Doxazosin 4mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Doxazosin 4mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Doxazosin 4 mg Tablet contains 4 mg doxazosin as doxazosin mesilate.

Excipient with known effect

Each Doxazosin 4 mg Tablet contains 80.1 mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

4 mg tablets: white, capsule shaped, scored tablets marked ‘DX|4’ on one side

4.1 Therapeutic indications

Essential Hypertension.

Doxazosin 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,

Doxazosin may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

Treatment of clinical symptoms in benign prostatic hyperplasia Doxazosin is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH). Doxazosin may be used in BPH patients who are either hypertensive or normotensive.

4.2 Posology and method of administration

Posology

Doxazosin may be administered in the morning or the evening

In hypertension

Doxazosin tablets are administered once daily to minimise the potential for postural hypotension and/or syncope (see section 4.4). The initial dose is 1 mg. Depending on the therapeutic response, the dose can be increased to 2 mg after 1 – 2 weeks. If necessary, the dose can then be doubled at intervals of 1 – 2 weeks. The majority of patients who respond to Doxazosin will do so at a dose of 4mg or less. The maximum dose is 16 mg doxazosin once daily, but daily doses over 8 mg seldom give further reductions in blood pressure.

Doxazosin tablets can be used as monotherapy or in combination with a thiazide diuretic or beta-blocking agent when treatment with these alone has not given the desired effect or is unsuitable.

In Benign Prostatic Hyperplasia

Doxazosin tablets are administered once daily to minimise the potential for postural hypotension and/or syncope (see section 4.4). The initial dose is 1 mg increasing at 1 – 2 weekly intervals until a satisfactory response is obtained. Depending on the individual patient's urodynamics and BPH symptomatology, the usual effective dosage is 2 – 4 mg once daily. The maximum daily dose is 8 mg doxazosin once daily.

Use in the elderly and in patients with renal impairment

Since the pharmacokinetics of doxazosin are unchanged in the elderly and in patients with renal insufficiency, the usual dose may be used in these patients. Dose increments should be made under close supervision.

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. In patients with severe hepatic impairment there is no clinical experience (see section 4.4 and section 5.2).

Paediatric population

The safety and efficacy of doxazosin mesilate in children and adolescents have not been established.

Method of administration

For oral use.

4.3 Contraindications

Doxazosin is contraindicated in

• Hypersensitivity to the active substance or to any of the excipients listed in section

  6.1 or to other quinazolines (e.g. prazosin, terazosin).

• 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 (for the hypertension indication only, see section 4.6).

• Patients with hypotension (for the 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

In relation with the alpha-blocking properties of doxazosin, n initiation of therapy or increasing of dose the patient should be monitored as patients may experience postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope) (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.

Patients should be instructed to avoid abrupt changes of positions or activities which may be adversely affected by dizziness or asthenia.

Special care should be taken with elderly patients, patients with hepatic or renal insufficiency, patients on a low-sodium diet or those treated with diuretics.

In patients treated for benign prostatic hyperplasia and without hypertension mean blood pressure changes are small, but hypotension, dizziness, fatigue occur in 10 – 20% of the patients and oedema and dyspnoea occur in less than 5% of patients.

Use in patients with benign prostatic hyperplasia

Patients with benign prostatic hyperplasia and having simultaneously obstruction of the upper urinary tract, chronic infection of the urinary tract or bladder stone should not be treated with doxazosin.

Use in patients with acute cardiac conditions

Because of its vasodilatory effect cautions is advised 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.

In hypertensive patients with one or more additional risk factors for cardiovascular disease, doxazosin should not be used as a single agent for the first-line treatment of hypertension due to a possible increased risk for development of heart failure (see section 5.1)

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. 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.

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.

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.

Use in hepatically impaired patients

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. Until further experience has been obtained, patients with mild to moderate impaired liver function should be closely monitored.

Doxazosin should be used with care in patients with Diabetic Autonomic Neuropathy.

Excipients

The medicinal product contains lactose and sodium. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicine also contains less than 1 mmol sodium (23 mg) per dosage unit, 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 potentiates the blood pressure lowering activity of other alpha-blockers or other anti-hypertensives, vasodilators and nitrates.

Sympathomimetics may reduce the antihypertensive effect of doxazosin; doxazosin may reduce blood pressure and vascular reactions to dopamine, ephedrine, epinephrine, metaraminol, methoxamine and phenylephrine.

As for other antihypertensive agents, non-steroidal antirheumatics or oestrogens may reduce the antihypertensive effect of doxazosin.

There are no studies concerning interactions with agents influencing hepatic metabolism. 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 interactions in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, and anticoagulants. However, data from formal drug/drug interaction studies are not present.

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 indomethacin.

Doxazosin may influence plasma renin activity and urinary excretion of vanillylmandelic acid. This should be considered when interpreting laboratory data.

In an open-label, randomised, 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 C_max 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 doxazosin during pregnancy has not yet 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 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 engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy.

4.8 Undesirable effects

Undesirable effects arise mainly from the pharmacological properties of the preparation. Most of the undesirable effects have been transient or have been tolerated on continued treatment.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: 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; not known (cannot be estimated from the available data).

Postural hypotension and, in rare cases, syncope can occur initially during treatment, especially at too high doses, but can also arise if therapy is restarted after a short break.

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

Toxicity

Experience of overdosing is limited. A 16 mg dose to a fasting adult caused syncope, a maximum of 40 mg to a 13 year old produced moderate intoxication. A 22-year-old male, who stated that he had ingested 40 mg of doxazosin, experienced sinus bradycardia with sinus arrhythmia and ST-segment elevation in the precordial leads.

Symptoms

Headache, dizziness, confusion, syncope, dyspnoea, hypotension, palpitations, tachycardia, arrhythmias, sinus bradycardia, ST-segment elevation, nausea, vomiting and possibly hypoglycaemia, hypokalaemia.

Treatment

Should overdosage 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group

ATC Code: C02C A04 Antihypertensives, alpha adrenoreceptor antagonists.

Mechanism of action

Doxazosin is a chinazolin derivative and exercises its vasodilating effect by selective and competitive blockade of post-synaptic alpha₁-receptors. Doxazosin is appropriate for oral administration in a once daily regimen in patients with essential hypertension.

Pharmacodynamic effects

Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance. Doxazosin is suitable for use in patients with co-existent asthma, left ventricular hypertrophy and in elderly patients.

Treatment with doxazosin has been shown to produce regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Doxazosin improves insulin sensitivity in patients with impairment.

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

Administration of Doxazosin to patients with symptomatic BPH results in a significant improvement in urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoceptors located in the muscular stroma and capsule of the prostate, and in the bladder neck.

5.2 Pharmacokinetic properties

Doxazosin is almost totally absorbed after oral administration in humans (young male adults or the elderly of either sex), and approximately two thirds of the dose is bioavailable. Bioavailability is about 63%. Maximal plasma concentration occurs after about 2 hours. Protein binding is high (98%). Distribution volume: 1 l/kg. Clearance: 1.3 ml/min/kg.

Doxazosin is metabolised mainly in the liver and is primarily excreted in the faeces as metabolites (63 to 65%) or unchanged drug (5%). The effective half-life at steady state is about 10 hours. The terminal half-life is about 22 hours thus making the drug suitable for once daily administration.

Elderly persons and patients with kidney insufficiency have not shown changed pharmacokinetics.

Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.

Major metabolites of doxazosin in man include the 6-O and 7-O-demethyl doxazosin, 6-hydroxy- and 7-hydroxy-doxazosin. 6-hydroxy-doxazosin is a potent and selective α-blocker and in man accounts for 5% of the oral dose. Therefore 6-hydroxy-doxazosin contributes little to the antihypertensive effect of doxazosin.

Other less significant metabolites of doxazosin include the 2-piperazinyl and the 2-amino compounds.

There are only limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 patients with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 30%. Therefore doxazosin should be administered with particular caution to patients with impaired hepatic function (see also Section 4.4 Special Warnings and Special Precautions for Use).

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.

Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at doses approximately 300 times greater than the maximum human recommended dose.

Studies in lactating rats given a single oral dose of radioactive doxazosin indicate that doxazosin accumulates in rat milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Lactose anhydrous

Sodium starch glycollate Type A

Magnesium stearate

Sodium laurilsulfate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special precautions for storage

6.5 Nature and contents of container

10, 20, 28, 30, 50, 60, 90, 100, 250, 500 and 1000 tablets in HDPE plastic bottles with tamper evident polypropylene cap.

10, 20, 28, 30, 50, 60, 90 and 100 tablets in aluminium foil/aclar blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

Any unused medicinal product should be disposed of in accordance with the local requirements.

7 MARKETING AUTHORISATION HOLDER

Generics (U.K.) Limited T/A Viatris,

Station Close,

Potters Bar,

EN6 1TL,

United Kingdom.

8 MARKETING AUTHORISATION NUMBER

PL 04569/0458

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 1998-05-15

Date of last renewal: 2008-05-15

10 DATE OF REVISION OF THE TEXT

08/05/2026