Doxazosin Mesylate: Package Insert and Label Information (Page 2 of 4)

INDICATIONS AND USAGE

Benign Prostatic Hyperplasia (BPH)

Doxazosin mesylate tablet is indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin mesylate may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with doxazosin mesylate monotherapy. Doxazosin mesylate provides rapid improvement in symptoms and urinary flow rate in 66 to 71% of patients. Sustained improvements with doxazosin mesylate were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies.

Hypertension

Doxazosin mesylate tablet is also indicated for the treatment of hypertension. Doxazosin mesylate may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers or angiotensin-converting enzyme inhibitors.

CONTRAINDICATIONS

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

WARNINGS

S yncope and “First-Dose” Effect: Doxazosin mesylate, 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 dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and 8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution.

Patients being titrated with doxazosin mesylate 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 mesylate in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin mesylate, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin mesylate dosing 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 1500 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 16 mg/day.

In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin mesylate reported syncope. Two of the patients were taking 1 mg doxazosin mesylate, while one patient was taking 2 mg doxazosin mesylate when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope.

If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.

Priapism

Rarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin mesylate, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this 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).

PRECAUTIONS

General

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 mesylate.

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.

ORTHOSTATIC HYPOTENSION

While syncope is the most severe orthostatic effect of doxazosin mesylate 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.

Hypertension

These symptoms were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and causing discontinuation of therapy in about 2%.

In placebo-controlled titration trials in hypertension, orthostatic effects were minimized by beginning therapy at 1 mg per day and titrating every two weeks to 2, 4, or 8 mg per day. There was an increased frequency of orthostatic effects in patients given 8 mg or more, 10%, compared to 5% at 1 to 4 mg and 3% in the placebo group.

Benign Prostatic Hyperplasia

In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin mesylate was 0.3% and did not increase with increasing dosage (to 8 mg/day). The incidence of discontinuations due to hypotensive or orthostatic symptoms was 3.3% with doxazosin mesylate 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 alpha1 antagonists can cause orthostatic effects, it is important to evaluate standing blood pressure two minutes after standing and patients should 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 with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin mesylate.

Information for Patients (See Patient Package Insert)

Patients should be made aware 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. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of doxazosin mesylate therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, 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 mesylate 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 know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for, if not treated promptly, it can lead to permanent erectile dysfunction (impotence).

Drug/Laboratory Tests Interactions

Doxazosin mesylate does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin mesylate, an alpha1 inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically metabolized. There is no definitive controlled clinical experience on the concomitant use of alpha1 inhibitors and 5-alpha reductase inhibitors at this time.

Impaired Liver Function

Doxazosin mesylate should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism (see CLINICAL PHARMACOLOGY).

Leukopenia/Neutropenia

Analysis of hematologic data from hypertensive patients receiving doxazosin mesylate in controlled hypertension clinical trials showed that the mean WBC (N=474) and mean neutrophil counts (N=419) were decreased by 2.4% and 1.0%, respectively, compared to placebo, a phenomenon seen with other alpha blocking drugs. In BPH patients the incidence of clinically significant WBC abnormalities was 0.4% (2/459) with doxazosin mesylate and 0% (0/147) with placebo, no statistically significant difference between the two treatment groups. A search through a data base of 2400 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. Two hypertensives had a single low value on the last day of treatment. Two hypertensives had stable, non-progressive neutrophil counts in the 1000/mm3 range over periods of 20 and 40 weeks. One BPH patient had a decrease from a 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 and neutrophil counts returned to normal after discontinuation of doxazosin mesylate. No patients became symptomatic as a result of the low WBC or neutrophil counts.

Drug Interactions

Most (98%) of plasma doxazosin mesylate is protein bound. In vitro data in human plasma indicate that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. There is no information on the effect of other highly plasma protein bound drugs on doxazosin mesylate binding. Doxazosin mesylate has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin mesylate on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin mesylate (p=0.006), and a slight but not statistically significant increase in mean C max and mean half-life of doxazosin mesylate. The clinical significance of this increase in doxazosin mesylate AUC is unknown.

In clinical trials, doxazosin mesylate tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin mesylate tablets have been used with the following drugs 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) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.

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 mesylate/kg/day and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin mesylate/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 mesylate/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human C max 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 (C max) in dogs 14 times the C max exposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (C max exposures 15 times human C max 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 mesylate 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 mesylate 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 C max 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 mesylate 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 mesylate (8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed as evidenced by slower body weight gain and a 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 mesylate 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 pediatric patients.

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.

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