DOXAZOSIN MESYLATE- doxazosin mesylate tablet 
REMEDYREPACK INC.

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DESCRIPTION

DESCRIPTIONDoxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha1 subtype of alpha adrenergic receptors. Thechemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazinemethanesulfonate. The molecular formula for doxazosin mesylate is C23H25N5O5 225 CH4O3S and the molecular weight is 547.6. It hasthe following structure: Doxazosin mesylate is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, andwater (0.8% at 25260C), and very slightly soluble in acetone and methylene chloride.Doxazosin Tablets, USP for oral administration, contain 1 mg, 2 mg, 4 mg or 8 mg of doxazosin as doxazosin mesylate. In addition,each tablet also contains the following

INACTIVE INGREDIENT

inactive ingredients: anhydrous lactose, colloidal silicon, magnesium stearate, microcrystallinecellulose, sodium lauryl sulfate and sodium starch glycolate. The 2 mg tablets also contain D&C Red No. 30 Aluminum Lake, the 4mg tablets contain FD&C Blue No. 2 Aluminum Lake, and the 8 mg tablets contain D&C Red No. 30 Aluminum Lake and FD&CBlue No. 2 Aluminum Lake.

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

PharmacodynamicsBenign Prostatic Hyperplasia (BPH)Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead tourinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rateassociated with BPH. The static component is related to an increase in prostate size caused, in part, by a proliferation of smoothmuscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlatewell with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostateand bladder neck. The degree of tone in this area is mediated by the alpha1 adrenoceptor, which is present in high density in theprostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve theobstruction and BPH symptoms. In the human prostate, doxazosin antagonizes phenylephrine (alpha1 agonist)-induced contractions,invitro, and binds with high affinity to the alpha1c adrenoceptor. The receptor subtype is thought to be the predominant functional typein the prostate. Doxazosin acts within 1 to 2 weeks to decrease the severity of BPH symptoms and improve urinary flow rate. Sincealpha1 adrenoceptors are of low density in the urinary bladder (apart from the bladder neck), doxazosin should maintain bladdercontractility.The efficacy of doxazosin was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials.Doxazosin treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosinwas seen as early as one week into the treatment regimen, with doxazosin 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-termstudies improvement was maintained for up to 2 years of treatment. In 66 to 71% of patients, improvements above baseline were seenin both symptoms and maximum urinary flow rate.In three placebo-controlled studies of 14 to 16 weeks duration obstructive symptoms (hesitation, intermittency, dribbling, weakurinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPHwere evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with amodified 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 to 6 hours post-dose) and/or trough (24 hourspost-dose) plasma concentrations of doxazosin.The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg doxazosin aresummarized in Table 1. In all three studies, doxazosin resulted in statistically significant relief of obstructive and irritative symptoms page 2 of 12 compared to placebo. Statistically significant improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin inStudies 1 and 2, compared to 0.1 to 0.7 mL/sec with placebo.TABLE 1 SUMMARY OF EFFECTIVENESS DATA IN PLACEBO-CONTROLLED TRIALS In one fixed dose study (Study 2) doxazosin therapy (4 to 8 mg, once daily) resulted in a significant and sustained improvement inmaximum urinary flow rate of 2.3 to 3.3 mL/sec (Table 1) compared to placebo (0.1 mL/sec). In this study, the only study in whichweekly evaluations were made, significant improvement with doxazosin vs. placebo was seen after one week. The proportion ofpatients who responded with a maximum flow rate improvement of 263 3 mL/sec was significantly larger with doxazosin (34 to 42%)than placebo (13 to 17%). A significantly greater improvement was also seen in average flow rate with doxazosin (1.6 mL/sec) thanwith placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated inFigure 1. *p < 0.05 Compared to Placebo;+p < 0.05 Compared to Baseline; Doxazosin Titration to Maximum of 8 mg.In BPH patients (N = 450) treated for up to 2 years in open-label studies, doxazosin therapy resulted in significant improvement abovebaseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin were maintained over the entire treatmentperiod.Although blockade of alpha1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascularresistance, doxazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect(Table 2). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic bloodpressure less than 60 mmHg at any time during treatment with doxazosin 1 to 8 mg once daily was 6.7% with doxazosin and notsignificantly different (statistically) from that with placebo (5%).TABLE 2 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 1 to 8 mg once daily. PLACEBO (N=85) DOXAZOSIN (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 243 0.05 compared to placeboHypertensionThe

MECHANISM OF ACTION

mechanism of action of doxazosin mesylate is selective blockade of the alpha1 (postjunctional) subtype of adrenergic receptors.Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine(an alpha1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize page 3 of 12 phenylephrine. The antihypertensive effect of doxazosin results from a decrease in systemic vascular resistance. The parent compounddoxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactivemetabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicatethat the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probablysmall. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 mcM, in vitro.Administration of doxazosin results in a reduction in systemic vascular resistance. In patients with hypertension there is little changein cardiac output. Maximum reductions in blood pressure usually occur 2 to 6 hours after dosing and are associated with a smallincrease in standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a greater effect on blood pressure andheart rate in the standing position.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 standingposition and about 9/5 mmHg in the supine position. Peak blood pressure effects (1 to 6 hours) were larger by about 50 to 75%(i.e., trough values were about 55 to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures. Therewas no apparent difference in the blood pressure response of caucasians and blacks or of patients above and below age 65. In thesepredominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2 to 3%), LDLcholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings isuncertain. In the same patient population, patients receiving doxazosin gained a mean of 0.6 kg compared to a mean loss of 0.1 kg forplacebo patients.

PHARMACOKINETICS

PharmacokineticsAfter oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate occur at about 2 to 3 hours. Bioavailabilityis approximately 65%, reflecting first pass metabolism of doxazosin by the liver. The effect of food on the pharmacokineticsof doxazosin was examined in a crossover study with 12 hypertensive subjects. Reductions of 18% in mean maximum plasmaconcentration and 12% in the area under the concentration-time curve occurred when doxazosin was administered with food. Neitherof these differences was statistically or clinically significant.Doxazosin is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation ofthe benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of thesemetabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mgintravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was foundin 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 radioactivityin the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses approximately 98% of thecirculating drug is bound to plasma proteins.Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies inhypertensive 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 1.2and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar withmorning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after eveningdosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs.3.5 hr).The pharmacokinetics of doxazosin in young (< 65 years) and elderly (263 65 years) subjects were similar for plasma half-life values andoral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterationscompared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-PughClass A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence thehepatic metabolism of doxazosin [e.g., cimetidine (see

PRECAUTIONS

PRECAUTIONS)]. As with any drug wholly metabolized by the liver, use ofdoxazosin in patients with altered liver function should be undertaken with caution.In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in themorning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin were similarin the two populations. Linear kinetics and dose proportionality were observed.INDICATIONS AND USAGEBenign Prostatic Hyperplasia (BPH)Doxazosin tablets are indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptomsassociated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of thebladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin may be used in all BPH patients whetherhypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with doxazosinmonotherapy. Doxazosin provides rapid improvement in symptoms and urinary flow rate in 66 to 71% of patients. Sustained page 4 of 12 improvements with doxazosin were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-labelstudies.HypertensionDoxazosin tablets are also indicated for the treatment of hypertension. Doxazosin may be used alone or in combination with diuretics,beta-adrenergic blocking agents, calcium channel blockers or angiotensin-converting enzyme inhibitors.

CONTRAINDICATIONS

CONTRAINDICATIONSDoxazosin tablets are contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or anyof the inert ingredients.

WARNINGS

WARNINGSSyncope and "First-dose" EffectDoxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position,with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dosebut can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease thelikelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATIONsection) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agentsshould be added with caution.Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur,during both the day and night.In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginningat 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. Inanother study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjectsexperienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. Inthis study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosindosing at 1 mg/day resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope.In multiple dose clinical trials in hypertension involving over 1,500 hypertensive patients with dose titration every one to two weeks,syncope was reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16mg/day.In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients weretaking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extensionfollow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient wastaking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mgexperienced syncope.If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.PriapismRarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin, have beenassociated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Becausethis condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition(see PRECAUTIONS:

INFORMATION FOR PATIENTS

Information for Patients).PRECAUTIONSGeneralProstate CancerCarcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma ofthe prostate should therefore be ruled out prior to commencing therapy with doxazosin.Cataract SurgeryIntraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated withalpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in responseto 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 possiblemodifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There doesnot appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery. page 5 of 12 Orthostatic HypotensionWhile syncope is the most severe orthostatic effect of doxazosin, other symptoms of lowered blood pressure, such as dizziness,lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases.HypertensionThese symptoms were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and causingdiscontinuation of therapy in about 2%.In placebo-controlled titration trials in hypertension, orthostatic effects were minimized by beginning therapy at 1 mg per day andtitrating every two weeks to 2, 4, or 8 mg per day. There was an increased frequency of orthostatic effects in patients given 8 mg ormore, 10%, compared to 5% at 1 to 4 mg and 3% in the placebo group.Benign Prostatic HyperplasiaIn placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin was 0.3% and did not increase withincreasing dosage (to 8 mg/day). The incidence of discontinuations due to hypotensive or orthostatic symptoms was 3.3% withdoxazosin and 1% with placebo. The titration interval in these studies was one to two weeks.Patients in occupations in which orthostatic hypotension could be dangerous should be treated with particular caution. As alpha1antagonists can cause orthostatic effects, it is important to evaluate standing blood pressure two minutes after standing and patientsshould be advised to exercise care when arising from a supine or sitting position.If hypotension occurs, the patient should be placed in the supine position and, if this measure is inadequate, volume expansion withintravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses ofdoxazosin.Information for Patients(See Patient Leaflet)Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, andurged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapywhen treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur duringinitiation of doxazosin therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressureoccur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness,lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered.Patients should also be told that drowsiness or somnolence can occur with doxazosin or any selective alpha1 adrenoceptor antagonist,requiring caution in people who must drive or operate heavy machinery.Patients should be advised about the possibility of priapism as a result of treatment with alpha1 antagonists. Patients should knowthat this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treatedpromptly it can lead to permanent erectile dysfunction (impotence).Drug/Laboratory Test InteractionsDoxazosin does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin,an alpha1 inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically metabolized. There is nodefinitive controlled clinical experience on the concomitant use of alpha1 inhibitors and 5-alpha reductase inhibitors at this time.Impaired Liver FunctionDoxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugsknown to influence hepatic metabolism (see CLINICAL PHARMACOLOGY).Leukopenia/NeutropeniaAnalysis of hematologic data from hypertensive patients receiving doxazosin in controlled hypertension clinical trials showed that themean WBC (N = 474) and mean neutrophil counts (N = 419) were decreased by 2.4% and 1%, respectively, compared to placebo, aphenomenon seen with other alpha blocking drugs. In BPH patients the incidence of clinically significant WBC abnormalities was0.4% (2/459) with doxazosin and 0% (0/147) with placebo, with no statistically significant difference between the two treatmentgroups. A search through a data base of 2,400 hypertensive patients and 665 BPH patients revealed 4 hypertensives in which drug-related neutropenia could not be ruled out and one BPH patient in which drug-related leukopenia could not be ruled out. Twohypertensives had a single low value on the last day of treatment. Two hypertensives had stable, non-progressive neutrophil countsin the 1000/mm3 range over periods of 20 and 40 weeks. One BPH patient had a decrease from WBC count of 4800/mm3 to 2700/mm3 at the end of the study; there was no evidence of clinical impairment. In cases where follow-up was available the WBCs andneutrophil counts returned to normal after discontinuation of doxazosin. No patients became symptomatic as a result of the low WBCor neutrophil counts. page 6 of 12

DRUG INTERACTIONS

Drug InteractionsMost (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on proteinbinding of digoxin, warfarin, phenytoin or indomethacin. There is no information on the effect of other highly plasma protein bounddrugs on doxazosin binding. Doxazosin has been administered without any evidence of an adverse drug interaction to patientsreceiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normalvolunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a 4-day regimen of oral cimetidine (400 mg twice daily)resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cmaxand mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown.In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formalinteraction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the followingdrugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen,indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g.,chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinalagents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and fluremedies.Cardiac Toxicity in AnimalsAn increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietaryadministration at concentrations calculated to provide 80 mg doxazosin/kg/day and after 12 months of dietary administration atconcentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cmax exposure in mice). Nocardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions werenot observed after 12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (Cmax)in dogs 14 times the Cmax exposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day(Cmax exposures 15 times human Cmax exposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur inhumans.Carcinogenesis, Mutagenesis, Impairment of FertilityChronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies areassociated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16mg/day.Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.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 timesthe AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. Therehave been no reports of any effects of doxazosin on male fertility in humans.

PREGNANCY

Pregnancy

TERATOGENIC EFFECTS

Teratogenic EffectsPregnancy Category CStudies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus. A dosageregimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. There are no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictive of human response, doxazosin should be used duringpregnancy only if clearly needed.Radioactivity was found to cross the placenta following oral administration of labeled doxazosin to pregnant rats.

NONTERATOGENIC EFFECTS

Nonteratogenic EffectsIn peri-postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (8 times human AUCexposure with a 12 mg/day therapeutic dose) was delayed as evidenced by slower body weight gain and a slightly later appearance ofanatomical features and reflexes.

NURSING MOTHERS

Nursing MothersStudies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breastmilk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this page 7 of 12 drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxazosin isadministered to a nursing mother.

PEDIATRIC USE

Pediatric UseThe safety and effectiveness of doxazosin as an antihypertensive agent have not been established in pediatric patients.

GERIATRIC USE

Geriatric UseThe safety and effectiveness profile of doxazosin in BPH was similar in the elderly (age 263 65 years) and younger (age < 65 years)patients.

CLINICAL STUDIES

Clinical studies of doxazosin did not include sufficient numbers of subjects aged 65 and over to determine whether they responddifferently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderlyand younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosingrange, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drugtherapy.

ADVERSE REACTIONS

ADVERSE REACTIONSBenign Prostatic HyperplasiaThe incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence ratespresented below (Table 3) are based on combined data from seven placebo-controlled trials involving once daily administration ofdoxazosin in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. The adverse events when the incidence in thedoxazosin group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared toplacebo was seen except for dizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related.TABLE 3 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES BENIGN PROSTATIC HYPERPLASIA Body System DOXAZOSIN(N=665) PLACEBO(N=300) BODY AS A WHOLE Back pain 1.8% 2.0% Chest Pain 1.2% 0.7% Fatigue 8.0%* 1.7% Headache 9.9% 9.0% Influenza-like symptoms 1.1% 1.0% Pain 2.0% 1.0% CARDIOVASCULAR SYSTEM Hypotension 1.7%* 0.0% Palpitation 1.2% 0.3% DIGESTIVE SYSTEM Abdominal Pain 2.4% 2.0% Diarrhea 2.3% 2.0% Dyspepsia 1.7% 1.7% Nausea 1.5% 0.7% METABOLIC AND NUTRITIONALDISORDERS Edema 2.7%* 0.7% NERVOUS SYSTEM Dizziness206 15.6%* 9.0% Mouth Dry 1.4% 0.3% Somnolence 3.0% 1.0% RESPIRATORY SYSTEM Dyspnea 2.6%* 0.3% Respiratory Disorder 1.1% 0.7% SPECIAL SENSES page 8 of 12 Vision Abnormal 1.4% 0.7% UROGENITAL SYSTEM Impotence 1.1% 1.0% Urinary Tract Infection 1.4% 2.3% SKIN & APPENDAGES Sweating Increased 1.1% 1.0% PSYCHIATRIC DISORDERS Anxiety 1.1% 0.3% Insomnia 1.2% 0.3% *p 243 0.05 for treatment differences206Includes vertigoIn these placebo-controlled studies of 665 doxazosin patients, treated for a mean of 85 days, additional adverse reactions have beenreported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with anincidence of less than 1% but of clinical interest are (doxazosin vs. placebo): Cardiovascular System: angina pectoris (0.6% vs. 0.7%),postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0.0%), tachycardia (0.9% vs. 0.0%); Urogenital System: dysuria (0.5% vs.1.3%), and Psychiatric Disorders: libido decreased (0.8% vs. 0.3%). The safety profile in patients treated for up to three years wassimilar to that in the placebo-controlled studies.The majority of adverse experiences with doxazosin were mild.HypertensionDoxazosin mesylate has been administered to approximately 4,000 hypertensive patients, of whom 1,679 were included in thehypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation oftreatment in only 7% of patients. In placebo-controlled studies adverse effects occurred in 49% and 40% of patients in the doxazosinand placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuationwere postural effects (2%), edema, malaise/fatigue, and some heart rate disturbance, each about 0.7%.In controlled hypertension clinical trials directly comparing doxazosin to placebo there was no significant difference in the incidenceof side effects, except for dizziness (including postural), weight gain, somnolence and fatigue/malaise. Postural effects and edemaappeared to be dose related. The prevalence rates presented below are based on combined data from placebo-controlled studiesinvolving once daily administration of doxazosin at doses ranging from 1 to 16 mg. Table 4 summarizes those adverse experiences(possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was atleast 0.5% or where the reaction is of particular interest.TABLE 4 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES HYPERTENSION DOXAZOSIN(N=339) PLACEBO(N=336) CARDIOVASCULAR SYSTEM Dizziness 19% 9% Vertigo 2% 1% Postural Hypotension 0.3% 0% Edema 4% 3% Palpitation 2% 3% Arrhythmia 1% 0% Hypotension 1% 0% Tachycardia 0.3% 1% Peripheral Ischemia 0.3% 0% SKIN & APPENDAGES Rash 1% 1% Pruritus 1% 1% MUSCULOSKELETAL SYSTEM Arthralgia/Arthritis 1% 0% Muscle Weakness 1% 0% Myalgia 1% 0% CENTRAL & PERIPHERAL N.S. page 9 of 12 Headache 14% 16% Paresthesia 1% 1% Kinetic Disorders 1% 0% Ataxia 1% 0% Hypertonia 1% 0% Muscle Cramps 1% 0% AUTONOMIC Mouth Dry 2% 2% Flushing 1% 0% SPECIAL SENSES Vision Abnormal 2% 1% Conjunctivitis/Eye Pain 1% 1% Tinnitus 1% 0.3% PSYCHIATRIC Somnolence 5% 1% Nervousness 2% 2% Depression 1% 1% Insomnia 1% 1% Sexual Dysfunction 2% 1% GASTROINTESTINAL Nausea 3% 4% Diarrhea 2% 3% Constipation 1% 1% Dyspepsia 1% 1% Flatulence 1% 1% Abdominal Pain 0% 2% Vomiting 0% 1% RESPIRATORY Rhinitis 3% 1% Dyspnea 1% 1% Epistaxis 1% 0% URINARY Polyuria 2% 0% Urinary Incontinence 1% 0% Micturition Frequency 0% 2% GENERAL Fatigue/Malaise 12% 6% Chest Pain 2% 2% Asthenia 1% 1% Face Edema 1% 0% Pain 2% 2% Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might haveoccurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reportedby < 0.5% of 3,960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including internationalstudies. Cardiovascular System: angina pectoris, myocardial infarction, cerebrovascular accident; Autonomic Nervous System: pallor;Metabolic: thirst, gout, hypokalemia; Hematopoietic: lymphadenopathy, purpura; Reproductive System: breast pain; Skin Disorders:alopecia, dry skin, eczema; Central Nervous System: paresis, tremor, twitching, confusion, migraine, impaired concentration;Psychiatric: paroniria, amnesia, emotional lability, abnormal thinking, depersonalization; Special Senses: parosmia, earache,taste perversion, photophobia, abnormal lacrimation; Gastrointestinal System: increased appetite, anorexia, fecal incontinence, page 10 of 12 gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary System: renal calculus; General BodySystem: hot flushes, back pain, infection, fever/rigors, decreased weight, influenza-like symptoms.Doxazosin has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverseeffects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin hasbeen associated with decreases in white blood cell counts (see PRECAUTIONS).In post-marketing experience the following additional adverse reactions have been reported: Autonomic Nervous System: priapism;Central Nervous System: hypoesthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System:allergic reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia; Liver/Biliary System: hepatitis,hepatitis cholestatic; Respiratory System: bronchospasm aggravated; Skin Disorders: urticaria; Special Senses: Intraoperative FloppyIris syndrome (see PRECAUTIONS: General: Cataract Surgery); Urinary System: hematuria, micturition disorder, micturitionfrequency, nocturia.

OVERDOSAGE

OVERDOSAGEExperience with doxazosin overdosage is limited. Two adolescents who each intentionally ingested 40 mg doxazosin with diclofenacor acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child whoaccidentally ingested 4 mg doxazosin was treated with gastric lavage and remained normotensive during the five-hour emergencyroom observation period. A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin and was reported to havebeen drowsy. A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg doxazosin(blood level 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting fromhypotension. A 39-year-old female who ingested 70 mg doxazosin, alcohol and flurazepam developed hypotension which respondedto fluid therapy.The oral LD50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would behypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysiswould not be indicated.DOSAGE AND ADMINISTRATIONDOSAGE MUST BE INDIVIDUALIZED. The initial dosage of doxazosin tablets in patients with hypertension and/or BPH is 1mg given once daily in the a.m. or p.m. This starting dose is intended to minimize the frequency of postural hypotension and firstdose syncope associated with doxazosin. Postural effects are most likely to occur between 2 and 6 hours after a dose. Therefore bloodpressure measurements should be taken during this time period after the first dose and with each increase in dose. If doxazosin tabletsadministration is discontinued for several days, therapy should be restarted using the initial dosing regimen.Benign Prostatic Hyperplasia 1 to 8 mg Once DailyThe initial dosage of doxazosin is 1 mg, given once daily in the a.m. or p.m. Depending on the individual patient's urodynamicsand BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximumrecommended dose for BPH. The recommended titration interval is 1 to 2 weeks. Blood pressure should be evaluated routinely inthese patients.Hypertension 1 to 16 mg Once DailyThe initial dosage of doxazosin is 1 mg given once daily. Depending on the individual patient's standing blood pressure response(based on measurements taken at 2 to 6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafterif necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. Increases in dose beyond 4 mg increasethe likelihood of excessive postural effects including syncope, postural dizziness/vertigo and postural hypotension. At a titrateddose of 16 mg once daily the frequency of postural effects is about 12% compared to 3% for placebo.

HOW SUPPLIED

HOW SUPPLIEDDoxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg, 2mg, 4 mg or 8 mg of doxazosin.The 1 mg are available as white to off-white, round, biconvex tablets debossed with M over D9 on one side of the tablet and scored onthe other side. They are available as follows:NDC 0378-4021-01bottles of 100 tabletsThe 2 mg are available as pink, round, biconvex tablets debossed with M over D10 on one side of the tablet and scored on the otherside. They are available as follows:NDC 0378-4022-01bottles of 100 tabletsNDC 0378-4022-05bottles of 500 tabletsThe 4 mg are available as blue, round, biconvex tablets debossed with M over D11 on one side of the tablet and scored on the otherside. They are available as follows: page 11 of 12 NDC 0378-4024-01bottles of 100 tabletsNDC 0378-4024-05bottles of 500 tabletsThe 8 mg are available as purple, round, biconvex tablets debossed with M over D12 on one side of the tablet and scored on the otherside. They are available as follows:NDC 0378-4028-01bottles of 100 tabletsStore at 20260 to 25260C (68260 to 77260F). [See USP for Controlled Room Temperature.]Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2007DXZN:R6pPATIENT INFORMATION ABOUT DOXAZOSIN TABLETS, USPFOR BENIGN PROSTATIC HYPERPLASIA (BPH)Read this leaflet:225before you start taking doxazosin.225each time you get a new prescription.You and your doctor should discuss this treatment and your (BPH) symptoms before you start taking doxazosin and at your regularcheckups. This leaflet does NOT take the place of discussions with your doctor.Doxazosin is used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describesdoxazosin as treatment for BPH (although you may be taking doxazosin for both your BPH and high blood pressure).WHAT IS BPH: BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder.The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. Thiscan lead to such symptoms as:225a weak or start-and-stop stream when urinating225a feeling that the bladder is not completely emptied after urination225a delay or difficulty in the beginning of urination225a need to urinate often during the day and especially at night225a feeling that you must urinate immediately.TREATMENT OPTIONS FOR BPH: The four main treatment options for BPH are:225If you are not bothered by your symptoms, you and your doctor may decide on a program of "watchful waiting". It is not an activetreatment like taking medication or surgery but involves having regular checkups to see if your condition is getting worse or causingproblems.225Treatment with doxazosin or other similar drugs. Doxazosin is the medication your doctor has prescribed for you. See "WhatDoxazosin Does", below.225Treatment with the medication class of 5-alpha reductase inhibitors (e.g., finasteride). It can cause the prostate to shrink. It may take6 months or more for the full benefit of finasteride to be seen.225Various surgical procedures. Your doctor can describe these procedures to you. The best procedure for you depends on your BPHsymptoms and medical condition.WHAT DOXAZOSIN DOES: Doxazosin works on a specific type of muscle found in the prostate, causing it to relax. This in turndecreases the pressure within the prostate, thus improving the flow of urine and your symptoms.225Doxazosin helps relieve the symptoms of BPH (weak stream, start-and-stop stream, a feeling that your bladder is not completelyempty, delay in beginning of urination, need to urinate often during the day and especially at night, and feeling that you musturinate immediately). It does not change the size of the prostate. The prostate may continue to grow; however a large prostate is not page 12 of 12 necessarily related to more symptoms or to worse symptoms. Doxazosin can decrease your symptoms and improve urinary flow,without decreasing the size of the prostate.225If doxazosin is helping you, you should notice an affect within 1 to 2 weeks after you start your medication. Doxazosin has beenstudied in over 900 patients for up to 2 years and the drug has been shown to continue to work during long-term treatment. Eventhough you take doxazosin and it may help you, doxazosin may not prevent the need for surgery in the future.225Doxazosin does not affect PSA levels. PSA is the abbreviation for Prostate Specific Antigen. Your doctor may have done a bloodtest called PSA. You may want to ask your doctor more about this if you have had a PSA test done.OTHER IMPORTANT FACTS:225You should see an improvement of your symptoms within 1 to 2 weeks. In addition to your other regular checkups you will need tocontinue seeing your doctor regularly to check your progress regarding your BPH and to monitor your blood pressure.225Doxazosin Mesylate is not a treatment for prostate cancer. Your doctor has prescribed doxazosin for your BPH and not for prostatecancer; however, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked forprostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). A higher incidence of prostatecancer has been noted in men of African-American descent. These checks should continue even if you are taking doxazosin.HOW TO TAKE DOXAZOSIN AND WHAT YOU SHOULD KNOW WHILE TAKING DOXAZOSIN FOR BPH: DoxazosinCan Cause a Sudden Drop in Blood Pressure After the VERY FIRST DOSE. You may feel dizzy, faint or "light-headed",especially after you stand up from a lying or sitting position. This is more likely to occur after you've taken the first few doses or ifyou increase your dose, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and thenrestart treatment. If you feel very dizzy, faint or "light-headed" you should contact your doctor. Your doctor will discuss with you howoften you need to visit and how often your blood pressure should be checked.Your blood pressure should be checked when you start taking doxazosin even if you do not have high blood pressure (hypertension).Your doctor will discuss with you the details of how blood pressure is measured.Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to be measured in the following way:measure your blood pressure after lying quietly on your back for five minutes. Then, after standing for two minutes measure yourblood pressure again. Your doctor will discuss with you what other times during the day your blood pressure should be taken, such astwo to six hours after a dose, before bedtime or after waking up in the morning. Note that moderate to high-intensity exercise can, overa period of time, lower your average blood pressure.You can take doxazosin either in the morning or at bedtime and it will be equally effective. If you take doxazosin at bedtime butneed to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It isimportant to get up slowly from a chair or bed at any time until you learn how you react to doxazosin. You should not drive or do anyhazardous tasks until you are used to the effects of medication. If you begin to feel dizzy, sit or lie down until you feel better.225You will start with a 1 mg dose of doxazosin once daily. Then the once daily dose will be increased as your body gets used to theeffects of the medication. Follow your doctor's instructions about how to take doxazosin. You must take it every day at the doseprescribed. Talk with your doctor if you don't take it for a few days for some reason; you may then need to restart the medication at a1 mg dose. Increase your dose gradually and again be cautious about possible dizziness. Do not share doxazosin with anyone else; itwas prescribed only for you.225Other side effects you could have while taking doxazosin, in addition to lowering of the blood pressure, include dizziness, fatigue(tiredness), swelling of the feet and shortness of breath. Most side effects are mild. However, you should discuss any unexpectedeffects you notice with your doctor.225WARNING: Extremely rarely, doxazosin and similar medications have caused painful erection of the penis, sustained for hoursand unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanentinability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon aspossible.225Keep doxazosin and all medicines out of the reach of children.FOR MORE INFORMATION ABOUT DOXAZOSIN AND BPH TALK WITH YOUR DOCTOR, NURSE, PHARMACISTOR OTHER HEALTH CARE PROVIDER.Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2007PL:DXZN:R3Revised: 01/2008Distributed by: Mylan Pharmaceuticals Inc.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

DRUG: Doxazosin mesylate

GENERIC: Doxazosin

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-004-02

STRENGTH:1 mg

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 2 mm

IMPRINT: 30

QTY: 30



IMAGE OF PRODUCT LABELIMAGE OF CARTON

DOXAZOSIN MESYLATE 
doxazosin mesylate tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:49349-004
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXAZOSIN MESYLATE (UNII: 86P6PQK0MU) (DOXAZOSIN - UNII:NW1291F1W8) DOXAZOSIN1 mg
Inactive Ingredients
Ingredient NameStrength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
STARCH, CORN (UNII: O8232NY3SJ)  
SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
Product Characteristics
ColorwhiteScoreno score
ShapeROUND (TABLET) Size2mm
FlavorImprint Code apo;093
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:49349-004-0230 in 1 BLISTER PACK; Type 0: Not a Combination Product07/29/201007/30/2011
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07558007/29/201007/30/2011
Labeler - REMEDYREPACK INC. (829572556)

Revised: 10/2016
 
REMEDYREPACK INC.