CARDURA Tablet Ref.[7834] Active ingredients: Doxazosin

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.

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

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per unit volume, that is to say essentially ‘sodium-free’. To be used with caution in children or in patients on a low sodium diet.

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).

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.

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).

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.

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.

The ability to drive or use machinery may be impaired, especially when initiating therapy.

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).

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

Common: Respiratory tract infection, urinary tract infection

Blood and the lymphatic system disorders

Very rare: Leukopenia, 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: Dizziness postural, paresthesia

Eye disorders

Very rare: Blurred vision

Unknown: Intraoperative 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

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: Bronchospasm

Gastrointestinal disorders

Common: Abdominal pain, dyspepsia, dry mouth, nausea

Uncommon: Constipation, flatulence, vomiting, gastroenteritis diarrhoea

Hepato-biliary disorders

Uncommon: Abnormal liver function tests

Very rare: Cholestasis, hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common: Pruritus

Uncommon: Skin rash

Very rare: Urticaria, alopecia, purpura

Musculoskeletal, connective tissue and bone disorders

Common: Back pain, myalgia

Uncommon: Arthralgia

Rare: Muscle cramps, muscle 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: Gynecomastia, 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

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.

Not applicable.