work, and other medicines may affect the way doxazosin tablets works causing side effects. Especially tell your healthcare provider if you take: other medicine for high blood pressure or medicine to treat erectile dysfunction (ED) called a phosphodiesterase type 5 (PDE-5) inhibitor. The use of doxazosin tablets with PDE-5 inhibitors can lead to a drop in blood pressure or to fainting. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take doxazosin tablets? Take doxazosin tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much doxazosin tablets to take and when to take it. Your healthcare provider may need to change your dose of doxazosin tablets until it is the right dose for you. What should I avoid while taking doxazosin tablets? Do not drive or perform any hazardous task until at least 24 hours after you have taken doxazosin tablets if you are taking: your first dose of doxazosin tablets doxazosin tablets for the first time after your healthcare provider has increased your dose of doxazosin tablets doxazosin tablets for the first time after any breaks (interruptions) in your treatment with doxazosin tablets What are the possible side effects of doxazosin tablets? Doxazosin tablets may cause serious side effects, including : A sudden drop in blood pressure , especially when you first start treatment or when there is an increase in your dose of doxazosin tablets, is common but can also be serious. This may cause you to faint, or to feel dizzy or lightheaded. Your risk of having this problem may be increased if you take doxazosin tablets with certain other medicines that lower blood pressure including PDE-5 inhibitors. Your healthcare provider may monitor your blood pressure while you take doxazosin tablets. See " What should I avoid while taking doxazosin tablets? " Eye problems during cataract surgery . A condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen during cataract surgery if you take or have taken alpha-blockers such as doxazosin tablets. If you need to have cataract surgery, be sure to tell your healthcare provider if you take or have taken doxazosin tablets . A painful erection that will not go away . Doxazosin tablets can cause a painful erection (priapism), which cannot be relieved by having sex. If this happens, get medical help right away. If priapism is not treated, you may not be able to get an erection in the future. The most common side effects of doxazosin tablets are: weakness or lack of energy (asthenia) dizziness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of doxazosin tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of doxazosin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use doxazosin tablets for a condition for which it was not prescribed. Do not give doxazosin tablets to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about doxazosin tablets. For more information, ask your healthcare provider. You can ask your healthcare provider or pharmacist for information that is written for healthcare professionals. What are the ingredients in doxazosin tablets? The size, shape and appearance of the tablet that you receive may vary, all the tablets have the same active ingredient, and this will not affect the way that the medicine works. You can identify the tablet that you have from the following information. Strength 1 mg Tablet White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "105" on the other side. 2 mg Tablet White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "106" on the other side. 4 mg Tablet White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "107" on the other side. 8 mg Tablet White to off-white, round scored tablets, debossed with "C" over bisect "E" on one side and "108" on the other side. Active ingredient: doxazosin mesylate Inactive ingredients: Lactose Monohydrate, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Sodium Starch Glycolate, Magnesium Stearate Manufactured for: Chartwell RX, LLC. Congers, NY 10920 For more information, go to www.chartwellpharma.com. or call 1-845-232-1683 L71480 Revised 05/2023
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Benign Prostatic Hyperplasia (BPH) The safety and effectiveness profile of doxazosin mesylate was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients. Hypertension Clinical studies of doxazosin mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of doxazosin mesylate have not been established in children.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary The limited available data with doxazosin mesylate in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical Considerations ] . In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 and 20 mg/kg, respectively (exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose). A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Data Animal Data Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats. Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental effects. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Monitor for hypotension. ( 8.6 , 12.3 )
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Doxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg, or 8 mg of doxazosin as the free base. NDC and Pack Size Strength Description NDC 62135-051-90 (Bottle of 90) 1 mg White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "105" on the other side. NDC 62135-052-90 (Bottle of 90) 2 mg White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "106" on the other side. NDC 62135-053-90 (Bottle of 90) 4 mg White to off-white, round scored tablets, debossed with "C" over bisect" E" on one side and "107" on the other side. NDC 62135-054-90 (Bottle of 90) 8 mg White to off-white, round scored tablets, debossed with "C" over bisect "E" on one side and "108" on the other side. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store in a dry place. Keep tightly closed. Avoid excessive heat. Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required. Keep this and all medication out of the reach of children.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API