Colixil XL 4 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Colixil XL 4 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 4 mg of doxazosin (as mesilate) For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

White, round, biconvex tablets with bossing “DL”

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

• Essential hypertension
• Symptomatic treatment of benign prostatic hyperplasia.

4.2 Posology and method of administration

Posology

The tablets can be taken with or without food. The tablets should be swallowed whole with a sufficient amount of liquid. Patients should not chew, divide or crush the tablets (see section 4.4).

Adults

The maximum recommended dose is 8 mg doxazosin once daily.

Essential hypertension

The recommended dose is 4 mg doxazosin once daily. It may take up to four weeks to reach optimal effect. Depending on the clinical response, the dose may be increased to 8 mg doxazosin once daily.

Doxazosin can be used as monotherapy or in combination with other medicinal products, such as thiazide diuretics, beta-adrenoceptor blocking medicinal products, calcium antagonists or ACE-inhibitors.

Symptomatic treatment of prostatic hyperplasia

The recommended dose is 4 mg doxazosin once daily. Depending on the clinical response, the dose may be increased to 8 mg doxazosin once daily.

Doxazosin may be used in benign prostatic hyperplasia (BPH) patients who are either hypertensive or normotensive, as the blood pressure changes in normotensive patients are clinically insignificant. In hypertensive patients both conditions are treated concomitantly.

Elderly

Same dose recommendations as for adults.

Renal impairment

Since the pharmacokinetics of doxazosin are unchanged in patients with impaired renal function, and there is no evidence that doxazosin aggravates existing renal impairment, the usual dose may be used in these patients (see section 4.4). In rare cases an increased sensitivity cannot be excluded; a more cautious approach as far as starting the treatment may be appropriate for such patients.

Hepatic impairment

Doxazosin should be given with particular caution to patients with evidence of hepatic impairment. In patients with severe hepatic impairment clinical experience is lacking and therefore the use of doxazosin is not recommended (see section 4.4).

Paediatric population

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

Method of administration

Oral use

4.3 Contraindications

Doxazosin is contraindicated in

• patients with a known hypersensitivity to the active substance or to other 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
• patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastrointestinal tract
• 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

Information to be given to the patient

Patients should be informed that doxazosin tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

For some prolonged-release formulations the active compound is surrounded by an inert, non absorbable coating that is designed to control the release of the active substance over a prolonged period. After transit through the gastrointestinal tract, the empty tablet shell is excreted. Patients should be advised not to be concerned if they occasionally observe remains in their stools that look like a tablet.

Abnormally short transit times through the gastrointestinal tract (e.g. following surgical resection) could result in incomplete absorption. In view of the long half life of doxazosin the clinical significance of this is unclear.

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. Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects. 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 anti-hypertensive agents with a vasodilator effect 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 patients with hepatic impairment

As with any active substance wholly metabolised by the liver, 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.

Use with PDE-5 inhibitors

Concomitant administration of doxazosin with phosphodiesterase-5 (PDE-5) inhibitors (e.g. sildenafil, tadalafil, vardenafil) should be done with caution as both active substances 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 PDE-5 inhibitors only if the patient is hemodynamically stabilized on alpha-blocker therapy.

Furthermore, it is recommended to initiate PDE-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.

Special warnings regarding excipients

This medicinal product 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

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with doxazosin prolonged release formulations.

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 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).

Immediate-release doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic medicinal products, uricosuric agents, and 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 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 (prescribed for males only).

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 doxazosin therapy.

4.8 Undesirable effects

In connection with the alpha receptor inhibitor characteristics of doxazosin, patients may experience orthostatic hypotension, expressed in dizziness or weakness or in rare occasions fainting (syncope), in particular at the beginning of treatment (see section 4.4).

The following undesirable effects have been observed and reported during treatment with doxazosin with the following frequencies:

Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1, 000, <1/100); rare (≥1/10, 000, <1/1, 000); very rare (<1/10, 000); not known (cannot be estimated from the available data)

Very Rare (<1/10,000)

Leukopenia,

thrombocytopenia

Agitation, nervousness

Dizziness postural, paresthesia Eye disorders Blurred vision

Bradycardia, cardiac

arrhythmias

Hot flushes

Bronchospasm

Cholestasis, hepatitis, jaundice

Alopecia,

purpura, urticaria

Muscle cramps, muscle weakness

Micturition disorder, nocturia, polyuria, increased diuresis Reproductive system

and breast disorders

Impotence Gynaecomastia, priapism

Fatigue, malaise

In clinical studies, the incidence of undesirable effects while using doxazosin by patients with benign prostate hyperplasia was lower than during the use of conventional doxazosin tablets. The nature of the undesirable effects was, however, comparable.

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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Should overdose 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoceptor antagonists ATC code: C02CA04

Hypertension:

Administration of doxazosin in hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24-hours post dose. After taking doxazosin, a gradual decrease in blood pressure comes about in hypertensive patients; orthostatic effects at the initiation of treatment are comparable to those of corresponding treatment methodologies. At the recommended dosage, patients with a normal blood pressure did not exhibit a reduction of their blood pressure with clinical significance. The majority of patients are controlled on the initial dose of 4 mg doxazosin. In patients with hypertension, the decrease in blood pressure during treatment with doxazosin was similar in both the sitting and standing position.

Patients treated with immediate release doxazosin tablets against hypertension can be transferred to doxazosin prolonged-release and the dose titrated upwards as needed, while maintaining effect and tolerability.

Unlike non-selective alpha adrenoreceptor blocking agents, tolerance has not been observed in long-term treatment with doxazosin in prolonged-release tablets. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained therapy.

Doxazosin has a positive effect on blood lipids with significant decline in the total cholesterol/HDL-C ratio and significant reduction of total glycerides and total cholesterol.

Doxazosin has no undesirable metabolic effects and can be prescribed for patients with asthma, diabetes, reduced left ventricular function, gout, benign prostate hyperplasia and in elderly patients.

Prostatic hyperplasia:

Administration of doxazosin to patients with symptomatic BPH results in a significant improvement in urodynamic parameters and symptoms as a result of a selective blockade of alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.

Most of the patients with prostatic hyperplasia are controlled with the initial dose.

Doxazosin has shown to be an effective blocker of 1A subtype of alpha-adrenoceptors which make up more than 70% of the adrenergic subtypes in prostate.

Throughout the recommended dosage range, doxazosin has only a minor or no effect on blood pressure in normotensive benign prostatic hyperplasia (BPH) patients.

5.2 Pharmacokinetic properties

Absorption

After oral administration of therapeutic doses, doxazosin from prolonged-release tablets is well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one third of those of the same dose of immediate-release doxazosin tablets. Trough levels at 24 hours are, however, similar.

The pharmacokinetic characteristics of doxazosin prolonged-release tablets lead to a smoother plasma profile.

Peak/trough ratio of doxazosin prolonged-release is less than half that of immediate-release doxazosin tablets.

At steady-state, the relative bioavailability of doxazosin from doxazosin prolonged-release tablets compared to immediate-release form was about 56%.

Distribution

Approximately 98% of doxazosin is protein-bound in plasma. The distribution volume of doxazosin is about 2.3 L/kg.

Biotransformation/Elimination

Doxazosin is biotransformed to a significant degree and is primarily excreted through the feces. Doxazosin is extensively metabolised with <5% excreted as unchanged product. The total bodily clearance of doxazosin is about 2.8 mL/min/kg. The plasma elimination is biphasic with the terminal elimination half-life being 16-30 hours and hence this provides the basis for once daily dosing.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation. 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.

Other special populations

Elderly

Pharmacokinetic studies with doxazosin prolonged-release tablets in the elderly have shown no significant alterations compared to younger patients.

Renal impairment

Pharmacokinetic studies with doxazosin immediate-release tablets in patients with renal impairment also showed no significant alterations compared with patients with normal renal function.

Hepatic impairment

There are only limited data in patients with hepatic impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In comparison to healthy volunteers, patients with mild to moderate hepatic function impairments were observed to have a statistically significant decrease in the total bodily clearance (about 40%) after the administration of 2 mg doxazosin. This resulted in an increase in AUC (about 45%) and the MRT (about 50%). The terminal elimination half-life was similar in both groups and was around 23 hours.

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, carcinogenicity, reproductive and development toxicity.

Studies in lactating rats show an accumulation of doxazosin. There is no information about the excretion of doxazosin into the milk of breast-feeding women.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Macrogol 200

Macrogol 900,

Butylhydroxytoluene (E321)

Cellulose microcrystalline,

Povidone K 30,

All-rac-α-tocopherol (E 307)

Colloidal anhydrous silica,

Sodium stearyl fumarate

Tablet coating

Methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30% Silica colloidal, hydrated

Macrogol 1300-1600

Titanium dioxide (E171).

6.2 Incompatibilities

Not applicable.

6.3. Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The tablets are packed in PVC/PVDC/ALU blister and inserted in a carton.

Pack size:

14, 28, 30, 56, 98, 100 tablets or 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/0703

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

26/04/2007

10 DATE OF REVISION OF THE TEXT

14/05/2020