Doxazosin precautions

Precautions
General Prostate Cancer Orthostatic Hypotension Hypertension Benign prostatic hyperplasia Information for Patients Drug/Laboratory Test Interactions Impaired Liver Function Leukopenia/Neutropenia Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Teratogenic Effects Non teratogenic Effects Nursing Mothers Pediatric Use Geriatric Use ---

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.

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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.

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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.

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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.

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Information for Patients
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).

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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.

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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.

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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.

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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.

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.

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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.

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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.

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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.

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Nursing Mothers
Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-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.

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Pediatric Use
The safety and effectiveness of Doxazosin mesylate as an antihypertensive agent have not been established in pediatric patients.

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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. 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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