Cardura

Cardura

doxazosin

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Doxazosin mesylate.
Description
Each Cardura tablet contains the following inert ingredients: Sodium starch glycolate, microcrystalline cellulose, lactose, magnesium stearate and sodium lauryl sulfate.
Action
Pharmacology: Cardura exerts its vasodilatory effect via selective and competitive blockade of post-junctional α1-adrenoceptors.
Pharmacodynamics: Hypertension: Administration of Cardura 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 α1-adrenoceptors located in the vasculature. With once-daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hrs post-dose. In patients with hypertension, blood pressure reductions during treatment with Cardura were similar in both the sitting and standing positions.
Unlike nonselective α-adrenoceptor-blocking agents, tolerance has not been observed in long-term therapy with Cardura. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained doxazosin therapy.
Doxazosin produces favourable effects on blood lipids, with a significant increase in the HDL/total cholesterol ratio and significant reductions in total triglycerides and total cholesterol, thereby, reducing 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 impairments.
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 (BPH): Administration of Cardura 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 α-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 α1-adrenoceptor which accounts for >70% of the subtypes in the prostate. This accounts for the action in BPH patients.
In a controlled clinical BPH trial, treatment with doxazosin in patients with sexual dysfunction was associated with improvement in sexual function.
Pharmacokinetics: Absorption: After oral administration of therapeutic doses, Cardura is well absorbed with peak blood levels occurring at about 2 hrs. Pharmacokinetic studies in the elderly and patients with renal insufficiency have shown no significant alterations compared to younger patients with normal renal function. There have been no studies of patients with liver impairment, nor studies of the effects of drugs known to influence hepatic metabolism.
Biotransformation/Elimination: The plasma elimination is biphasic with the terminal elimination half-life being 22 hrs and hence, this provides the basis for once-daily dosing.
Cardura is extensively metabolised with <5% excreted as unchanged drug.
Biotransformation/Elimination: The plasma elimination is biphasic with the terminal elimination half-life being 22 hrs. 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 (eg, 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.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 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 2 weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Indications/Uses
Hypertension: 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, Cardura may be used in combination with another agent eg, a thiazide diuretic, a β-blocker, a calcium antagonist or an angiotensin-converting enzyme inhibitor.
Benign Prostatic Hyperplasia: Treatment of clinical symptoms in benign prostatic hyperplasia (BPH) and for reduced urinary flow associated with BPH. Cardura 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 Cardura monotherapy.
Dosage/Direction for Use
The optimal effect of doxazosin 4 mg 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.
Hypertension: Full Dosage Range: 1-16 mg daily. It is recommended that therapy be initiated at 1 mg given once daily for 1 or 2 weeks. 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 gradulally at similar intervals to 4, 8 and 16 mg as determined by patient response to achieve the desired reduction in blood pressure.
Usual Dose: 2-4 mg once daily.
Benign Prostatic Hyperplasia: Initial Dosage: 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 up to the maximum recommended dose of 8 mg.
Recommended Titration Interval: 1-2 weeks.
Usual Recommended Dose: 2-4 mg once daily.
Renal Impairment: 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.
Hepatic Impairment: See Precautions.
Elderly: Normal adult dosage is recommended.
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
Patients with known hypersensitivity to quinazolines, doxazosin or any of the excipients of Cardura.
Special Precautions
Postural Hypotension/Syncope: As with all α-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 α-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 PDE-5 Inhibitors: Concomitant administration of doxazosin with a 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 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 α1-blockers. As IFIS may lead to increased procedural complications during the operation, current or past use of α-blockers should be made known to the ophthalmologic surgeon in advance of surgery.
Effects on the Ability to Drive or Operate Machinery: The ability to engage in activities eg, operating machinery or a motor vehicle may be impaired, especially when initiating therapy.
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. Animal studies have shown that doxazosin accumulates in breastmilk.
As there are no adequate and well-controlled studies in pregnant or nursing women, the safety of doxazosin during pregnancy or lactation has not yet been established. Accordingly, during pregnancy or lactation, Cardura should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.
Use in Children: The safety and efficacy of doxazosin in children have not been established.
Use In Pregnancy & Lactation
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. Animal studies have shown that doxazosin accumulates in breastmilk.
As there are no adequate and well-controlled studies in pregnant or nursing women, the safety of doxazosin during pregnancy or lactation has not yet been established. Accordingly, during pregnancy or lactation, Cardura should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.
Adverse Reactions
Hypertension: In controlled hypertension clinical trials, the most common reactions associated with Cardura were of a postural type (rarely associated with syncope) or nonspecific, and included dizziness, headache, fatigue, malaise, postural dizziness, vertigo, edema, asthenia, somnolence, nausea and rhinitis. Extremely rare cases of urinary incontinence were reported; this effect may be related to Cardura's pharmacologic action. 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: Tachycardia, palpitation, chest pain, angina pectoris, myocardial infarction, cerebrovascular accidents and cardiac arrhythmias.
Benign Prostatic Hyperplasia: Experience in controlled clinical trials in BPH indicates a similar adverse event profile to that seen in hypertension.
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 Disorder: Tinnitus.
Eye Disorder: Blurred vision, IFIS (see Precautions).
Gastrointestinal Disorders: Constipation, diarrhea, dyspepsia, flatulence, dry mouth, vomiting.
General Disorders and Administration Site Conditions: Fatigue, malaise, pain.
Hepatobiliary Disorders: Cholestasis, hepatitis, jaundice.
Immune System Disorder: Allergic reaction.
Investigations: Abnormal liver function tests, increased weight.
Metabolism and Nutrition: Anorexia.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle cramps, muscle weakness.
Nervous System Disorders: Postural dizziness, hypoesthesia, paresthesia, syncope, tremor.
Psychiatric Disorders: Agitation, anxiety, depression, insomnia, nervousness.
Renal and Urinary Disorders: Dysuria, hematuria, micturition disorder and frequency, nocturia, polyuria, urinary incontinence.
Reproductive System and Breast Disorders: Gynecomastia, impotence, priapism, retrograde ejaculation.
Respiratory, Thoracic and Mediastinal Disorders: Aggravated bronchospasm, cough, 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 Precautions.
Others: Most (98%) of 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, furosemide, β-blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs, uricosuric agents or anticoagulants.
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
Tab 1 mg x 100's. 2 mg x 100's. 4 mg x 100's.
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