Doxazosin Mesylate (Page 4 of 7)

Cardiac Toxicity in Animals

An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day, and after 12 months of dietary administration at concentrations 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). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions were not 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 in humans.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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.

Pregnancy

Teratogenic Effects, Pregnancy Category C

Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Doxazosin mesylate should be used during pregnancy only if clearly needed.

Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.

Nonteratogenic Effects

In peri-postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (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.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of Doxazosin mesylate as an antihypertensive agent have not been established in children.

Geriatric Use

The safety and effectiveness profile of Doxazosin mesylate in BPH was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.

For 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.

ADVERSE REACTIONS

A. 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 3) are based on combined data from seven placebo-controlled trials involving once-daily administration of Doxazosin mesylate in doses of 1–16 mg in hypertensives and 0.5–8 mg in normotensives. The adverse events when the incidence in the Doxazosin mesylate group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared to placebo 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
Doxazosin mesylate PLACEBO
Body System (N=665) (N=300)
*
p ≤0.05 for treatment differences
Includes vertigo
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 NUTRITIONAL DISORDERS
Edema 2.7%* 0.7%
NERVOUS SYSTEM
Dizziness 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
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%

In these placebo-controlled studies of 665 Doxazosin mesylate patients treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with an incidence of less than 1% but of clinical interest are ( Doxazosin mesylate 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 was similar to that in the placebo-controlled studies.

The majority of adverse experiences with Doxazosin mesylate were mild.

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