1.1 Benign Prostatic Hyperplasia (BPH)

Doxazosin tablets are indicated for the treatment of the signs and symptoms of BPH.

1.2 Hypertension

Doxazosin tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk offatal 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 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 tablets, monitor blood pressure for at least 6 hours followingadministration. If doxazosin tablets 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 tablets are 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 tablets are 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 tablets. 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 tablets 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 alpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery.

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 tablets for the treatment of BPH.

5.4 Priapism

Alpha1 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.

Hypertension

Doxazosin tablets have 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 tablets 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.

Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with doxazosin tablets vs placebo but plausibly related to doxazosin tablets use include vertigo, hypotension, hot flushes, epistaxis and oedema.

Doxazosin tablets have been associated with decreases in white blood cell counts.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxazosin tablets. 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 tablets are used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3)].

7.2 Phosphodiesterase-5(PDE-5) inhibitors

Concomitant administration of doxazosin tablets 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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of doxazosin tablets have not been established in children.

8.5 Geriatric Use

8.6 Hepatic Impairment

Doxazosin tablets are extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to doxazosin. Use of doxazosin tablets 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)].

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 Cmax 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 (Cmax) 14 times the Cmax exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar rats at Cmax exposures 15 times human Cmax exposure. There is no evidence that similar lesions occur in humans.

14.1 Benign Prostatic Hyperplasia (BPH)

The efficacy of doxazosin tablets was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin tablets treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosin tablets was seen as early as one week into the treatment regimen, with doxazosin tablets-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 tablets.

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 tablets 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 tablets 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 tablets 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 tablets vs. placebo was seen after one week. The proportion of patients who responded with a maximum flowrate improvement of ≥3mL/sec was significantly larger with doxazosin tablets (34–42%) than placebo (13–17%). A significantly greater improvement was also seen in average flow rate with doxazosin tablets (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

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 tablets gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.

Recommended Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP for Controlled Room Temperature]. [see USP Controlled Room Temperature].

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 hoursafterthefirstdose,aftera dosage increase, and after interruption of therapy when treatment is resumed. Advisepatientsto report symptoms to their healthcare provider.

Priapism

Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur.

Manufactured by:

UNICHEM LABORATORIES LTD.

Pilerne Ind. Estate, Pilerne, Bardez,

Goa 403 511, India.

Manufactured for:

East Brunswick, NJ 08816.

03-R-10/2023

13014728