DOXAZOSIN TABLETS 4 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Doxazosin Tablets 4mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 4mg doxazosin (as mesilate).

Excipients(s) with known effect

Lactose monohydrate

Sunset yellow FCF (E 110)

For the full list of excipients, see section 6.1.

Tablet.

Light orange to pink, odourless biconvex uncoated tablets with D and 4 on either side of the score line and plain on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

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

Posology

Doxazosin may be administered in the morning or evening.

Adults and the elderly:

Hypertension:                D­oxazosin Tablets should be taken once a day.

Initial dosage is 1mg to minimise the potential for postural hypotension and/or syncope (see section 4.4). 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: The recommended initial dosage of Doxazosin 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 doxazosin mesilate (Doxazosin Tablets) in children and adolescents have not been established.

Patients with renal impairment:

Since there is no change in pharmacokinetics in patients with impaired renal function, the usual adult dose of doxazosin is recommended. Doxazosin is not dialyzable.

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, Doxazosin 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

Hypersensitivity to the active substance or other types of quinazolines (e.g. prazosin, terazosin) or to any of the excipients listed in section 6.1.

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:

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 (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 doxazosin 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

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 (see section 4.2). 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 use 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 (doxazosin) 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.

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.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains Sunset yellow FCF (E 110) which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of doxazosin with phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) 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 indicates 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, betablockers, non-steroidal 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 alphablockers 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

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 been established. Accordingly, during pregnancy Doxazosin 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 patient’s ability to drive and use machines may be impaired, particularly when treatment with doxazosin is first started.

4.8 Undesirable effects

Hypertension:

In clinical trials involving patients with hypertension, the most common reactions associated with doxazosin 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 Doxazosin 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) and not known (cannot be estimated from the available data).

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 should be performed if thought 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoceptor antagonists ATC code: C02CA04

Mechanism of action:

Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor antagonist.

This action results in a decrease in systemic blood pressure. 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 result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, 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 an improvement of urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoreceptors located in the muscular stroma and capsule of the prostate, and in the bladder neck.

5.2 Pharmacokinetic properties

Absorption:

Following oral administration in humans (young male adults or the elderly of either sex), doxazosin is well absorbed and approximately two thirds of the dose is bioavailable.

Biotransforma­tion/Eliminati­on:

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is extensively metabolised in man and in the animal species tested, with the faeces being the predominant route of excretion.

The mean plasma elimination half-life is 22 hours thus making the drug suitable for once daily administration.

After oral administration of doxazosin the plasma concentrations of the metabolites are low. The most active (6' hydroxy) metabolite is present in man at one fortieth of the plasma concentration of the parent compound, which suggests that the antihypertensive activity is in the main due to doxazosin.

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 subjects 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 40%. As with any drug wholly metabolised by the liver, doxazosin should be administered with caution to patients with impaired liver function (see section 4.4).

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional animal studies in safety pharmacology, repeated dose toxicity, genotoxicity and 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

Sodium lauryl sulphate

Sunset yellow FCF (E 110)

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

U.K