Cardura (Doxazosin Mesylate)

CARDURA-1™ CARDURA-2™ CARDURA-4™

Astra

Doxazosin Mesylate

Antihypertensive Agent – Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

Action And Clinical Pharmacology: The mechanism of action of doxazosin is selective blockade of alpha1 subtype of post-synaptic, post-junctional alpha-adrenergic receptors.

Pharmacodynamics: Hypertension: Administration of doxazosin 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 to 6 hours after dosing and are associated with a small increase in standing heart rate. Doxazosin 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 to 11 mmHg systolic and 5 to 9 mmHg diastolic. The response in the standing position tended to be larger by 3 to 5 mmHg. Peak blood pressure effects (1 to 6 hours) were larger by about 50 to 75% (i.e., trough values were about 55 to 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 doxazosin 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 the alpha1 adrenoceptor which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockage of the alpha1 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 alpha1A-adrenoceptor subtype, thought to be the predominant functional type in the prostate.

The effect of doxazosin in BPH is thought to result from selective blockade of the alpha1A-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 doxazosin was evaluated. In 2 studies doxazosin 4 to 8 mg once daily significantly improved maximum urinary flow rate (MFR) 2.3 to 3.3 mL/s (placebo 0.1 to 0.7 mL/s). Significant improvements were usually noticed within 2 weeks of commencing doxazosin treatment and a significantly larger proportion of patients (32 to 42%) responded with MFR improvements 3 mL/s (placebo 13 to 17%). As well, average flow rate also improved with doxazosin, 1.3 to 2.1 mL/s (placebo 0.2 to 0.3 mL/s). Doxazosin 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, doxazosin 2 mg improved MFR 3.4 mL/s, and reduced urethral resistance 7.5 to 13.5 cmH2O (placebo, MFR-0.6 mL/s and resistance of 3.3 cmH2O).

In a 29 week controlled BPH trial in 100 patients, doxazosin 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 doxazosin 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 doxazosin demonstrate statistically significant improvements in urodynamics and symptomatology compared to placebo.

Pharmacokinetics: After oral administration of therapeutic doses of doxazosin absorption occurs with peak blood levels at about 2 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 accumulation of plasma levels of doxazosin 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 doxazosin.

In a cross-over study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. Doxazosin may, therefore, be administered as a single daily morning or evening dose (see Dosage).

Doxazosin is extensively metabolized, mainly by 0-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.

The disposition of doxazosin 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 (see Precautions, Patients with Impaired Liver Function).

Indications And Clinical Uses: Hypertension: 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.

Doxazosin may be tried as a sole therapy in those patients in whom treatment with other agents caused adverse effects or is inappropriate.

Benign Prostatic Hyperplasia (BPH): Doxazosin 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 to 2 weeks. The effect on these variables was maintained over the entire study duration (up to 4 years). Doxazosin may be used in BPH patients who are either hypertensive or normotensive.

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.

Contra-Indications: Patients with a known sensitivity to doxazosin or quinazolines.

Manufacturers’ Warnings In Clinical States: Syncope and “First Dose” Effect: Doxazosin 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 doxazosin the incidence of syncopal episodes was 0.7%. Initial dose of 1 mg/day resulted in a 4% incidence of postural side effects with no cases of syncope. In controlled clinical trials in BPH in normotensive patients, there was a 0.2% occurrence of syncope with doxazosin. In controlled trials in patients with both BPH and hypertension receiving doxazosin, the incidence of syncope was 0.8%.

The likelihood of syncopal episodes or excessive hypotension can be minimized by limiting the initial dose of doxazosin to 1 mg, by increasing the dosage slowly and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see Dosage).

Occupational Hazards: 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 doxazosin 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 and if this measure is inadequate, volume expansion with i.v. fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin.

Priapism: Rarely (probably less frequently than once in every several thousand patients), alpha1-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.

Precautions: General: Doxazosin 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 volume 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 doxazosin therapy to rule out the presence of carcinoma of the prostate.

Doxazosin should not be used in patients with PSA >10 ng/mL unless cancer of the prostate has been ruled out.

Orthostatic Hypotension: While syncope is the most severe orthostatic effect of doxazosin (see Warnings), 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 5% at 1 to 4 mg and 3% in the placebo group.

In placebo controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin 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 doxazosin and 1/1 mm Hg with placebo.

Patients with occupations in which such events represent potential problems should be treated with particular caution.

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 doxazosin, 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.

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.

Patients with Impaired Renal Function: The use of doxazosin in patients with impaired renal function requires careful monitoring. Clinical studies indicate that the disposition of doxazosin 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/s 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.

Patients with recent history of myocardial infarction, transient ischemic attacks, or cerebrovascular accident within the past 6 months.

Pregnancy: There are no studies in pregnant women. Doxazosin is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus.

Doxazosin 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-postnatal 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.

Lactation: 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 doxazosin is administered to a nursing mother and in general, nursing should be interrupted.

Children: The use of doxazosin is not recommended in children since safety and efficacy have not been established.

Geriatrics: Doxazosin 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.

Peripheral Edema: Fluid retention resulting in weight gain may occur during doxazosin therapy. In placebo controlled monotherapy trials, patients receiving doxazosin gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients. The overall incidence of body weight gain reported as a side effect in controlled clinical trials was 0.8%.

Leukopenia/Neutropenia: Analysis of hematologic data from patients receiving doxazosin 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 1 000/mmrange over periods of 20 and 40 weeks. No patients became symptomatic as a result of the low WBC or neutrophil counts.

In BPH patients the incidence of clinically significant WBC abnormalities was 0.4% with doxazosin.

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 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 similarly conducted study (up to 18 months of dietary administration) in mice. 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 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 2 weeks of drug withdrawal.

Drug Interactions: Doxazosin is highly (98%) bound to plasma protein. In vitro data in human plasma indicates that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin.

Doxazosin has been administered to patients receiving thiazide diuretics, beta-adrenergic blocking agents and nonsteroidal anti-inflammatory drugs. No unexpected interactions were reported. An additive hypotensive effect was observed when doxazosin was coadministered with thiazide diuretics and beta-adrenergic blocking agents. There is limited experience with doxazosin 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 coadministration 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.

Adverse Reactions: Hypertension: Doxazosin 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 reaction 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 reactions 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 doxazosin due to adverse reactions was required in 7% of patients.

The following other adverse reactions occurred with an incidence of 0.5% in the controlled clinical trials program (n=1 679): Cardiovascular: palpitation (3.6%); vertigo (3.0%); tachycardia (1.6%); postural hypotension (0.9%); arrhythmia (0.8%); syncope (0.7%).

Skin and Appendages: rash (1.7%); pruritus (0.8%).

Musculoskeletal: myalgia (1.3%); arthralgia (0.8%).

Nervous System: somnolence (4.9%); sexual dysfunction (3.5%); dry mouth (3.4%); anxiety/nervousness (2.3%); insomnia (2.2%); paresthesia (1.7%); depression/apathy (1.6%); increased sweating (1.4%); hypoesthesia (1.6%); agitation (0.7%); flushing (0.7%); tremor (0.6%); paroniria (0.5%).

Special Senses: vision/accommodation abnormality (2.4%); conjunctivitis/eye pain (1.2%); tinnitus (0.8%).

Gastrointestinal: nausea (3.9%); diarrhea (2.9%); dyspepsia (2.1%) abdominal pain (1.6%); flatulence (1.4%); constipation (1.3%); vomiting (0.7%).

Respiratory: dyspnea (3.9%); rhinitis (3.0%); epistaxis (0.8%); sinusitis (0.6%); bronchospasm/bronchitis (0.5%).

Urinary: micturition frequency (1.2%); polyuria (1.0%); urinary incontinence (0.8%); urinary disorder (0.7%).

General Body: chest pain (2.7%); asthenia (2.7%); muscle cramps (1.7%); pain (1.3%); face edema (0.8%); weight increase (0.8%); general edema (0.5%).

Hematology: decreases in platelets (3.9%), white blood cell (2.4%), hematocrit (1.6%), hemoglobin (1.4%), neutrophil count (1.0%) (see Precautions).

Cardiovascular: angina pectoris, peripheral ischemia, hypotension.

Nervous System: paresis, twitching, migraine, amnesia, movement disorders, emotional lability, abnormal thinking, depersonalization, pallor, hypertonia, ataxia.

Metabolic: thirst, gout, hypokalemia.

Hematopoietic: lymphadenopathy, purpura.

Reproductive: breast pain.

Skin Disorders: alopecia, dry skin, eczema.

Special Senses: taste perversion, photophobia, abnormal lacrimation.

Gastrointestinal: increased appetite, anorexia, fecal incontinence.

Respiratory: coughing, pharyngitis.

General Body: hot flushes, back pain, infection, fever/rigors, muscle weakness.

In uncontrolled trials or postmarketing experience the following occurred with an incidence of less than 0.5%: myocardial infarction, cerebrovascular accident, confusion, impaired concentration, pallor, parosmia, earache, tinnitus, renal calculus, influenza-like symptoms, priapism, jaundice.

No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, urea nitrogen or creatinine. Doxazosin has been associated with decreases in white blood cell count (see Precautions). Isolated cases of elevated liver transaminases have occurred.

Benign Prostatic Hyperplasia: Doxazosin has been administered once daily to 665 both hypertensive and normotensive patients with BPH in controlled clinical trials. The most serious adverse reaction occurring in the controlled trials was syncope (0.5%).

The most frequent adverse reactions in controlled trials were dizziness (15.6%), headache (9.8%) and fatigue (8%).

Discontinuation rate of doxazosin due to adverse reactions was 9%.

The following other adverse reactions occurred with an incidence of ³0.5% in the controlled clinical BPH trials (n=665 doxazosin patients):

Cardiovascular: dizziness (15.6%); edema (2.7%); hypotension (1.7%); palpitation (1.2%); tachycardia (0.9%); angina (0.6%); syncope (0.5%); postural hypotension (0.3%).

Skin and Appendages: increased sweating (1.1%); pruritus (0.5%); rash (0.5%).

Musculoskeletal: myalgia (0.6%).

Central and Peripheral Nervous System: headache (9.8%); paresthesia (0.6%).

Autonomic: dry mouth (1.4%); flushing (0.6%).

Special Senses: abnormal vision (1.4%); conjunctivitis (0.5%); tinnitus (0.5%).

Psychiatric: somnolence (3.0%); insomnia (1.2%); anxiety (1.1%); libido decrease (0.8%); depression (0.6%); nervousness (0.5%).

Gastrointestinal: diarrhea (2.3%); abdominal pain (2.3%); dyspepsia (1.8%); nausea (1.5%); flatulence (0.8%).

Respiratory: dyspnea (2.6%); respiratory disorder (1.1%); rhinitis (0.8%); epistaxis (0.6%).

Reproductive Disorders: impotence (1.1%).

Neoplasm: carcinoma (0.5%).

Urinary: urinary tract infection (1.2%); dysuria (0.5%).

General: fatigue (8%); pain (2%); back pain (1.8%); chest pain (1.2%); asthenia (0.8%); influenza-like symptoms (0.8%); viral infection (0.6%); fever (0.5%); weight increase (0.5%); malaise (0.5%).

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.

Cardiovascular: myocardial infarction, bradycardia, sudden death.

Autonomic Nervous System: pallor.

Metabolic: hyperglycemia, gout.

Hematopoietic: lymphadenopathy.

Reproductive: prostatic disorder, ejaculation failure, epididymitis.

Skin Disorders: dry skin, genital pruritus, urticaria, maculopapular rash, erythematous rash, aggravated psoriasis, eczema.

CNS: hypoesthesia, hypertonia, leg cramps, confusion, speech disorder, ataxia.

Psychiatric: abnormal thinking, depersonalization, paroniria, emotional lability, impaired concentration, amnesia.

Special Senses: earache, taste perversion, eye pain, visual field defect, cataract.

Gastrointestinal: melena, constipation, vomiting, gingivitis, increased appetite.

Respiratory: coughing, bronchospasm, bronchitis, upper respiratory tract infection, sinusitis, pneumonia.

Urinary: urinary retention, micturition disorder, abnormal urine, renal pain, urinary incontinence, cystitis.

Musculoskeletal: arthritis, tendon disorder, arthralgia, hernia.

General Body: rigors, hot flushes, allergy, sepsis, fungal infection.

Platelet Bleeding and Clotting Disorder: hematuria, subarachanoid hemorrhage.

Data from long-term (up to 50 months), open BPH studies (n=450) indicate a higher rate 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).

A summary of selected adverse events, with an incidence of 1.0%, experienced by patients treated with doxazosin in short-term placebo-controlled and long-term, open clinical trials is outlined in Table I.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available in regard to overdosage with doxazosin in humans.

Should administration of doxazosin 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 doxazosin is highly protein bound, dialysis may not be of benefit.

Dosage And Administration: Dosage must be individualized.

The absorption of doxazosin is not affected by food.

When doxazosin is being added to the existing antihypertensive therapy, the patient should be carefully monitored for the occurrence of hypotension. If a diuretic or other antihypertensive agent is being added to doxazosin regimen, dosage reduction of doxazosin and retitration with careful monitoring may be necessary.

If doxazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen.

Hypertension: 1 to 16 mg Once Daily: The initial dose of doxazosin 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 to 8 mg Once Daily: The initial dosage of doxazosin is 1 mg given once daily. 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 to 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.

Availability And Storage: 1 mg: Each white tablet, engraved ASTRA on one side and CARDURA with 1 on the other side, contains: doxazosin mesylate equivalent to doxazosin 1 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Gluten- and tartrazine-free. Opaque plastic (high density polyethylene) bottles of 100.

2 mg: Each white tablet, engraved ASTRA on one side and CARDURA with 2 on the other side, contains: doxazosin mesylate equivalent to doxazosin 2 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Gluten- and tartrazine-free. Opaque plastic (high density polyethylene) bottles of 100.

4 mg: Each white tablet, engraved ASTRA on one side and CARDURA with 4 on the other side, contains: doxazosin mesylate equivalent to doxazosin 4 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Gluten- and tartrazine-free. Opaque plastic (high density polyethylene) bottles of 100.

Store at room temperature, 15 to 30°C. (Shown in Product Recognition Section)

CARDURA-1™ CARDURA-2™ CARDURA-4™ Astra Doxazosin Mesylate Antihypertensive Agent – Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

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