Doxazosin (Page 4 of 5)
13.2 Animal Toxicology and Pharmacology
An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6 to 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.
14 CLINICAL STUDIES
14.1 Benign Prostatic Hyperplasia (BPH)
The efficacy of doxazosin 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 to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate.
In three placebo-controlled studies of 14 to 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 to 6 hours post-dose) and/or trough (24 hours post-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 are summarized in Table 3. In all three studies, doxazosin resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin tablets in Studies 1 and 2, compared to 0.1 to 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 to 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 flow rate improvement of ≥3 mL/sec was significantly larger with doxazosin tablets (34 to 42%) than placebo (13 to 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 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. 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.
| ||||
PLACEBO (N=85) | Doxazosin Tablets (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 |
16 HOW SUPPLIED/STORAGE AND HANDLING
Doxazosin tablets, USP are available as white to off-white tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 4 mg of the active constituent, doxazosin. 4 mg (white to off-white, capsule shaped, scored tablets, imprinted “APO” on one side and “095” with a partial bisect on the other side)
bottles of 30 NDC 68071-3298-3
bottles of 60 NDC68071-3298-6
bottles of 90 NDC 68071-3298-9
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container [see USP].
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.
APOTEX INC.
DOXAZOSIN TABLETS, USP
1 mg, 2 mg, 4 mg and 8 mg
Manufactured by | Manufactured for |
Apotex Inc. | Apotex Corp. |
Toronto, Ontario | Weston, Florida |
Canada M9L 1T9 | 33326 |
Revised: April 2017
Rev. 5
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