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Doxazosin Tablets 2mg

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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.

Paediatric population:

The safety and efficacy of Doxazosin mesilate (Doxazosin Tablets) in children and adolescents have not been established.

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.

MedDRA System Organ Class

Frequency

Undesirable Effects

Infections and

Common

Respiratory tract infection, urinary tract

infestations

infection

Blood and lymphatic system disorders

Very rare

Leukopenia, thrombocytopenia

Immune system disorders

Uncommon

Allergic drug reaction

Metabolism and

Common

Anorexia

nutrition disorders

Uncommon

Gout, increased appetite

Psychiatric disorders

Common

Anxiety, insomnia, nervousness

Uncommon

Agitation, depression

Nervous system

Very common

Dizziness, headache

disorders

Common

Dizziness postural, paraesthesia, somnolence

Uncommon

Cerebrovascular accident, hypoaesthesia, syncope, tremor

Eye disorders

Very rare

Blurred vision

Unknown

Intraoperative Floppy Iris Syndrome (see section 4.4)

Ear and labyrinth

Common

Vertigo

disorders

Uncommon

Tinnitus

Cardiac disorders

Common

Palpitations, tachycardia

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 disorders

Common

Cystitis, urinary incontinence

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

17/07/2015