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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Doxazosin 4mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin mesilate 4.85 mg equivalent to 4 mg doxazosin.

For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, capsule shaped, biconvex tablets plain on both sides.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of hypertension. As a mono-agent Doxazosin Tablets can control blood pressure in most hypertensive patients. In patients inadequately controlled on single antihypertensive therapy, doxazosin can be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist, or an angiotensin- converting enzyme inhibitor.

Doxazosin Tablets are also indicated for the treatment of urinary outflow obstruction and the symptoms associated with benign prostatic hyperplasia (BPH).

4.2    Posology and method of administration

Adults:

Hypertension: Doxazosin is taken in a once daily regimen. The initial dose is 1 mg. After one to two weeks of therapy, the dose may be increased to 2 mg and thereafter to 4mg. Most patients who will respond to doxazosin will do so at a dose of 4 mg daily or less. If necessary, the daily dosage can be further increased to 8 mg or to the maximum daily dose of 16 mg.

Benign prostatic hyperplasia: Initial dose is 1mg once daily. The dosage may then be increased, according to the individual patient’s response, to 2 mg and thereafter to 4mg and up to the maximum daily dose of 8mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4 mg daily.

Elderly : Normal adult dosage

Children: There is not enough experience to recommend the use of Doxazosin Tablets in children.

Patients with renal impairment: There is no change in pharmacokinetics of doxazosin in patients with impaired renal function. Normal adult dosage is therefore recommended. Doxazosin is not dialysable.

Patients with hepatic impairment: Since doxazosin is wholly metabolised by the liver, it should be used with caution in such patients.

Method of administration: For oral administration.

4.3 Contraindications

Doxazosin is contra-indicated 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)¹.

5)    Patients with hypotension .

Doxazosin is contraindicated as monotherapy in patients with overflow bladder, anuria or progressive renal insufficiency.

¹    For the hypertension indication only

₂

For benign prostatic hyperplasia indication only

4.4 Special warnings and precautions for use

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. Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects. 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

-    heart failure at high output

-    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, doxazosin should be administered with particular caution to patients with evidence of impaired, hepatic function. 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 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 of developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors.

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.

Doxazosin 4mg Tablets contains lactose. Therefore, it should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

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).

Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicates that doxazosin has no effect on protein binding of warfarin, digoxin, phenytoin or indometacin.

Conventional doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta- blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, and 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

As there are no adequate and well controlled studies in pregnant women, the safety of doxazosin during pregnancy has not been established. Accordingly, during pregnancy, doxazosin should be used only if the potential benefit outweighs the risk. Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at high doses. (see section 5.3).

Doxazosin is contraindicated during lactation as the drug 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)

4.7 Effects on ability to drive and use machines

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy.

4.8 Undesirable effects

Frequencies used are as follows: Very common > 1/10, Common > 1/100 and < 1/10, Uncommon > 1/1000 and < 1/100, Rare > 1/10,000 and <1/1,000, Very rare < 1/10,000

MedDRA System Organ Class	Frequency	Undesirable Effects
Infections and infestations	Common	Respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders	Very Rare	Leucopenia, thrombocytopenia
Immune System Disorders	Uncommon	Allergic drug reaction
Metabolism and Nutrition Disorders	Common Uncommon	Anorexia Gout, increased appetite
Psychiatric Disorders	Common	Anxiety, insomnia, nervousness
	Uncommon	Agitation, depression
Nervous System Disorders	Very common	Dizziness, headache
	Common	Dizziness postural, paraesthesia, somnolence
	Uncommon	Cerebrovascular accident, hypoesthesia, syncope, termor
Eye Disorders	Very Rare	Blurred vision
	Unknown	Introperative floppy iris syndrome (see section 4.4)
Ear and Labyrinth Disorders	Common	Vertigo
	Uncommon	Tinnitus
Cardiac Disorders	Common	Palpitation, tachycardia
	Uncommon	Angina pectoris, myocardial infarction, cardiac arrhythmias
	Very Rare	Bradycardia
Vascular Disorders	Common	Hypotension, postural hypotension
	Uncommon	Hot flushes
Respiratory, Thoracic and Mediastinal Disorders	Common	Bronchitis, cough, dyspnea, rhinitis
	Uncommon	Epistaxis, cough
	Very Rare	Bronchospasm aggravated
Gastrointestinal Disorders	Common	Abdominal pain, dyspepsia, dry mouth, nausea, diarrhoea
	Uncommon	Constipation, flatulence, vomiting, gastroenteritis
	Unknown	Taste disturbances
Hepatobiliary Disorders	Uncommon	Abnormal liver function tests
	Very Rare	Cholestasis, hepatitis, jaundice, abnormal liver function tests
Skin and Subcutaneous Tissue Disorders	Common	Pruritus
	Uncommon	Skin rash, alopecia, purpura
	Very Rare	Urticaria
Musculoskeletal and Connective Tissue Disorders	Common	Back pain, myalgia
	Uncommon	Arthralgia, muscle cramps, muscle weakness
Renal and Urinary Disorders	Common	Cystitis, urinary incontinence
	Uncommon	Dysuria, micturition frequency, hematuria, polyuria, urinary incontinence
	Very Rare	Increased diuresis, micturition disorder, nocturia
Reproductive System and Breast Disorders	Uncommon	Impotence

	Very Rare	Gynecomastia, priapism
	Unknown	Retrograde ejaculation
General Disorders and Administration Site Conditions	Common	Asthenia, chest pain, influenza-like symptoms, peripheral oedema, fatigue, malaise
	Uncommon	Pain, Facial oedema
Investigations	Uncommon	Weight increase

4.9 Overdose

Should overdose 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.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The ATC code of doxazosin is C02CA04. The ATC-classification is: Cardiovascular system; antihypertensives; adrenergic agents, peripherally acting; alpha-adrenoceptor blocking agents.

Doxazosin is a potent, competitive and selective antagonist of postjunctional alpha-1-adrenoceptors. It causes a decrease in systemic blood pressure and is suitable for oral administration in a once daily dosage regimen for patients with essential hypertension.

Doxazosin does not cause adverse metabolic side effects and it is therefore suitable for patients with coexistent insulin resistance, gout and coexistent diabetes mellitus.

Doxazosin is also suitable for patients with coexistent left ventricular hypertrophy, asthma and in elderly patients. Doxazosin treatment has been demonstrated to reduce left ventricular hypertrophy, inhibit platelet aggregation and enhances activity of tissue plasminogen activator. Doxazosin also improves insulin sensitivity in patients with insulin resistance.

Long term studies have shown that doxazosin also produces a modest reduction in total plasma cholesterol, LDL cholesterol and triglyceride concentrations. It may therefore be of benefit for hypertensive patients with concomitant hyperlipidaemia.

Doxazosin significantly improves symptoms such as hesitancy, impaired urinary stream, nocturia and urgency in patients with symptomatic BPH. Its action in BPH is thought to be due to the selective blockade of the alpha adrenoceptors in the prostatic muscular stroma, capsule and bladder neck.

5.2 Pharmacokinetic properties

Doxazosin is well absorbed after oral administration with peak blood levels reached between 2 and 4 hours and with a bioavailability of about 65%. The average plasma elimination half-life is 22 hours, thus making the drug suitable to be taken as a once daily regimen.

Doxazosin is highly metabolised in both humans and in animal species tested. It is mainly excreted in the faeces.

Following oral administration of doxazosin, the plasma concentrations of metabolites are low. The 6’ hydroxy metabolite is the most active metabolite and is present in humans at one fortieth of the plasma concentration of the parent compound. Hence doxazosin is the main antihypertensive component.

5.3 Preclinical safety

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate; magnesium stearate; microcrystalline cellulose; sodium lauryl sulphate; sodium starch glycollate (Type A).

6.2 Incompatibilities

Not applicable

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/03/2009

10    DATE OF REVISION OF THE TEXT

29/07/2011