Colixil XL 4 mg Prolonged-release Tablets

Doxazosin

Each prolonged-release tablet contains 4 mg doxazosin (as mesilate)

For a full list of excipients, see section 6.1

Prolonged-release tablet.

White, round, biconvex tablets marked with “DL”

- Essential hypertension

- Symptomatic treatment of benign prostatic hyperplasia.

The tablets can be taken with or without food. The tablets must be swallowed whole with a sufficient amount of liquid. The tablets should not be chewed, divided or crushed.

The maximum recommended dose is 8 mg doxazosin once daily.

Essential hypertension:

Adults: Usually 4 mg doxazosin once daily. It may take up to four weeks to reach optimal effect. If necessary, the dosage may be increased to 8 mg doxazosin once daily.

Doxazosin can be used as sole agent or in combination with another medicinal product e.g. a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an ACE-inhibitor.

Symptomatic treatment of prostatic hyperplasia:

Adults: Usually 4 mg doxazosin once daily. If necessary, the dosage 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 dosage as for adults.

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function, and since there are no signs that doxazosin aggravates existing renal impairment, the usual dose can be used in these patients (see section 4.4).

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

Children and adolescents: Doxazosin is not recommended for use in children and adolescents due to a lack of clinical experience.

Doxazosin is contraindicated in

- patients with a known hypersensitivity to quinazolines (e.g. prazosin, terazosin, doxazosin), or any of the excipients

- 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

- during lactation (see section 4.6) ¹

- patients with hypotension ²

Doxazosin is contraindicated as monotherapy in patients with either overflow bladder, anuria or progressive renal insufficiency.

¹ For the hypertension indication only

² For the benign prostatic hyperplasia indication only

Information to be given to the Patient:

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:

Use in patients with 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:

Use with PDE-5 inhibitors:

Concomitant use of phosphodiesterase-5-inhibitors (eg sildenafil, tadalafil, 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 before initiating use of phospodiesterase-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:

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.

Conventional 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 drugs, 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.

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 high doses (see section 5.3).

Doxazosin is contraindicated during lactation as the drug accumulates in milk of lactating rats and there is no information about the excretion of the drug into the milk of lactating women.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (Please see section 5.3).

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy.

The following adverse reactions have been reported:

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)

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 : anorexia, gout, increased appetite

Psychiatric disorders:

Uncommon : anxiety, depression, insomnia

Very rare: agitation, nervousness

Nervous system disorders:

Common : dizziness, headache, somnolence

Uncommon : cerebrovascular accident, hypoesthesia, syncope, tremor

Very rare : dizziness postural, paraesthesia

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 : palpitations, tachycardia

Uncommon : angina pectoris, myocardial infarction

Very rare: bradycardia, cardiac arrhythmias

Vascular disorders:

Common : hypotension, postural hypotension

Very rare : flush

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, diarrhoea, flatulence, vomiting, gastroenteritis

Unknown : taste disturbances

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 : alopecia, purpura, urticaria

Musculoskeletal, connective tissue and bone disorders:

Common : back pain, myalgia

Uncommon : arthralgia

Very rare: muscle cramps, muscle weakness

Renal and urinary disorders:

Common : cystitis, urinary incontinence

Uncommon : dysuria, hematuria, micturition frequency

Very rare : micturition disorder, nocturia, polyuria, increased diuresis

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 edema

Uncommon : pain

Very rare : fatigue, malaise, facial oedema

Investigations

Uncommon : weight increase

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.

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. 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.

Habituation has not been observed during long-term treatment with doxazosin. Increase in plasma renin activity and tachycardia have rarely been seen during long-term treatment.

Doxazosin has a beneficial effect on blood lipids with significant increase of HDL/total cholesterol ratio (app. 4-13% of base line values), and significant reduction in total glycerides and total cholesterol. The clinical relevance of these findings is still unknown.

Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation as well as enhanced capacity of tissue plasminogen-activator. The clinical relevance of these findings is still uncertain.

Additionally, doxazosin improves insulin sensitivity in patients with impaired sensitivity to insulin, but also concerning this finding the clinical relevance is still uncertain.

Doxazosin has shown to be free of metabolic adverse effects and is suitable for treatment of patients with coexistent asthma, diabetes, left ventricular dysfunction or gout.

Prostatic hyperplasia:

Administration of doxazosin to patients with prostatic hyperplasia results in a significant improvement in urodynamics 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.

Absorption:

After oral administration of therapeutic doses, doxazosin in [To be completed nationally] 4 mg Prolonged-release Tablets is well absorbed with peak blood levels gradually reached at 6 to 8 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 properties of doxazosin lead to a minor variation in plasma levels. 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 compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.

Distribution:

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

Biotransformation:

Doxazosin is extensively metabolised with <5% excreted as unchanged product.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

Elimination:

The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basic for once daily dosing

Elderly:

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

Renal impairment:

Pharmacokinetic studies with doxazosin in patients with renal impairment also showed no significant alterations compared to patients with normal renal function.

Liver impairment:

There are only limited data in patients with liver impairment and on the effects of medicinal products 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 of AUC of 43% and a decrease in oral clearance of app. 40%. Doxazosin therapy in patients with hepatic impairment should be performed with caution (see section 4.4.).

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Studies in pregnant rabbits and rats at daily doses resulting in plasma concentrations 4 and 10 times the human exposure (C_max and AUC), respectively, revealed no evidence of harm to the foetus. A dosage regime of 82 mg/kg/day (8 times the human exposure) was associated with reduced foetal survival.

Studies in lactating rats given a single oral dose of radioactive doxazosin gave an accumulation in the breast milk with a maximum concentration of about 20 times greater than the maternal plasma concentration. Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.

Core

Macrogol 200

Macrogol 900,

Butylhydroxytoluene (E321)

Cellulose microcrystalline,

Povidone K 30,

α-Tocopherol (E307),

Colloidal anhydrous silica,

Sodium stearyl fumarate

Coating

Methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30%

Silica colloidal anhydrous

Macrogol 1300-1600

Titanium dioxide (E171).

Not applicable.

5 years

This medicinal product does not require any special storage conditions.

PVC/PVDC//Al blister: 14, 28, 30, 56, 98, 100 tablets or 500 tablets (for hospital use only).

Not all pack sizes may be marketed.

No special requirements.

Sandoz Ltd

37 Woolmer Way

Bordon

Hamsphire

GU35 9QE

PL 04416/0703

26 April 2007

09/11/2009