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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Doxazosin Tablets 2mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg doxazosin (as mesilate).

For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Tablet.

Light orange to pink, biconvex uncoated tablet, scored with a division mark on both sides and embossed with “DZS 2” on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Doxazosin Tablets are indicated for management of hypertension, as the sole agent, or in combination with a thiazide diuretic, ACE inhibitor, beta-blocker or calcium antagonist, and for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH).

4.2 Posology and method of administration

Adults and the elderly:

Hypertension:    Doxazosin Tablets should be taken once a day.

Initial dosage 1mg once daily preferably at bedtime. This may be increased after 1-2 weeks to 2mg daily, and thereafter to 4mg daily, if necessary. The majority of patients who respond to doxazosin will do so at a dose of 4mg or less.

Dosage can be further increased if necessary to 8mg or to a maximum daily dose of 16mg.

Benign prostatic hyperplasia: Initial dosage 1mg once daily preferably at

bedtime. Depending on the patient’s response, the daily dosage may be increased to 2mg, and thereafter 4mg, up to a maximum dosage of 8mg per day. The recommended titration interval is 1-2 weeks and the usual recommended dose is 24mg daily.

Children:

Doxazosin Tablets are not recommended for children. Oral administration.

4.3. Contra-indications

Doxazosin Tablets are contra-indicated in • patients with known hypersensitivity to quinazolines

•    patients with a history of orthostatic hypotension

•    patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones

• during lactation (see section 4.6 Pregnancy and Lactation).

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

Doxazosin should be used with care in patients with a prior history of cerebrovascular incidents.

Initiation of Therapy: in relation to 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 antihypertensive 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 experiences in patients with severe hepatic impairment, use in these patients is not recommended.

Use with PDE-5 inhibitors: concomitant administration of phosphodiesterase-5- inhibitors (e.g. sildenafil, tadalafil and 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 the 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. 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.

Excipients: Doxazosin Tablets 2mg contain lactose. Therefore, they should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Following the initial dose, postural hypotension may occur which may be severe and lead to collapse. This reaction can be avoided by starting treatment with a low dose at bedtime.

4.5. Interactions with other Medicaments and other forms of Interaction

Doxazosin is able to increase the antihypertensive effect of other

antihypertensive agents.

Although doxazosin binds well to plasma proteins it has not been found to have any effect on the protein binding of digoxin, phenytoin, warfarin or indomethacin in vitro, however the potential for such interaction should be borne in mind. No adverse interactions have been observed with frusemide, thiazide diuretics, beta-blockers, non steroidal anti-inflammatory drugs, anticoagulants, antibiotics, oral hypoglycaemics or uricosuric drugs.

Care should be taken when doxazosin is co-administered with antidepressants known to block alpha-1-adrenoceptors.

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil and 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 indicate that doxazosin has no effect on protein binding of digoxin, warfarin, 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 interactions studies are not present.

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

In an open-label, randomised, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1mg dose of doxazosin on day 1 of a four-day regiment of oral cimetidine (400mg 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 of doxazosin with placebo.

4.6. Fertility, Pregnancy and Lactation

Doxazosin Tablets are not recommended during pregnancy, unless in the opinion of the physician the potential benefit to the mother outweighs the potential risk to the child.

Teratogenic effects were not seen during animal testing, but reduced foetal survival was observed with very high doses (approximately 300 times the maximum recommended human dose). There have been no studies in pregnant women and therefore safety of use during pregnancy has not been established.

Doxazosin Tablets are contra-indicated during lactation. Animal studies have shown that doxazosin accumulates in breast milk. The clinical safety of

Doxazosin Tablets during lactation has not been established, consequently Doxazosin Tablets are contra-indicated in nursing mothers.

4.7 Effects on ability to drive and use machines

The patient’s ability to drive and use machines may be impaired, particularly when treatment with doxazosin is first started.

4.8. Undesirable Effects

Frequencies used are as follows: very commofi 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.

	Uncommon	Angina pectoris, myocardial infarction,
		cardiac arrhythmias,
	Very rare	Bradycardia
Vascular disorders	Common	Hypotension, postural hypotension

	Uncommon	Hot flushes
Respiratory, thoracic	Common	Bronchitis, cough, dyspnoea, rhinitis
and mediastinal disorders	Uncommon	Epistaxis, cough
	Very rare	Bronchospasm aggravated
Gastrointestinal	Common	Abdominal pain, dyspepsia, dry mouth,
disorders		nausea, diarrhoea
	Uncommon	Constipation, flatulence, vomiting, gastroenteritis
	Unknown	Taste disturbances
Hepatobiliary disorders	Uncommon	Abnormal liver function tests
	Very rare	Cholestasis, hepatitis, jaundice
Skin and subcutaneous	Common	Pruritus
tissue disorders	Uncommon	Skin rash, alopecia, purpura
	Very rare	Urticaria
Musculoskeletal and	Common	Back pain, myalgia
connective tissue disorders	Uncommon	Arthralgia, muscle cramps, muscle weakness
Renal and urinary	Common	Cystitis, urinary incontinence
disorders	Uncommon	Dysuria, micturition frequency increased, haematuria, polyuria
	Very rare	Increased diuresis, micturition disorder, nocturia
Reproductive system	Uncommon	Impotence
and breast disorders	Very rare	Gynecomastia, priapism
	Unknown	Retrograde ejaculation

General disorders and	Common	Asthenia, chest pain, influenza-like
administration site		symptoms, peripheral oedema, fatigue,
conditions		malaise
	Uncommon	Pain, facial oedema
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 at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

In the event of overdose, supportive measures may be appropriate. If overdosage leads to hypotension, the patient should be placed in a supine, head down position straight away. As doxazosin is highly protein bound, dialysis is not recommended.

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

Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor agonist which acts to lower systemic blood pressure. In benign prostatic hyperplasia, doxazosin improves symptoms by selective blockade of alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.

In addition to the antihypertensive effect of doxazosin, a modest reduction in plasma total cholesterol, LDL-cholesterol and triglyceride concentrations has been observed in long-term studies. Doxazosin may therefore be of particular benefit to hypertensive patients with concomitant hyperlipidaemia.

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

5.2 Pharmacokinetic properties

Following oral administration, doxazosin is well absorbed and binds to plasma proteins (98%) with approximately 60-65% of the dose being available. Peak plasma levels occur approximately 2 hours after an oral dose. Plasma concentrations of metabolites remain low. Plasma elimination is biphasic; the mean plasma elimination half-life being approximately 22 hours.

Doxazosin is extensively metabolised in the liver, and excreted in the faeces as metabolites and a low quantity of unchanged drug.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline cellulose Sodium lauryl sulphate Sunset yellow FCF (E110)

Lactose monohydrate Sodium starch glycollate Colloidal silicon dioxide Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store in the original package. Do not store above 25°C.

6.5 Nature and contents of container

PVC/PVdC/aluminium blister strips packed in an outer carton, Amber glass type III jars with HDPE child resistant closures, or HDPE tablet containers with polypropylene child resistant closures. Pack sizes: 28, 30 or 56.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4

Riverside Industrial Estate

Riverside Way

Dartford

DA1 5BS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0028

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/07/2012

10 DATE OF REVISION OF THE TEXT

19/02/2015