SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Doxazosin 4 mg Tablets Doxadura 4 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Doxazosin 4 mg (as mesilate).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets

Doxazosin 4mg is white to off-white, capsule shaped biconvex tablet, scored on both sides and marked “D4” on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension: Doxazosin 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, Doxazosin may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

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

4.2    Posology and method of administration

Doxazosin may be administered in the morning or the evening.

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

Benign prostatic hyperplasia: The recommended initial dosage of Doxazosin 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 2 mg and thereafter to 4 mg and up to the maximum recommended dose of 8 mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4 mg daily.

Children and Adolescents: The safety and efficacy of Doxazosin in children and adolescents 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 Doxazosin is recommended.

Doxazosin 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, Doxazosin should be administered with caution to patients with evidence of impaired liver function (see section 4.4 and section 5.2).

4.3 Contraindications

Doxazosin is contraindicated in:

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

2.    Patients with a history of orthostatic hypotension.

3.    During lactation (Please see section 4.6)

For benign prostatic hyperplasia indication only:

1.    Patients with concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones.

2.    Patients with hypotension.

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: 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 Doxazosin 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 with PDE-5 Inhibitors: Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and Doxazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk for developing postural hypotension the patient should be stable on alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors.

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.

Impaired liver 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 section 4.2). Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

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.

This medicine contains lactose. 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

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). No adverse drug interactions have been observed 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.

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and Doxazosin may lead to symptomatic hypotension in some patients (see section 4.4).

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 C_max 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    Pregnancy and lactation

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

Use during lactation: Doxazosin is contraindicated during lactation. Animal studies have shown that Doxazosin accumulates in breast milk of lactating rats. There is no information on the excretion of the drug into the milk of lactating women. The clinical safety of Doxazosin during lactation has not been established; consequently Doxazosin is contraindicated in nursing mothers.

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 Doxazosin 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: Very common > 1/10, Common > 1/100, Uncommon > 1/1,000, Rare > 1/10,000, Very Rare < 1/10,000, Unknown - cannot be estimated from available data.

MedDRA System Organ Class	Frequency	Undesirable effects
Infections and infestations	Common	Respiratory tract infection, urinary tract infection
Blood and Lymphatic Disorders	Very rare	Leucopenia, thrombocytopenia
Immune System Disorders	Uncommon	Allergic drug reaction
Metabolism and Nutrition Disorders	Uncommon	Gout, increased appetite, anorexia
Psychiatric Disorders	Uncommon	Agitation, depression, anxiety, insomnia, nervousness
Nervous System Disorders	Common	Somnolence, dizziness, headache

	Uncommon	Cerebrovascular accident, hypoesthesia, syncope, tremor
	Very rare	Postural dizziness, paraesthesia
Eye Disorders	Very rare	Blurred vision
	Unknown	Intraoperative floppy iris syndrome (see section 4.4)
Ear and Labyrinth Disorders	Common	Vertigo
	Uncommon	Tinnitus
Cardiac disorder	Common	Palpitation, tachycardia
	Uncommon	Angina pectoris, myocardial infarction
	Very rare	Bradycardia, cardiac arrhythmias
Vascular Disorders	Common	Hypotension, postural hypotension
	Very rare	Hot flushes
Respiratory, Thoracic and Mediastinal Disorders	Common	Bronchitis, cough, dyspnoea, rhinitis
	Uncommon	Epistaxis
	Very rare	Aggravated bronchospasm
Gastrointestinal Disorders	Common	Abdominal pain, dyspepsia, dry mouth, nausea
	Uncommon	Constipation, flatulence, vomiting, gastroenteritis, diarrhoea
Hepatobiliary Disorders	Uncommon	Abnormal liver function tests
	Very rare	Cholestasis, hepatitis, jaundice
Skin and Subcutaneous Tissue Disorders	Common	Pruritis
	Uncommon	Skin rash
	Very rare	Urticaria, alopecia, prupura
Musculoskeletal and Connective Tissue Disorders	Common	Back pain, myalgia
	Uncommon	Arthralgia
	Rare	Muscle cramps, muscles weakness
Renal and Urinary Disorders	Common	Cystitis, urinary incontinence
	Uncommon	Dysuria, micturition frequency, haematuria
	Rare	Polyuria
	Very rare	Increased diuresis, micturition disorder, nocturia
Reproductive System and Breast Disorders	Uncommon	Impotence
	Very rare	Gynaecomastia, priapism
	Unknown	Retrograde ejaculation

General Disorders and Administration Site Conditions	Common	Asthenia, chest pain, influenza-like symptoms, peripheral oedema
	Uncommon	Pain, facial oedema
	Very rare	Fatigue, malaise
Investigations	Uncommon	Weight increase

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard

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    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonist

ATC code: C02C A04

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

Doxazosin has been shown to be free of adverse metabolic effects and are suitable for use in patients with co-existent diabetes mellitus, gout and insulin resistance.

Doxazosin is suitable for use in patients with coexistent 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 Doxazosin 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 monohydrate magnesium stearate microcrystalline cellulose sodium lauryl sulphate sodium starch glycolate (type A) colloidal anhydrous silica

6.2    Incompatibilities

None

Shelf life

3 years

6.4    Special precautions for storage

No special precautions for storage.

6.5    Nature and contents of container

Aluminium PVC/PVDC blister:

28 tablets in a calendar pack.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Dexcel®-Pharma Ltd 7 Sopwith Way Drayton Fields Daventry Northamptonshire NN11 8PB UK

8    MARKETING AUTHORISATION NUMBER

PL 14017/0034

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/05/2002

02/03/2009

10 DATE OF REVISION OF THE TEXT

27/04/2015