CARDURA™

Doxazosin mesilate:

1.213mg equivalent to 1mg doxazosin

2.43mg equivalent to 2mg doxazosin

For excipients, see 6.1.

Tablets for oral administration.

1mg round tablets marked CN1 on one side and 'PFIZER' on the other.

2mg oblong tablets marked CN2 on one side and 'PFIZER' on the other.

Hypertension: Cardura is indicated for the treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. In patients inadequately controlled on single antihypertensive therapy, Cardura may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

Benign prostatic hyperplasia:Cardura is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH). Cardura may be used in BPH patients who are either hypertensive or normotensive.

Cardura may be administered in the morning or the evening.

Hypertension: Cardura is used in a once daily regimen: the initial dose is 1mg, to minimise the potential for postural hypotension and/or syncope (see section 4.4). Dosage may then be increased to 2mg after an additional one or two weeks of therapy and thereafter, if necessary to 4mg. The majority of patients who respond to Cardura will do so at a dose of 4mg or less. Dosage can be further increased if necessary to 8mg or the maximum recommended dose of 16mg.

Benign prostatic hyperplasia: The recommended initial dosage of Cardura is 1mg given once daily to minimise the potential for postural hypotension and/or syncope (see section 4.4). Depending on the individual patient's urodynamics and BPH symptomatology dosage may then be increased to 2mg and thereafter to 4mg and up to the maximum recommended dose of 8mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4mg daily.

Children: The safety and efficacy of Cardura in children have not been established.

Elderly: Normal adult dosage.

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function, the usual adult dose of Cardura is recommended.

Cardura is not dialysable.

Patients with hepatic impairment: There are only limited data in patients with liver impairment and on the effect of drugs known to influence hepatic metabolism (e.g. cimetidine). As with any drug wholly metabolised by the liver, Cardura should be administered with caution to patients with evidence of impaired liver function (see section 4.4 and section 5.2).

Doxazosin is contraindicated in:

1) Patients with a known hypersensitivity to quinazolines (e.g. prazosin, terazosin, doxazosin), or any of the excipients

2) Patients with a history of orthostatic hypotension

3) Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones.

4) During lactation (please see section 4.6)

5) Patients with hypotension (for benign prostatic hyperplasia indication only)

Doxazosin is contraindicated as monotherapy in patients with either overflow bladder or anuria with or without progressive renal insufficiency.

Postural Hypotension/Syncope:

Initiation of Therapy - 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 (see section 4.2). Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects.

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 Cardura therapy.

Use in patients with Acute Cardiac Conditions:

As with any other vasodilatory anti-hypertensive agent it is prudent medical practice to advise caution when administering doxazosin to patients with the following acute cardiac conditions:

- pulmonary oedema due to aortic or mitral stenosis

- high-output cardiac failure

- right-sided heart failure due to pulmonary embolism or pericardial effusion

- left ventricular heart failure with low filling pressure.

Use in Hepatically Impaired patients:

As with any drug wholly metabolised by the liver, Cardura should be administered with particular caution to patients with evidence of impaired hepatic function (see section 4.2). Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

Use with PDE-5 Inhibitors:

Concomitant administration of doxazosin with phosphodiesterase-5-inhibitors (eg sildenafil, tadalafil, and vardenafil) should be done with caution as both drugs have vasodilating effects and may lead to symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension it is recommended to initiate the treatment with phosphodiesterase-5-inhibitors only if the patient is hemodynamically stabilized on alpha-blocker therapy. Furthermore, it is recommended to initiate phosphodiesterase-5-inhibitor treatment with the lowest possible dose and to respect a 6-hour time interval from intake of doxazosin. No studies have been conducted with doxazosin prolonged release formulations.

Use in patients undergoing cataract surgery:

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 tamsulosin. Isolated reports have also been received with other alpha-1 blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Phosphodiesterase-5-inhibitors (eg. sildenafil, tadalafil, vardenafil)

Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with doxazosin prolonged release formulations.

Doxazosin is highly bound to plasma proteins (98%). In vitro data in human plasma indicates that doxazosin has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indometacin).

Conventional doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta-blocking agents, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, or anticoagulants. However, data from formal drug/drug interaction studies are not present.

Doxazosin potentiates the blood pressure lowering activity of other alpha-blockers and other antihypertensives.

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 four-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.

For the hypertension indication:

Use during pregnancy: As there are no adequate and well-controlled studies in pregnant women, the safety of Cardura during pregnancy has not yet been established. Accordingly, Cardura should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk. Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at extremely high doses (see Section 5.3). These doses were approximately 300 times the maximum recommended human dose.

Use during lactation:

Doxazosin is contraindicated during lactation as animal studies have shown that doxazosin accumulates in milk of lactating rats, and there is no information about the excretion of the drug into the milk of lactating women. The clinical safety of Cardura during lactation has not been established, consequently Cardura is contra-indicated in nursing mothers.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (Please see section 5.3).

For the benign prostatic hyperplasia indication: This section is not applicable

The ability to drive or use machinery may be impaired, especially when initiating therapy.

Hypertension: In clinical trials involving patients with hypertension, the most common reactions associated with Cardura therapy were of a postural type (rarely associated with fainting) or non-specific.

Benign prostatic hyperplasia: Experience in controlled clinical trials in BPH indicates a similar adverse event profile to that seen in hypertension.

Frequencies used are as follows: Very common 1/10, Common 1/100 and < 1/10, Uncommon 1/1,000 and < 1/100, Rare 1/10,000 and < 1/1,000, Very rare < 1/10,000, Unknown (cannot be estimated from the available data).

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures may be appropriate in individual cases.

If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressor should then be used. Renal function should be monitored and supported as needed.

Since Cardura is highly protein bound, dialysis is not indicated.

Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor antagonist. This action results in a decrease in systemic blood pressure. Cardura is appropriate for oral administration in a once daily regimen in patients with essential hypertension.

Cardura has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance.

Cardura is suitable for use in patients with co-existent asthma, left ventricular hypertrophy and in elderly patients. Treatment with Cardura has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, Cardura improves insulin sensitivity in patients with impairment.

Cardura, in addition to its antihypertensive effect, has in long term studies produced a modest reduction in plasma total cholesterol, LDL-cholesterol and triglyceride concentrations and therefore may be of particular benefit to hypertensive patients with concomitant hyperlipidaemia.

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 alpha-adrenoceptors located in the muscular stroma and capsule of the prostate, and in the bladder neck.

Absorption: Following oral administration in humans (young male adults or the elderly of either sex), doxazosin is well absorbed and approximately two thirds of the dose is bioavailable.

Biotransformation/Elimination: Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is extensively metabolised in man and in the animal species tested, with the faeces being the predominant route of excretion.

The mean plasma elimination half-life is 22 hours thus making the drug suitable for once daily administration.

After oral administration of Cardura the plasma concentrations of the metabolites are low. The most active (6' hydroxy) metabolite is present in man at one fortieth of the plasma concentration of the parent compound, which suggests that the antihypertensive activity is in the main due to doxazosin.

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 metabolised by the liver, Cardura should be administered with caution to patients with impaired liver function (see section 4.4).

Preclinical data reveal no special hazard for humans based on conventional animal studies in safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. For further information see section 4.6.

Lactose, magnesium stearate, microcrystalline cellulose, sodium lauril sulfate and sodium starch glycollate.

Not applicable.

5 years.

Do not store above 30ºC.

Cardura 1mg and 2mg Tablets are available as calendar packs of 28 tablets. Aluminium/PVC/PVdC blister strips, 14 tablets/strip, 2 strips in a carton box.

No special requirements.

Pfizer Limited

Ramsgate Road

Sandwich

Kent, CT13 9NJ

United Kingdom

Cardura 1mg PL 00057/0276

Cardura 2mg PL 00057/0277

11 October 2006

August 2009

POM

Ref: CR10_3 UK