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SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

CARDURA 2mg Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin mesilate

2.43mg equivalent to 2mg doxazosin.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM Tablets

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2    Posology and method of administration Posology

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.

Paediatric population: The safety and efficacy of Cardura in children and adolescents have not been established.

Elderly patients: 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).

Method of administration

Oral administration

4.3    Contraindications

Doxazosin is contraindicated in:

1)    Hypersensitivity to the active substance or other types of quinazolines (e.g. prazosin, terazosin, doxazosin), or to any of the excipients listed in section 6.1.

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 (for the hypertension indication only 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.

4.4    Special warnings and precautions for use

Postural Hypotension/Syncope:

Initiation of Therapy - In relation with the alpha-blocking properties of

doxazosin, patients may experience 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.

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.

Screening for Prostate Cancer:

Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders can co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin for treatment of BPH symptoms.

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

4.5    Interaction with other medicinal products and other forms of interaction

Phosphodiesterase-5-inhibitors (e.g. 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, nonsteroidal 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.

4.6    Fertility, pregnancy and lactation

For the hypertension indication:

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, during pregnancy, 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.

Breast-feeding

Cardura 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 Cardura is necessary (see section 5.3).

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

4.7    Effects on ability to drive and use machines

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

4.8    Undesirable effects

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.

The following undesirable effects have been observed and reported during treatment with Cardura with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000).

System Organ Class	Very Common (>1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very Rare (<1/10,000)	Unknown
Infections and infestations		Respiratory tract infection, urinary tract infection
Blood and the lymphatic system disorders					Leukopenia 5 thrombocyt openia
Immune system disorders			Allergic drug reaction
Metabolism and nutrition disorders			Gout, increased appetite, anorexia

Psychiatric disorders			Agitation, depression, anxiety, insomnia, nervousness
Nervous system disorders		Somnolence dizziness, headache	Cerebrovascular accident, hypoesthesia, syncope, tremor		Dizziness postural, paresthesia
Eye disorders					Blurred vision	Intraoperativ e floppy iris syndrome (see section 4.4)
Ear and labyrinth disorders		Vertigo	Tinnitus
Cardiac disorders		Palpitation, tachycardia	Angina pectoris, myocardial infarction		Bradycardi a, cardiac arrhythmias
Vascular disorders		Hypotension, postural hypotension			Hot flushes
Respiratory, thoracic and mediastinal disorders		Bronchitis, cough, dyspnea, rhinitis	Epistaxis,		Bronchospa sm,
Gastrointestinal disorders		Abdominal pain, dyspepsia, dry mouth, nausea	Constipation, flatulence, vomiting, gastroenteritis diarrhoea
Hepato-biliary disorders			Abnormal liver function tests		Cholestasis, hepatitis, jaundice
Skin and subcutaneous tissue disorders		Pruritus	Skin rash		Urticaria, alopecia, purpura
Musculoskeletal, connective tissue and bone disorders		Back pain, myalgia	Arthralgia	Muscle cramps, muscle weakness
Renal and urinary disorders		Cystitis, urinary incontinence	Dysuria, micturition frequency, hematuria,	Polyuria	Increased diuresis, micturition disorder,

					nocturia
Reproductive system and breast disorders			Impotence		Gynecomas tia, priapism	Retrograde ejaculation
General disorders and administration site conditions		Asthenia, chest pain, influenzalike symptoms, peripheral oedema	Pain, facial oedema		Fatigue, malaise
Investigations			Weight increase

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

4.9    Overdose

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 doxazosin is highly protein bound, dialysis is not indicated.

5.1    Pharmacodynamic properties

Mode of action

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.

Pharmacodynamic effects

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.

5.2 Pharmacokinetic properties

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 doxazosin 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, doxazosin should be administered with caution to patients with impaired liver function (see section 4.4).

5.3 Preclinical safety data

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.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Lactose

10 DATE OF REVISION OF THE TEXT

22/11/2016