Product Monograph - Cardura-1,2,and 4
ACTIONS AND CLINICAL PHARMACOLOGY
The mechanism of action of CARDURA (doxazosin mesylate) is selective blockade of alpha1 subtype of post-synaptic, post-junctional alpha-adrenergic receptors.
Pharmacodynamics
Hypertension
Administration of CARDURA results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2-6 hours after dosing and are associated with a small increase in standing heart rate. CARDURA has a greater effect on blood pressure and heart rate in the standing position. Tolerance has not been observed in long-term therapy.
Systolic and diastolic blood pressure is lowered in both the supine and standing positions. In clinical trials, blood pressure responses were measured at the end of the dosing interval (24 hours), with the usual supine response 6-11 mm Hg systolic and 5-9 mm Hg diastolic. The response in the standing position tended to be larger by 3-5 mm Hg. Peak blood pressure effects (1-6 hours) were larger by about 50-75% (i.e., trough values were about 55-70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and Blacks or of patients above and below age 65.
During controlled clinical studies, predominantly normocholesterolemic patients receiving CARDURA had small but statistically significant reductions in total serum cholesterol (2.7%) and LDL cholesterol (4.3%), and increase in the HDL/total cholesterol ratio (4.3%) relative to placebo. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo.
Benign Prostatic Hyperplasia (BPH)
Benign Prostatic Hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma.
However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by α1-adrenoceptors which are present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockage of the α1-receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. In 30 to 70% of patients with symptomatic BPH, placebo has also shown a remarkable and sometimes dramatic effect in controlled short-term studies.
The symptoms may subside or fade away without treatment in approximately 20% of patients.
Doxazosin antagonizes phenylephrine-induced contractions, in vitro, in the human prostate. Doxazosin is bound with high affinity to the α1A-adrenoceptor subtype, thought to be the predominant functional type in the prostate.
The effect of CARDURA in BPH is thought to result from selective blockade of the α1A-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck. This action results in relief of the urinary outlet obstruction and symptomatology associated with BPH.
In controlled clinical trials in over 900 patients, the efficacy of CARDURA was evaluated. In two studies CARDURA 4-8 mg once daily significantly improved maximum urinary flow rate (MFR) by 2.3-3.3 mL/sec (placebo 0.1-0.7 mL/sec).
Significant improvements were usually noticed within two weeks of commencing CARDURA treatment and a significantly larger proportion of patients (32-42%) responded with MFR improvements ≥ 3 mL/sec (placebo 13-17%). Average flow rate also improved with CARDURA treatment, (1.3-2.1 mL/sec vs placebo 0.2-0.3 mL/sec). CARDURA also resulted in a significant relief of the obstructive and irritative symptoms associated with BPH.
Using invasive urodynamics in a controlled clinical trial in 43 BPH patients, CARDURA 2 mg improved MFR 3.4 mL/sec, and reduced urethral resistance 7.5-13.5 cmH2O (placebo, MFR - 0.6 mL/sec and resistance of 3.3 cmH2O).
In a 29-week controlled BPH trial in 100 patients, CARDURA was significantly more effective than placebo in improving urinary flow rates and reducing BPH symptoms; the effect was sustained over the entire treatment period. No tolerance to the effect of CARDURA on urodynamics or BPH symptomatology was observed in patients treated for up to 4 years in open-label studies.
Both hypertensive and normotensive BPH patients treated with CARDURA demonstrate statistically significant improvements in urodynamics and symptomatology compared to placebo.
Pharmacokinetics
After oral administration of therapeutic doses of CARDURA absorption occurs with peak blood levels at about two hours. Bioavailability is approximately 65%. Food has little or no effect on the bioavailability.
Approximately 98% of the circulating drug is bound to plasma proteins. Plasma elimination is biphasic with a terminal elimination half-life of about 22 hours. There is an accumulation of plasma doxazosin levels following steady state dosing, consistent with the terminal elimination half-life.
In a study of elderly hypertensive patients the pharmacokinetic parameters of doxazosin at steady state were similar to those observed in a previous study of young and elderly healthy subjects who received a single oral dose of CARDURA.
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. CARDURA may, therefore, be administered as a single daily morning or evening dose (see DOSAGE and ADMINISTRATION).
CARDURA is extensively metabolized, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Excretion is mainly via the feces with 9% of the dose excreted in urine as doxazosin (<0.5%) or metabolites. Less than 5% is excreted as the unchanged drug, mainly in the feces.
The disposition of CARDURA in patients with renal insufficiency is similar to that in patients with normal renal function. Only limited data are available in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g., cimetidine) (see PRECAUTIONS - Use in Patients with Impaired Liver Function).
INDICATIONS AND CLINICAL USE
Hypertension
CARDURA (doxazosin mesylate) is indicated in the treatment of mild to moderate essential hypertension. It is employed in a general treatment program in association with a thiazide diuretic and/or other antihypertensive agents, as needed, for proper patient response. CARDURA may be tried as a sole therapy in those patients for whom treatment with other agents caused adverse effects or is inappropriate.
Benign Prostatic Hyperplasia (BPH)
CARDURA is also indicated for the treatment of symptoms of benign prostatic hyperplasia (BPH). The onset of effect is rapid, with improvement in peak flow and symptoms observed within 1-2 weeks. The effect on these variables was maintained over the entire study duration (up to 4 years). CARDURA may be used in BPH patients who are either hypertensive or normotensive. While the reduction in blood pressure in normotensive patients with BPH is clinically insignificant, patients with hypertension and BPH have both conditions effectively treated with doxazosin monotherapy (see DOSAGE and ADMINISTRATION for dosage regimens).
A number of clinical conditions can mimic symptomatic BPH (i.e., stricture of urethra, stricture of bladder neck, urinary bladder stones, neurogenic bladder dysfunction secondary to diabetes, Parkinsonism, etc.). These conditions should therefore be ruled out before doxazosin therapy is initiated.
CONTRAINDICATIONS
It is contraindicated in patients with a known sensitivity to CARDURA (doxazosin mesylate) or quinazolines.
WARNINGS
Syncope and "First Dose" Effect
CARDURA (doxazosin mesylate) can cause marked hypotension, especially postural hypotension and syncope in association with the first dose or first few doses of therapy. A similar effect can occur if therapy is reinstated following interruption for more than a few doses. Postural effects are most likely to occur between 2 and 6 hours after dose.
In controlled studies of CARDURA the incidence of syncopal episodes was 0.7%. An initial dose of 1 mg/day resulted in a 4% incidence of postural side effects with no cases of syncope. In controlled clinical trials for BPH in normotensive patients, there was a 0.2% occurrence of syncope with CARDURA. In controlled trials in patients with both BPH and hypertension receiving CARDURA, the incidence of syncope was 0.8%.
The likelihood of syncopal episodes or excessive hypotension can be minimized by limiting the initial dose of CARDURA to 1 mg, by increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient's regimen with caution (see DOSAGE AND ADMINISTRATION).
Patients should be advised of the possibility of syncopal and orthostatic symptoms, and to avoid driving or hazardous tasks for 24 hours: after the initial dose of CARDURA, after the dose is increased, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur. If syncope occurs, the patient should be placed in the supine position. 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 CARDURA.
Orthostatic Hypotension
While syncope is the most severe orthostatic effect of CARDURA, other symptoms of lowered blood pressure such as dizziness, lightheadedness or vertigo can occur. These 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, there was an increased frequency of orthostatic effects in patients given 8 mg or more (10%) compared to patients given 1-4 mg (5%) or placebo (3%).
In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with CARDURA was ≤1%. With maintenance doses of up to 8 mg/day in normotensive patients with BPH, the average decreases in both sitting and standing blood pressure were small: 5/2 mm Hg with CARDURA and 1/1 mm Hg with placebo.
Patients with occupations in which such events represent potential problems should be treated with particular caution.
Concomitant administration of doxazosin with a PDE-5 inhibitor such as sildenafil, tadalafil or vardenafil, should be used with caution as it may lead to symptomatic hypotension.
Patients should be advised of the need to lie down when symptoms of lowered blood pressure occur, and to be careful when arising from a 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, requiring caution in people who must drive or operate heavy machinery.
If hypotension occurs, place the patient in the recumbent position and institute supportive measures as necessary.
Priapism
Rarely (probably less frequently than once in every several thousand patients), α1-antagonists such as doxazosin have been associated with priapism. Because this condition can lead to permanent impotence if not promptly treated, patients should be advised about the seriousness of the condition.
Hematological Events
Analysis of hematologic data from patients receiving CARDURA in controlled clinical trials showed that the mean white blood cell (WBC) (n=474) and mean neutrophil counts (n=419) were decreased by 2.4% and 1.0% respectively, compared to placebo. A search through a data base of 2,400 patients revealed 4 cases in which drug-related neutropenia could not be ruled out. Two had a single low value on the last day of treatment. Two had stable, non-progressive neutrophil counts in the 1000/mm3 range over periods of 20 and 40 weeks. No patients became symptomatic as a result of the low WBC or neutrophil counts.
In BPH patients treated with doxazosin, the incidence of clinically significant WBC abnormalities was 0.4%.
In post-marketing experience, rare cases of hematopoietic events such as leukopenia and thrombocytopenia have been reported.
Hepatic Events
In post-marketing experience, rare cases of abnormal liver function tests, cholestasis, jaundice and hepatitis have been reported.
Peripheral Edema
Fluid retention resulting in weight gain may occur during CARDURA therapy. In placebo-controlled monotherapy trials, patients receiving CARDURA gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo-treated patients. The overall incidence of body weight gain reported as a side effect in controlled clinical trials was 0.8%.
PRECAUTIONS
General
CARDURA (doxazosin mesylate) therapy does not modify the natural history of benign prostatic hyperplasia (BPH). It does not retard or stop the progression of BPH, nor does it improve urine flow sufficiently to significantly reduce the residual urine volume. However, significant reduction of the mean residual volume have been shown in patients with baseline residual volumes of >50 mL. The patient may continue to be at risk of developing urinary retention and other BPH complications during doxazosin therapy.
Long-Term Safety and Efficacy
The long-term safety and efficacy (i.e., >4 years) has not yet been established for the use of doxazosin in the treatment of benign prostatic hyperplasia.
Prostatic Cancer
Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined prior to starting CARDURA therapy to rule out the presence of carcinoma of the prostate. CARDURA should not be used in patients with PSA >10 ng/mL unless cancer of the prostate has been ruled out.
Use in Patients with Impaired Liver Function
As with any drug wholly metabolized by the liver, doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism.
Use in Patients with Impaired Renal Function
The use of CARDURA in patients with impaired renal function requires careful monitoring. Clinical studies indicate that the disposition of CARDURA in patients with renal insufficiency is similar to that in patients with normal renal function, however accumulation of the drug with chronic dosing may occur. Less than 10% of the dose of doxazosin is excreted in the urine as unchanged drug and metabolites.
Concomitant Conditions
Doxazosin should not be prescribed to patients with symptomatic BPH who have the following concomitant conditions:
Chronic urinary retention, high residual urine (over 200 mL), peak urine flow of 5 mL/sec or less, history of prior prostatic surgery, chronic fibrous or granulomatous prostatitis, urethral stricture, history of pelvic irradiation, presence of prostatic calculi, presence of large median lobe of prostate, presence of calculi in urinary bladder, recent history of epididymitis, gross hematuria, presence of neurogenic bladder dysfunction (diabetes mellitus, Parkinsonism, uninhibited neurogenic bladder, etc.), hydronephrosis, presence of carcinoma of the prostate. Nor should doxazosin be prescribed to patients having experienced a myocardial infarction, transient ischemic attacks, or cerebrovascular accident within the past 6 months.
Use in Pregnancy
There are no studies in pregnant women. CARDURA is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus.
CARDURA crosses the placental barrier.
Studies in pregnant rabbits and rats at daily oral doses of up to 40 and 20 mg/kg, respectively, have revealed no evidence of teratogenic effect. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival, an increase in embryomortality as well as increases in fetal and placental weights.
In peri- and post-natal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin was delayed as evidenced by slower body weight gain and a slightly later appearance of anatomical features and reflexes.
Use in Nursing Mothers
Studies in lactating rats indicate that doxazosin accumulates in rat breast milk. It is not known whether this drug is excreted in human milk. Caution should be exercised when CARDURA is administered to a nursing mother and in general, nursing should be interrupted.
Use in Children
The use of CARDURA is not recommended in children since safety and efficacy have not been established.
Use in Elderly
CARDURA should be used cautiously in elderly patients because of the possibility of postural hypotension. There was an age-related trend towards an increased incidence of postural hypotension and postural dizziness in elderly hypertensive patients treated with this drug.
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.
Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months. 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 and Wistar rats at maximum doses of 20 and 100 mg/kg/day, respectively. There is no evidence that similar lesions occur in humans.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated concentrations (highest dose 40 mg/kg/day) revealed no evidence of carcinogenicity in rats. There was also no evidence of carcinogenicity in a similar study conducted in mice (up to 18 months of dietary administration). The mouse study, however, was compromised by the failure to use a maximally tolerated dose of doxazosin. A subsequent 24-month dietary study of doxazosin mesylate at maximally tolerated concentrations (highest dose 120 mg/kg/day) showed no carcinogenic effect in mice.
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. This effect was reversible within two weeks of drug withdrawal.
Drug Interactions
Doxazosin is highly (98%) bound to plasma protein. In vitro data in human plasma indicates that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin.
CARDURA has been administered to patients receiving thiazide diuretics, beta-adrenergic blocking agents and non-steroidal anti-inflammatory drugs. No unexpected interactions were reported. An additive hypotensive effect was observed when CARDURA was co-administered with thiazide diuretics and beta-adrenergic blocking agents. There is limited experience with CARDURA in combination with ACE inhibitors or calcium channel blockers. Digoxin
Serum digoxin concentrations were not affected by treatment with doxazosin.
Cimetidine
In a randomized, open-label, cross-over study in 22 male subjects, the single co-administration of 1 mg doxazosin with 400 mg b.i.d. cimetidine 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 effect of further administration of cimetidine has not been studied.
PDE-5 Inhibitors
Symptomatic hypotension has been reported during the concomitant use of PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) and CARDURA (see WARNINGS).
ADVERSE REACTIONS
Hypertension
CARDURA (doxazosin mesylate) has been administered to approximately 4,000 patients in clinical trials of whom 1,679 patients were included in controlled trials. The most serious adverse event occurring in the controlled clinical trials was syncope occurring in 0.7% of patients and resulting in a discontinuation rate of 0.2%.
The most frequent adverse events in controlled clinical trials were: headache (16.5%), fatigue/malaise (14.8%), dizziness (14.6%), postural dizziness (8.7%) and edema (6.6%). Discontinuation of CARDURA due to adverse events was required in 7% of patients.
Adverse events which occurred with an incidence of ≥ 1% in the controlled clinical trials in patients with mild to moderate essential hypertension were as shown in the following table.
ADVERSE EVENT INCIDENCE (n=1679)
All Adverse Events 49.0%
Headache 16.5%
Fatigue 14.8%
Dizziness 14.6%
Postural Dizziness 8.7%
Edema 6.6%
Somnolence 4.9%
Nausea 3.9%
Dyspnea 3.9% ADVERSE EVENT INCIDENCE (n=1679)
Decrease in Platelets 3.9%
Palpitation 3.6%
Sexual Dysfunction 3.5%
Dry Mouth 3.4%
Vertigo 3.0%
Rhinitis 3.0%
Diarrhea 2.9%
Chest Pain 2.7%
Asthenia 2.7%
Vision/Accommodation Abnormalities 2.4%
Decrease in White Blood Cells 2.4%
Anxiety/Nervousness 2.3%
Insomnia 2.2%
Dyspepsia 2.1%
Rash 1.7%
Paresthesia 1.7%
Muscle Cramps 1.7%
Tachycardia 1.6%
Depression/Apathy 1.6%
Hypoesthesia 1.6%
Abdominal Pain 1.6%
Decrease in Hematocrit 1.6%
Increased Sweating 1.4%
Flatulence 1.4%
Decrease in Hemoglobin 1.4%
Pain (general body) 1.3%
Myalgia 1.3%
Constipation 1.3%
Conjunctivitis/Eye Pain 1.2%
Micturition Frequency 1.2%
Polyuria 1.0%
Decrease in Neutrophil Count 1.0%
The following other adverse events occurred in hypertensive patients with an incidence of <1% in controlled clinical trials (n=1679): postural hypotension, arrhythmia, syncope, pruritus, arthralgia, agitation, flushing, tremor, paroniria, tinnitus, vomiting, epistaxis, sinusitis, bronchospasm/bronchitis, urinary incontinence, urinary disorder, face edema, weight increase, general edema, angina pectoris, peripheral ischemia, hypotension, paresis, twitching, migraine, amnesia, movement disorders, emotional lability, abnormal thinking, depersonalization, pallor, hypertonia, ataxia, thirst, gout, hypokalemia, lymphadenopathy, purpura, breast pain, alopecia, dry skin, eczema, taste perversion, photophobia, abnormal lacrimation, increased appetite, anorexia, fecal incontinence, coughing, pharyngitis, hot flushes, back pain, infection, fever/rigors and muscle weakness.
Benign Prostatic Hyperplasia
CARDURA (doxazosin mesylate) has been administered once daily to 665 both hypertensive and normotensive patients with BPH in controlled clinical trials. The most serious adverse event occurring in the controlled trials was syncope (0.5%).
The most frequent adverse events in controlled trials were dizziness (15.6%), headache (9.8%) and fatigue (8%).
Discontinuation rate of CARDURA due to adverse events was 9%.
Adverse events which occurred with an incidence of ≥ 1% in the controlled clinical trials in normotensive or hypertensive patients with BPH were as shown in the following table.
ADVERSE EVENT INCIDENCE
Short Term*
(n=665)
Long Term** (n=450)
All Adverse Events 45.0% 66.0%
Dizziness 15.6% 20.7%
Headache 9.8% 12.2%
Fatigue 8.0% 11.6%
Somnolence 3.0% 4.9%
Edema 2.7% 4.9%
Dyspnea 2.6% <1%
Diarrhea 2.3% 3.8%
Abdominal Pain 2.3% 1.8%
Pain 2.0% 5.1%
Back Pain 1.8% 2.9%
Dyspepsia 1.8% 2.4%
Hypotension 1.7% 2.5% ADVERSE EVENT INCIDENCE
Short Term*
(n=665)
Long Term** (n=450)
Nausea 1.5% 3.1%
Dry Mouth 1.4% <1%
Abnormal Vision 1.4% 2.2%
Palpitation 1.2% 1.8%
Chest Pain 1.2% 3.8%
Insomnia 1.2% 1.3%
Urinary Tract Infection 1.2% 1.1%
Anxiety 1.1% <1%
Respiratory Disorder 1.1% 2.5%
Impotence 1.1% 4.9%
Increased Sweating 1.1% <1%
Leg Cramps <1% 1.6%
Hypertonia <1% 1.1%
Paresthesia <1% 1.1%
Tremor - 1.1%
Asthenia <1% 1.1%
Depression <1% 3.1%
Decreased Libido <1% 2.7%
Constipation <1% 1.3%
Prostatic Disorder <1% 1.8%
Ejaculation Failure <1% 1.1%
Urinary Retention <1% 1.6%
Dermatitis - 1.3%
Rash <1% 1.3%
Arthralgia <1% 1.3%
Arrhythmia - 1.1%
Myocardial Infarction <1% 1.3%
Hematuria <1% 1.8%
Tinnitus <1% 1.3% * Placebo-controlled clinical trials; treated with doxazosin from 1-203 days. ** Open label extension of 3 placebo controlled clinical trials; treated for up to 50 months.
The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in short-term controlled clinical trials (n=665): tachycardia, angina, syncope, postural hypotension, pruritus, rash, myalgia, paresthesia, flushing, conjunctivitis, tinnitus, decreased libido, depression, nervousness, flatulence, rhinitis, epistaxis, carcinoma, dysuria, asthenia, influenza like symptoms, viral infection, fever, weight increase, malaise, myocardial infarction, bradycardia, sudden death, pallor, hyperglycemia, gout, lymphadenopathy, prostatic disorder, ejaculation failure, epididymitis, dry skin, genital pruritus, urticaria, maculopapular rash, erythematous rash, aggravated psoriasis, eczema, hypoesthesia, hypertonia, leg cramps, confusion, speech disorder, ataxia, abnormal thinking, depersonalization, paroniria, emotional lability, impaired concentration, amnesia, earache, taste perversion, eye pain, visual field defect, cataract, melena, constipation, vomiting, gingivitis, increased appetite, coughing, bronchospasm, bronchitis, upper respiratory tract infection, sinusitis, pneumonia, urinary retention, micturition disorder, abnormal urine, renal pain, urinary incontinence, cystitis, arthritis, tendon disorder, arthalgia, hernia, rigors, hot flushes, allergy, sepsis, fungal infection, hematuria and subarachnoid hemorrhage.
The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in long-term controlled clinical trials (n=450): convulsions, encephalopathy, hypokinesia, migraine, fever, malaise, rigor, enlarged abdomen, allergic reaction/allergy, weight increase, nervousness, amnesia, anxiety, depersonalization, impaired concentration, abnormal thinking, flatulence, melena, vomiting, rectal hemorrhage, abnormal semen, tooth disorder, increased appetite, diverticulitis, esophagitis, gastric ulcer, tenesmus, tongue disorder, tooth hypoplasia, syncope, aneurysm, cardiac failure, abnormal ECG, hypertension, epistaxis, pharyngitis, rhinitis, bronchitis, pulmonary carcinoma, epididymitis, perineal pain, cystitis, dysuria, polyuria, urinary incontinence, oliguria, abnormal urine, increased sweating, seborrhea, maculopapular rash, skin disorder, nail disorder, photosensitivity reaction, pruritus, skin hypertrophy, urticaria, conjunctivitis, diplopia, eye abnormality, eye pain, myopia, visual field defect, myalgia, arthritis, polymyalgia rheumatica, atrial fibrillation, tachycardia, extra systoles, angina pectoris, myocardial ischemia, flushing, dry mouth, aggravated hypertension, sexual dysfunction, purpura, deafness, earache, cerebrovascular disorder/accident, intermittent claudication, carcinoma, herpes simplex, herpes zoster, fungal infection, otitis media, dehydration, hyperglycemia, hyperuricemia, cholelithiasis, SGOT increase, SGPT increase and breast neoplasm.
Data from long-term (up to 50 months), open BPH studies (n=450) indicate higher rates of dizziness in younger hypertensive (27%) and normotensive (22%) patients, impotence in younger hypertensive (8%) patients, and discontinuation rates in patients due to adverse events (16.7%) compared to data from short-term placebo-controlled BPH studies (n=665).
Uncontrolled Trials and Post-Marketing Experience
The following additional adverse events have also been reported in patients with essential hypertension and in normotensive or hypertensive patients with BPH: parosmia, renal calculus, priapism, ejaculation disorders such as retrograde ejaculation, jaundice, cholestasis and hepatitis.
Laboratory Abnormalities
No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen or creatinine. Decreases in white blood cells, neutrophils, platelets (see WARNINGS), hemoglobin and hematocrit have been reported. Abnormal liver function tests have occurred.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
No data are available regarding overdosage with CARDURA (doxazosin mesylate) in humans.
Should administration of CARDURA lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressors should be used. Renal function should be monitored and supported as needed. As CARDURA is highly protein bound, dialysis may not be of benefit.
DOSAGE AND ADMINISTRATION
Dosage must be individualized. Doxazosin may be administered either in the morning or in the evening.
The absorption of CARDURA (doxazosin mesylate) is not affected by food.
When CARDURA is being added to existing antihypertensive therapy, the patient should be carefully monitored for the occurrence of hypotension (see WARNINGS – Syncope and “First Dose” Effect). If a diuretic or other antihypertensive agent is being added to a CARDURA regimen, reducing the dose of CARDURA and retitration, with careful monitoring, may be necessary.
If CARDURA administration is discontinued for several days, or longer, therapy should be reinstituted using the initial dosing regimen.
Hypertension - 1-16 mg Once Daily
The initial dose of CARDURA in patients with hypertension is 1 mg given once daily and this dose should not be exceeded. This starting dose is intended to minimize postural hypotensive effects. The maximum reduction in blood pressure normally occurs between 2 and 6 hours after a dose.
The dose may be slowly increased to achieve the desired blood pressure response. The usual dose range is 1 to 8 mg once daily. The maximum recommended daily dose is 16 mg once daily.
Increases in dose beyond 4 mg increased the likelihood of excessive postural effects including syncope, postural dizziness/vertigo and postural hypotension. At a titrated dose of 16 mg once daily, the frequency of postural effects is about 12% compared to 3% for placebo.
Benign Prostatic Hyperplasia - 1-8 mg Once Daily
The initial dosage of CARDURA is 1 mg given once daily (see WARNINGS – Syncope and “First Dose” Effect). Depending on the individual patient's urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose. The recommended titration interval is 1-2 weeks. Blood pressure should be evaluated routinely in these patients.
Doxazosin should be discontinued if the drug has been increased to the maximum tolerated dose and improvement in urinary flowmetry is less than 25%, or if doxazosin side effects are more bothersome than BPH symptoms, or if the patient develops a urinary complication secondary to BPH while on doxazosin therapy.
PHARMACEUTICAL INFORMATION
Chemistry
Trade name: CARDURA*
Proper name: Doxazosin mesylate
Chemical Name: 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-
ylcarbonyl)piperazine methanesulfonate 
Structural Formula:
Molecular Formula: C23H25N5O5·CH4O3S
Molecular Weight: 547.6
Description: Doxazosin mesylate is a white to off-white crystalline solid of uniform appearance. It is freely soluble in dimethylsulphoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% w/v at 25°C), and very slightly soluble in acetone and methylene chloride. The pKa of the doxazosin moiety is 6.93 at 25°C and the melting point of doxazosin mesylate is 273.7°C.
Composition
CARDURA is formulated as white tablets containing doxazosin mesylate equivalent to 1, 2 and 4 mg of doxazosin.
Non-Medicinal Ingredients: microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate, and sodium lauryl sulphate.
Stability and Storage Recommendations
CARDURA (doxazosin mesylate) Tablets 1, 2 and 4 mg: store at room temperature, 15-30°C.
AVAILABILITY OF DOSAGE FORMS
Availability
CARDURA is available as white tablets containing doxazosin mesylate equivalent to 1, 2 or 4 mg of doxazosin. Tablets are engraved ASTRA on one side and CARDURA with 1, 2, or 4 on the other side, corresponding to the milligram tablet strength. CARDURA is supplied in opaque plastic (high density polyethylene) bottles of 100 tablets.