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.

Hepatic/Renal impairment

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) 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 (e.g. 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. If priapism is not treated immediately, it could result in penile tissue damage and permanent loss of potency, therefore the patient should seek immediate medical assistance.

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.

Excipient information:

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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).

In vitro studies suggest that doxazosin is a substrate of cytochrome P450 3A4 (CYP 3A4). Caution should be exercised when concomitantly administering doxazosin with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole (see section 5.2).

Conventional doxazosin has been administered without any adverse drug interaction 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.

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).

Breast-feeding

The excretion of doxazosin in breast milk was demonstrated to be very low (with the relative infant dose less than 1%) however human data is very limited. A risk to the newborn or infant cannot be excluded and therefore doxazosin should be used only when in the opinion of the physician, the potential benefit outweighs the potential risk.

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, thrombocytopenia

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

Intraoperative floppy iris syndrome (see section 4.4)

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Palpitation, tachycardia

Angina pectoris, myocardial infarction

Bradycardia, cardiac arrhythmias

Vascular disorders

Hypotension, postural hypotension

Hot flushes

Respiratory, thoracic and mediastinal disorders

Bronchitis, cough, dyspnea, rhinitis

Epistaxis,

Bronchospasm,

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

Gynecomastia, priapism

Retrograde ejaculation

General disorders and administration site conditions

Asthenia, chest pain, influenza-like symptoms, peripheral oedema

Pain, facial oedema

Fatigue, malaise

Investigations

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.