Cardura Information
Cardura (Doxazosin) Description
Cardura (Doxazosin) ® (doxazosin mesylate) is a quinazoline compound that is a selective inhibitor of the alpha subtype of alpha-adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is CHNO • CHOS and the molecular weight is 547.6. It has the following structure:
Cardura (Doxazosin) (doxazosin mesylate) is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. Cardura (Doxazosin) is available as colored tablets for oral use and contains 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) of doxazosin as the free base.
The inactive ingredients for all tablets are: microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and sodium lauryl sulfate. The 2 mg tablet contains D & C yellow 10 and FD & C yellow 6; the 4 mg tablet contains FD & C yellow 6; the 8 mg tablet contains FD & C blue 10 and D & C yellow 10.
Cardura (Doxazosin) Clinical Pharmacology
After oral administration of therapeutic doses, peak plasma levels of Cardura (Doxazosin) occur at about 2–3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of Cardura (Doxazosin) was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when Cardura (Doxazosin) was administered with food. Neither of these differences was statistically or clinically significant.
Cardura (Doxazosin) is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.
Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2–16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.
In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs. 3.5 hr).
The pharmacokinetics of Cardura (Doxazosin) in young (
In two placebo-controlled studies of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of Cardura (Doxazosin) were similar in the two populations. Linear kinetics and dose proportionality were observed.
Cardura (Doxazosin) Contraindications
Cardura (Doxazosin) is contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients.
Cardura (Doxazosin) Warnings
Doxazosin, 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 ), 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 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 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, 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 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 reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin 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.
Cardura (Doxazosin) Precautions
(See )
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 Cardura (Doxazosin) or any selective alpha 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 alpha 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).
Most (98%) of plasma doxazosin is protein bound. data in human plasma indicate that Cardura (Doxazosin) 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. Cardura (Doxazosin) 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 C and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown.
In clinical trials, Cardura (Doxazosin) tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Cardura (Doxazosin) 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 Cardura (Doxazosin) with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see ).
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.
The safety and effectiveness profile of Cardura (Doxazosin) in BPH was similar in the elderly (age ≥ 65 years) and younger (age
For hypertension: Clinical studies of Cardura (Doxazosin) 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.
Cardura (Doxazosin) Adverse Reactions
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 Cardura (Doxazosin) in doses of 1–16 mg in hypertensives and 0.5–8 mg in normotensives. The adverse events when the incidence in the Cardura (Doxazosin) 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.
In these placebo-controlled studies of 665 Cardura (Doxazosin) 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 (Cardura (Doxazosin) vs. placebo): 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%); dysuria (0.5% vs. 1.3%); and 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 Cardura (Doxazosin) were mild.
Cardura (Doxazosin) has been administered to approximately 4000 hypertensive patients, of whom 1679 were included in the hypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. In placebo-controlled studies, adverse effects occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuation were postural effects (2%), edema, malaise/fatigue, and some heart rate disturbance, each about 0.7%.
In controlled hypertension clinical trials directly comparing Cardura (Doxazosin) to placebo, there was no significant difference in the incidence of side effects, except for dizziness (including postural), weight gain, somnolence, and fatigue/malaise. Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once-daily administration of doxazosin at doses ranging from 1–16 mg. Table 4 summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction is of particular interest.
Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and 1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reported by
Cardura (Doxazosin) has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Cardura (Doxazosin) has been associated with decreases in white blood cell counts (see ).
In post-marketing experience, the following additional adverse reactions have been reported: priapism; hypoesthesia; gynecomastia; vomiting; allergic reaction; bradycardia; leukopenia, thrombocytopenia; hepatitis, hepatitis cholestatic; bronchospasm aggravated; urticaria; Intraoperative Floppy Iris Syndrome (see ); hematuria, micturition disorder, micturition frequency, nocturia.
Cardura (Doxazosin) Overdosage
Experience with Cardura (Doxazosin) overdosage is limited. Two adolescents, who each intentionally ingested 40 mg Cardura (Doxazosin) with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidently ingested 4 mg Cardura (Doxazosin) was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of Cardura (Doxazosin) and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg Cardura (Doxazosin) (blood level = 0.9 µg/mL; normal values in hypertensives = 0.02 µg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg Cardura (Doxazosin) , alcohol, and Dalmane® (flurazepam) developed hypotension which responded to fluid therapy.
The oral LD of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated.
Cardura (Doxazosin) Dosage And Administration
Concomitant administration of Cardura (Doxazosin) with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking Cardura (Doxazosin) .
Cardura (Doxazosin) How Supplied
Cardura (Doxazosin) (doxazosin mesylate) is available as colored tablets for oral administration. Each scored tablet contains doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow), 4 mg (orange) or 8 mg (green) of the active constituent, doxazosin.
Cardura (Doxazosin)
Cardura (Doxazosin) Patient Information About Cardura®generic Name:doxazosin Mesylatefor Benign Prostatic Hyperplasia (bph)
Read this leaflet:
You and your doctor should discuss this treatment and your BPH symptoms before you start taking Cardura (Doxazosin) and at your regular checkups. This leaflet does NOT take the place of discussions with your doctor.
Cardura (Doxazosin) is used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describes Cardura (Doxazosin) as treatment for BPH (although you may be taking Cardura (Doxazosin) for both your BPH and high blood pressure).
BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. This can lead to such symptoms as:
The four main treatment options for BPH are:
Cardura (Doxazosin) works on a specific type of muscle found in the prostate, causing it to relax. This in turn decreases the pressure within the prostate, thus improving the flow of urine and your symptoms.
Your blood pressure should be checked when you start taking Cardura (Doxazosin) even if you do not have high blood pressure (hypertension). Your doctor will discuss with you the details of how blood pressure is measured.
You can take Cardura (Doxazosin) either in the morning or at bedtime and it will be equally effective. If you take Cardura (Doxazosin) at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It is important to get up slowly from a chair or bed at any time until you learn how you react to Cardura (Doxazosin) . You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better.
LAB-0070-3.0January 2010
Cardura (Doxazosin) Principal Display Panel - Mg Bottle Label
Cardura (Doxazosin) Principal Display Panel - Mg Bottle Label
Cardura (Doxazosin) Principal Display Panel - Mg Bottle Label
Cardura (Doxazosin) Principal Display Panel - Mg Bottle Label
