CARDURA™ XL 4mg CARDURA™ XL 8mg

Doxazosin mesilate:

4.85mg equivalent to 4mg doxazosin.

9.70mg equivalent to 8mg doxazosin.

For excipients, see 6.1.

Modified release tablet

Cardura XL 4mg and 8mg tablets are white, round, biconvex shaped tablets with a hole in one side, marked CXL4 and CXL8.

Hypertension: Cardura XL 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 XL 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 XL is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH).

Cardura XL may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are not usually clinically significant, patients with hypertension and BPH have had both conditions effectively treated with doxazosin monotherapy.

Hypertension and benign prostatic hyperplasia: The initial dose of Cardura XL is 4mg once daily. Over 50% of patients with mild to moderate severity hypertension will be controlled on Cardura XL 4mg once daily. Optimal effect of Cardura XL may take up to 4 weeks. If necessary, the dosage may be increased following this period to 8mg once daily according to patient response.

The maximum recommended dose of Cardura XL is 8mg once daily.

Cardura XL can be taken with or without food.

The tablets should be swallowed whole with a sufficient amount of liquid.

Children: The safety and efficacy of Cardura XL 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 XL is recommended. Doxazosin is not dialysable.

Patients with hepatic impairment: As with any drug wholly metabolised by the liver, Cardura XL should be administered with caution to patients with evidence of impaired hepatic function (see section 4.4 and section 5.2).

Cardura XL is contraindicated in:

1) Patients with a known hypersensitivity to quinazolines, (e.g. doxazosin, prazosin, terazosin), 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) Patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.

5) During lactation (see section 4.6)

6) 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.

Information to be given to the Patient: Patients should be informed that Cardura XL tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

In Cardura XL, the active compound is surrounded by an inert, non-absorbable shell that has been specially designed to control the release of the drug over a prolonged period. After transit through the gastrointestinal tract the empty tablet shell is excreted. Patients should be advised that they should not be concerned if they occasionally observe remains in their stools that look like a tablet.

Abnormally short transit times through the gastrointestinal tract (e.g. following surgical resection) could result in incomplete absorption. In view of the long half life of doxazosin the clinical significance of this is unclear.

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. 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 XL 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 XL should be administered with particular caution to patients with evidence of impaired hepatic function (see section 4.2 and section 5.2). 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.

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 indomethacin).

Conventional doxazosin has been administered without any adverse drug interactions in clinical experience with thiazide diuretics, frusemide, 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 XL during pregnancy has not yet been established. Accordingly, Cardura XL 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.

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

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

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

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

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 existing data).

The adverse events for Cardura XL are similar to those with immediate release doxazosin tablets.

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.

Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor antagonist.

Administration of Cardura XL 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-adrenoreceptors 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 dose. In patients with hypertension, the decrease in blood pressure during treatment with Cardura XL was similar in both the sitting and standing position.

Subjects treated with immediate release doxazosin tablets can be transferred to Cardura XL 4mg and the dose titrated upwards as needed.

Doxazosin 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.

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

Doxazosin, 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 XL 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 prostatic muscular stroma, capsule and bladder neck.

Absorption:After oral administration of therapeutic doses, Cardura XL 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 immediate release doxazosin tablets. Trough levels at 24 hours are, however, similar.

Peak/trough ratio of Cardura XL is less than half that of immediate release doxazosin tablets.

At steady-state, the relative bioavailability of doxazosin from Cardura XL compared to immediate release form was 54% at the 4mg dose and 59% at the 8mg dose.

Pharmacokinetic studies with Cardura XL 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 and hence this provides the basic for once daily dosing. Doxazosin is extensively metabolised with <5% excreted as unchanged drug.

Pharmacokinetic studies with doxazosin in patients with renal impairment also showed 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%.

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

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.

Polyethylene oxide, sodium chloride, hypromellose, red ferric oxide (E172), titanium dioxide (E171), magnesium stearate, cellulose acetate, Macrogol, pharmaceutical glaze, black iron oxide (E172), ammonium hydroxide and propylene glycol.

None stated.

2 years.

Do not store above 30°C.

Store in the original package.

Blister strips of aluminium foil/aluminium foil of 7 tablets in pack size of 28 tablets.

No special requirements.

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

Cardura XL 4mg PL 00057/0417

Cardura XL 8mg PL 00057/0418

6^th November 2006

September 2009

POM

Ref: CX8_2 UK