Cardura/Cardura XL

Cardura/Cardura XL

doxazosin

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Doxazosin mesylate.
Description
Active ingredient: doxazosin.
Cardura: The tablets contain doxazosin mesylate salt equivalent to 2 mg doxazosin.
Cardura XL: The GITS tablets contain doxazosin mesylate equivalent to 4 mg and 8 mg doxazosin.
Excipients/Inactive Ingredients: Cardura: Doxazosin mesylate tablets include the following inert ingredients: sodium starch glycolate, microcrystalline cellulose, lactose, magnesium stearate and sodium lauryl sulfate.
Cardura XL: Doxazosin mesylate GITS tablets include the following inert ingredients: polyethylene oxide, sodium chloride, hydroxypropyl methylcellulose, red ferric oxide (E172), titanium dioxide (E171), magnesium stearate, cellulose acetate, macrogol, pharmaceutical glaze and black iron oxide (E172).
Action
Pharmacology: Pharmacodynamics: Hypertension: Cardura: Administration of doxazosin to hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once-daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hours post-dose. A gradual reduction in blood pressure occurs, with maximum reductions usually occurring 2 to 6 hours after dosing. In patients with hypertension, blood pressures during treatment with doxazosin were similar in both the supine and standing positions. Unlike non-selective alpha-adrenoceptor blocking agents, tolerance has not been observed in long-term therapy with doxazosin. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained therapy.
Doxazosin produces favorable effects on blood lipids, with a significant increase in the high-density lipoprotein (HDL)/total cholesterol ratio and significant reductions in total triglycerides and total cholesterol. It therefore confers an advantage over diuretics and beta-adrenoceptor blocking agents, which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favorable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in the risk of developing coronary heart disease.
Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation, and enhanced tissue plasminogen activator capacity. Additionally, doxazosin improves insulin sensitivity in patients who have impairment.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with asthma, diabetes, left ventricular dysfunction, and gout.
An in vitro study has demonstrated the antioxidant properties of the 6'- and 7'-hydroxy metabolites of doxazosin at concentrations of 5 μm.
In a controlled clinical trial in hypertensive patients, treatment with doxazosin was associated with improvement of erectile dysfunction. In addition, the patients who received doxazosin reported fewer new cases of erectile dysfunction than those who received other antihypertensive agents.
Cardura XL: Administration of doxazosin GITS to hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once-daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hours post dose. The majority of patients are controlled on the initial 4 mg dose of doxazosin GITS. In patients with hypertension, blood pressure reductions during treatment with doxazosin GITS were similar in both the sitting and standing positions.
Subjects treated with standard doxazosin for hypertension can be transferred to doxazosin GITS and titrated upwards, as needed, while maintaining efficacy and tolerability.
Unlike non-selective alpha-adrenoceptor blocking agents, tolerance has not been observed in long-term therapy with doxazosin GITS. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained doxazosin therapy.
Doxazosin produces favorable effects on blood lipids, with a significant increase in the high-density lipoprotein (HDL)/total cholesterol ratio and significant reductions in total triglycerides and total cholesterol. It, therefore, confers an advantage over diuretics and beta-adrenoceptor blocking agents, which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favorable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in risk of developing coronary heart disease.
Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation, and enhanced tissue plasminogen activator capacity. Additionally, doxazosin improves insulin sensitivity in patients who have impairment.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with asthma, diabetes, left ventricular dysfunction, and gout.
An in vitro study has demonstrated the antioxidant properties of the 6'- and 7'-hydroxy metabolites of doxazosin at concentrations of 5 micromolar.
Benign Prostatic Hyperplasia: Administration of doxazosin GITS to patients with symptomatic BPH results in a significant improvement in urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoceptors located in the muscular stroma and capsule of the prostate and in the bladder neck.
Doxazosin has been shown to be an effective blocker of the 1A subtype of the alpha-1- adrenoceptor, which accounts for over 70% of the subtypes in the prostate. This accounts for the action in BPH patients.
Doxazosin GITS has demonstrated sustained efficacy and safety in the long term-treatment of BPH.
Doxazosin GITS given in the recommended dosage regimen has little or no effect on blood pressure in normotensive patients.
In a controlled clinical BPH trial, treatment with doxazosin in patients with sexual dysfunction was associated with improvement in sexual function.
Pharmacokinetics: Absorption: Cardura: After oral administration of therapeutic doses, doxazosin is well absorbed with peak blood levels occurring at about 2 hours.
Cardura XL: After oral administration of therapeutic doses, doxazosin GITS is well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one-third of those of the same dose of standard doxazosin tablets. Trough levels at 24 hours are, however, similar.
The pharmacokinetic characteristics of doxazosin GITS will lead to a smoother plasma profile.
Peak/trough ratio of doxazosin GITS is less than half that of standard doxazosin tablets.
At steady state, the relative bioavailability of doxazosin from doxazosin GITS compared to the standard form was 54% at the 4 mg dose and 59% at the 8 mg dose.
Pharmacokinetic studies with doxazosin GITS in the elderly have shown no significant alterations compared to younger patients.
Biotransformation/Elimination: The plasma elimination is biphasic, with the terminal elimination half-life being 22 hours. This provides the basis for once-daily dosing. Doxazosin is extensively metabolized, with <5% excreted as unchanged drug.
Pharmacokinetic studies with standard doxazosin in patients with renal impairment have shown no significant alterations compared to patients with normal renal function.
There are only limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g., cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single-dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 40%. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution (see Precautions).
Approximately 98% of doxazosin is protein-bound in plasma.
Doxazosin is primarily metabolized by O-demethylation and hydroxylation.
Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.
Toxicology: Preclinical Safety Data: Carcinogenesis: Chronic dietary administration (up to 24 months) of doxazosin 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 the human AUC at a dose of 16 mg/day, respectively.
Mutagenesis: Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
Impairment of Fertility: Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 mg/kg/day (but not 5 or 10 mg/kg/day), about 4 times the human AUC at a dose of 12 mg/day. This effect was reversible within 2 weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Lactation: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.
Indications/Uses
Hypertension: Doxazosin/Doxazosin GITS is indicated for the treatment of hypertension and can be used as the initial agent to control blood pressure in the majority of patients. In patients not adequately controlled on a single antihypertensive agent, doxazosin may be used in combination with another agent such as a thiazide diuretic, a beta-blocker, a calcium antagonist or an angiotensin-converting enzyme inhibitor.
Benign Prostatic Hyperplasia: Cardura: Doxazosin is also indicated for the treatment of the urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH). Doxazosin may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are clinically insignificant, patients with hypertension and BPH have had both conditions effectively treated with doxazosin monotherapy.
Cardura XL: Doxazosin GITS is indicated for the treatment of clinical symptoms in benign prostatic hyperplasia (BPH) and for reduced urinary flow associated with BPH. Doxazosin GITS may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are clinically insignificant, patients with hypertension and BPH have had both the conditions effectively treated with doxazosin GITS monotherapy.
Dosage/Direction for Use
Cardura: Doxazosin may be administered either in the morning or in the evening.
Hypertension: The full dosage range of doxazosin is 1 mg to 16 mg daily. It is recommended that therapy be initiated at 1 mg once daily for 1 or 2 weeks to minimize the potential for postural hypotension and/or syncope (see Precautions). The dosage may then be increased to 2 mg once daily for an additional 1 or 2 weeks. If necessary, the daily dosage should then be increased gradually at similar intervals to 4 mg, 8 mg, and 16 mg, as determined by patient response, to achieve the desired reduction in blood pressure. The usual dose is 2 mg to 4 mg once daily.
Benign Prostatic Hyperplasia: The recommended initial dosage of doxazosin is 1 mg once daily to minimize the potential for postural hypotension and/or syncope (see Precautions). Depending on the individual patient's urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and up to the maximum recommended dose of 8 mg. The recommended titration interval is 1 to 2 weeks. The usual recommended dose is 2 to 4 mg once daily.
Cardura XL: Hypertension and Benign Prostatic Hyperplasia: Doxazosin GITS can be taken with or without food.
The GITS tablets should be swallowed whole with a sufficient amount of liquid. Patients should not chew, divide or crush the tablets (see Information for Patients under Precautions).
The initial dose of doxazosin GITS is 4 mg once daily. Over 50% of patients with mild to moderate severity hypertension will be controlled on doxazosin GITS 4 mg once daily. The optimal effect of doxazosin may take up to 4 weeks. If necessary, the dosage may be increased following this period to 8 mg once daily according to patient response.
The maximum recommended dose is 8 mg once daily.
Use in Elderly: Normal adult dosage is recommended.
Use in Renally Impaired Patients: Doxazosin is not dialysable. Since the pharmacokinetics of doxazosin are unchanged in patients with renal insufficiency, and there is no evidence that doxazosin aggravates existing renal dysfunction, the usual dosages may be used in these patients.
Use in Hepatically Impaired Patients: See Precautions.
Use in Children: The safety and efficacy of doxazosin in children have not been established.
Overdosage
Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head-down position. Other supportive measures should be performed if thought appropriate in individual cases. Since doxazosin is highly protein bound, dialysis is not indicated.
Contraindications
Doxazosin GITS is contraindicated in patients with a known hypersensitivity to quinazolines, doxazosin, or any of the inert ingredients.
Special Precautions
Postural Hypotension/Syncope: As with all alpha-blockers, a very small percentage of patients have experienced postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope), particularly with the commencement of therapy. When instituting therapy with any effective alpha-blocker, the patient should be advised how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of doxazosin therapy.
Use with Phosphodiesterase Type-5 Inhibitors: Concomitant administration of doxazosin with a phosphodiesterase type-5 (PDE-5) inhibitor should be used with caution as it may lead to symptomatic hypotension in some patients.
Impaired Hepatic Function: As with any drug wholly metabolized by the liver, doxazosin should be administered with caution to patients with evidence of impaired hepatic function (see Pharmacology: Pharmacokinetics under Actions).
Intraoperative Floppy Iris Syndrome: The intraoperative floppy iris syndrome (IFIS), a variant of small pupil syndrome has been observed during cataract surgery in some patients on or previously treated with alpha1-blockers. As IFIS may lead to increased procedural complications during the operation, current or past use of alpha-blockers should be made known to the ophthalmologic surgeon in advance of surgery.
Priapism: Prolonged erections and priapism have been reported with alpha-1 blockers including doxazosin in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
Information for Patients: Patients should be informed that doxazosin GITS should be swallowed whole. Patients should not chew, divide or crush the tablets. Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. In doxazosin GITS, the medication is contained within a non-absorbable shell that has been specially designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Effects on Ability to Drive and Use Machines: The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating doxazosin/doxazosin GITS therapy.
Cardura XL: Use with Phosphodiesterase Type-5 Inhibitors: No studies have been conducted with doxazosin GITS.
Gastrointestinal Disorders: Markedly reduced gastrointestinal (GI) retention times of doxazosin GITS may influence the pharmacokinetic profile and hence the clinical efficacy of the drug. As with any other non-deformable material, caution should be used when administering doxazosin GITS in patients with preexisting severe GI narrowing (pathologic or iatrogenic).
There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained-release formulation.
Use In Pregnancy & Lactation
Although no teratogenic effects were seen in animal testing with doxazosin, reduced fetal survival was observed in animals at extremely high doses. These doses were approximately 300 times the maximum human recommended dose.
A single case report demonstrated transfer of doxazosin into human breast milk and animal studies have shown that doxazosin accumulates in breast milk (see Pharmacology: Toxicology: Preclinical safety data under Actions).
As there are no adequate and well-controlled studies in pregnant or nursing women, the safety of doxazosin GITS during pregnancy or lactation has not yet been established. Accordingly, during pregnancy or lactation, doxazosin GITS should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.
Adverse Reactions
Cardura: Hypertension: In controlled clinical trials, the most common reactions associated with doxazosin were of a postural type (rarely associated with syncope) or non-specific and included: Ear and Labyrinth Disorders: vertigo.
Gastrointestinal Disorders: nausea.
General Disorders and Administration Site Conditions: edema, asthenia, fatigue, malaise.
Nervous System Disorders: dizziness, headache, postural dizziness, somnolence, syncope.
Respiratory, Thoracic and Mediastinal Disorders: rhinitis.
Benign Prostatic Hyperplasia: Experience in controlled clinical trials in BPH indicates a similar adverse event profile to that seen in hypertension.
In post-marketing experience, the following additional adverse events have been reported: Blood and Lymphatic Disorders: leukopenia, thrombocytopenia.
Ear and Labyrinth Disorders: tinnitus.
Eye Disorders: blurred vision, IFIS (see Precautions).
Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, mouth dry, vomiting.
General Disorders and Administrations Site Conditions: pain.
Hepatobiliary Disorders: cholestasis, hepatitis, jaundice.
Immune System Disorders: allergic reaction.
Investigations: abnormal liver function tests, weight increase.
Metabolism and Nutrition: anorexia.
Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, muscle cramps, muscle weakness, myalgia.
Nervous System Disorders: hypoesthesia, paresthesia, tremor.
Psychiatric Disorders: agitation, anxiety, depression, insomnia, nervousness.
Renal and Urinary Disorders: dysuria, hematuria, micturition disorder, micturition frequency, nocturia, polyuria, urinary incontinence.
Reproductive System and Breast Disorder: gynecomastia, impotence, priapism, retrograde ejaculation.
Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated, coughing, dyspnea, epistaxis.
Skin and Subcutaneous Tissue Disorders: alopecia, pruritus, purpura, skin rash, urticaria.
Vascular Disorders: hot flushes, hypotension, hypotension postural.
The following additional adverse events have been reported in marketing experience among patients treated for hypertension but these, in general, are not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin: bradycardia, tachycardia, palpitation, chest pain, angina pectoris, myocardial infarction, cerebrovascular accidents and cardiac arrhythmias.
Cardura XL: The following lists the common (>1%) adverse events reported in pre-marketing placebo-controlled clinical trials with doxazosin GITS. It is important to emphasize that events reported during therapy may not necessarily be caused by the therapy.
Hypertension: Cardiac Disorder: palpitation, tachycardia.
Ear and Labyrinth Disorders: vertigo.
Gastrointestinal Disorders: abdominal pain, mouth dry, nausea.
General Disorders and Administration Site Conditions: asthenia, chest pain, peripheral edema.
Musculoskeletal and Connective Tissue Disorders: back pain, myalgia.
Vascular Disorders: postural hypotension.
Nervous System Disorders: dizziness, headache.
Respiratory, Thoracic and Mediastinal Disorders: bronchitis, coughing.
Skin and Subcutaneous Tissue Disorders: pruritus.
Renal and Urinary Disorders: cystitis, urinary incontinence.
Benign Prostatic Hyperplasia: Ear and Labyrinth Disorders: vertigo.
General Disorders and Administration Site Conditions: asthenia, peripheral edema.
Gastrointestinal Disorders: abdominal pain, dyspepsia, nausea.
Infection and Infestations: influenza-like symptoms, respiratory tract infection, urinary tract infection.
Musculoskeletal and Connective Tissue Disorders: back pain, myalgia.
Nervous System Disorders: dizziness, headache, somnolence.
Respiratory, Thoracic and Mediastinal Disorders: bronchitis, dyspnea, rhinitis.
Vascular Disorders: hypotension, postural hypotension.
The incidence of adverse events following treatment with doxazosin GITS (41%) in clinical studies of patients with BPH was broadly similar to that following placebo (39%) and less than that following standard doxazosin (54%).
The adverse event profile in elderly (>65 years) BPH patients showed no difference from the profile in the younger population.
In post-marketing experience, the following additional adverse events have been reported: Blood and Lymphatic Disorders: leukopenia, thrombocytopenia.
Ear and Labyrinth Disorders: tinnitus.
Eye Disorders: blurred vision, IFIS (see Precautions).
Gastrointestinal Disorders: gastrointestinal obstruction, constipation, diarrhea, dyspepsia, flatulence, dry mouth, vomiting.
General Disorders and Administration Site Conditions: fatigue, malaise, pain.
Hepatobiliary Disorders: cholestasis, hepatitis, jaundice.
Immune System Disorders: allergic reaction.
Investigations: abnormal liver function tests, weight increase.
Metabolism and Nutrition: anorexia.
Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, muscle weakness.
Nervous System Disorder: dizziness postural, hypoesthesia, paresthesia, syncope, tremor.
Psychiatric Disorders: agitation, anxiety, depression, insomnia, nervousness.
Renal and Urinary Disorders: dysuria, hematuria, micturition disorder, micturition frequency, nocturia, polyuria, urinary incontinence.
Reproductive System and Breast Disorder: gynecomastia, impotence, priapism, retrograde ejaculation.
Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated, coughing, dyspnea, epistaxis.
Skin/Appendages: alopecia, pruritus, purpura, skin rash, urticaria.
Vascular Disorders: hot flushes, hypotension.
The following additional adverse events have been reported in marketing experience among patients treated for hypertension but these, in general, are not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin: bradycardia, tachycardia, palpitation, chest pain, angina pectoris, myocardial infarction, cerebrovascular accidents, and cardiac arrhythmias.
Drug Interactions
Use with PDE-5 Inhibitors: See Use with Phosphodiesterase Type-5 Inhibitors under Precautions.
CYP3A4 Inhibitors: In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering doxazosin with a strong CYP3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole (see Pharmacology: Pharmacokinetics under Actions).
Other: Most (98%) of the plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. Doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, frusemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs, uricosuric agents, or anticoagulants.
Cardura: In an open-label, randomized, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1 mg dose of doxazosin on Day 1 of a 4-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and no statistically significant changes in mean Cmax and mean half-life of doxazosin. The 10% increase in the mean AUC for doxazosin with cimetidine is within intersubject variation (27%) of the mean AUC for doxazosin with placebo.
Caution For Usage
Special Instructions for Use/Handling: Cardura XL: Not Applicable.
Incompatibilities: None.
Storage
Store below 30°C.
ATC Classification
C02CA04 - doxazosin ; Belongs to the class of alpha-adrenoreceptor antagonists, peripherally-acting antiadrenergic agents. Used in the treatment of hypertension.
Presentation/Packing
Cardura tab 2 mg x 100's. Cardura XL CR tab 4 mg x 100's.
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