Doxazosin Mesylate (Page 3 of 7)

Priapism

Rarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin, 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.

a) 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 1–4 mg and 3% in the placebo group.

b) Benign Prostatic Hyperplasia

In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin 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 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 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 Test Interactions

Doxazosin mesylate does not affect the plasma concentration of prostate-specific antigen in patients treated for up to 3 years. Both doxazosin, 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, Pharmacokinetics).

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, with 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 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 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 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 (p=0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin. The clinical significance of this increase in doxazosin 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.

Concomitant administration of Doxazosin mesylate with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION).

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