PRINCIPAL DISPLAY PANEL - 8 mg Tablet Bottle Label - NDC 59762-2480-7

NDC 59762-2480-7
100 Tablets

GREENSTONE® BRAND

doxazosin
tablets

8 mg*
Rx only

5 WARNINGS AND PRECAUTIONS

5.1 Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of Doxazosin. 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 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 tablet 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.

Postural hypotension with or without syncope may occur. (5.1)

Risk of Intraoperative Floppy Iris Syndrome during cataract surgery. (5.2)

Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards. (5.3)

6 ADVERSE REACTIONS

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 tablet 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 vs placebo are summarized in Table 1.

Table 1. Adverse Reactions Occurring more than 1% More Frequently in BPH Patients Treated with Doxazosin Versus Placebo

BODY SYSTEM	Doxazosin N=665	Placebo N=300
NERVOUS SYSTEM DISORDERS
Includes vertigo
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%

Other adverse reactions occurring less than 1% more frequently in BPH patients treated with Doxazosin vs placebo but plausibly related to Doxazosin include: palpitations.

Hypertension

Doxazosin 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 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 versus Placebo

BODY SYSTEM	Doxazosin 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 vs placebo but plausibly related to Doxazosin use include vertigo, hypotension, hot flushes, epistaxis and oedema.

Doxazosin 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. In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of Doxazosin. 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. 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis**:**Chronic dietary administration (up to 24 months) of Doxazosin at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, 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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Doxazosin is available as tablets for oral administration. Each tablet contains Doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow or white), 4 mg (orange or white) or 8 mg (green or white) of doxazosin as the free base.

NDC and Pack Size	Strength	Description
NDC 59762-2310-6 (Bottle of 100)	1 mg	White, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "1 mg" on the other side.
NDC 59762-2410-7 (Bottle of 100)	1 mg	White, round tablet engraved "CN1" on one side and "Pfizer" on the other side.
NDC 59762-2320-6 (Bottle of 100)	2 mg	Yellow, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "2 mg" on the other side.
NDC 59762-2420-7 (Bottle of 100)	2 mg	White, capsule shaped tablet with break score and engraved "CN2" on one side and "Pfizer" on the other side.
NDC 59762-2340-6 (Bottle of 100)	4 mg	Orange, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "4 mg" on the other side.
NDC 59762-2440-7 (Bottle of 100)	4 mg	White, diamond shaped tablet with break score and engraved "CN4" on one side and "Pfizer" on the other side.
NDC 59762-2380-6 (Bottle of 100)	8 mg	Green, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "8 mg" on the other side.
NDC 59762-2480-7 (Bottle of 100)	8 mg	White, capsule shaped tablet with break score and engraved "CN8" on one side and "Pfizer" on the other side.

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

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.greenstonellc.com.