DOXADURA 2 MG TABLETS, DOXAZOSIN 2 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Doxazosin 2 mg Tablets

Doxadura 2 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin 2 mg (as mesilate).

Excipient(s) with known effect:

Each tablet contains 80.88 mg of lactose monohydrate.

3 PHARMACEUTICAL FORM

Tablets

Doxazosin 2mg is white to off-white, capsule shaped biconvex tablet, scored on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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, betaadrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

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.

Hypertension: Doxazosin is used in a once daily regimen: the initial dose is 1 mg to minimise the potential for postural hypotension and/or syncope (see section 4.4). Dosage may then be increased to 2 mg after an additional one or two weeks of therapy and thereafter, if necessary to 4 mg. The majority of patients who respond to Doxazosin will do so at a dose of 4 mg or less. Dosage can be further increased if necessary to 8 mg or the maximum recommended dose of 16 mg.

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 2 mg and thereafter to 4 mg and up to the maximum recommended dose of 8 mg. The recommended titration interval is 1–2 weeks. The usual recommended dose is 2–4 mg daily.

Paediatric population: The safety and efficacy of Doxazosin 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 Doxazosin is recommended.

Doxazosin 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, 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

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 bladders 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 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

– 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, Doxazosin 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 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.

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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Phosphodiesterase-5-inhibitors (eg. sildenafil, tadalafil, vardenafil):

Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4: Special warnings and precautions for use).

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 indomethacin).

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, nonsteroidal 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 doxazosin during pregnancy has not yet been established. Accordingly, during pregnancy doxazosin should be used only when, in the opinion of the physician, the potential benefit outweighs 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 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).

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 website: 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonist

ATC code:                       ­C02C A04

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 co-existent diabetes mellitus, gout and insulin resistance.

Doxazosin is suitable for use in patients with coexistent 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 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

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).

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.

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

lactose monohydrate

magnesium stearate

microcrystalline cellulose

sodium lauryl sulphate

sodium starch glycolate (type A)

colloidal anhydrous silica

6.2 Incompatibilities

None

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Aluminium PVC/PVDC blister:

28 tablets in a calendar pack.

6.6 Special precautions for disposal

No special requirements.