This information is intended for use by health professionals

1. Name of the medicinal product

Slocinx XL 4 mg prolonged-release tablets

2. Qualitative and quantitative composition

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

Excipients with known effect:

Each film-coated tablet contains 0.10 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged-release tablet.

White round biconvex tablets marked “DL” on one side.

4. Clinical particulars
4.1 Therapeutic indications

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

Benign prostatic hyperplasia: Slocinx XL is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH).

Slocinx XL may be used in BPH patients who are either hypertensive or normotensive. While the blood pressure changes in normotensive patients with BPH are not usually clinically significant, patients with hypertension and BPH have had both conditions effectively treated with doxazosin monotherapy.

4.2 Posology and method of administration

Posology

Hypertension and benign prostatic hyperplasia

The initial dose of Slocinx XL is 4 mg doxazosin once daily. Over 50% of patients with mild to moderate severity hypertension will be controlled on Slocinx XL 4 mg once daily. Optimal effect of Slocinx XL may take up to 4 weeks. If necessary, the dosage may be increased following this period to 8 mg once daily according to patient response. The maximum recommended dose of Slocinx XL is 8 mg once daily.

Slocinx XL 4 mg can be used as sole agent to control blood pressure in the majority of patients. In patients inadequately controlled on single antihypertensive therapy, Slocinx XL 4 mg may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an ACE-inhibitor.

Paediatric population

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

Elderly

Normal adult dosage.

Renal impairment

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

Hepatic impairment

As with any drug wholly metabolised by the liver, Slocinx XL should be administered with caution to patients with evidence of impaired hepatic function (see sections 4.4 and 5.2).

Method of administration

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

4.3 Contraindications

Doxazosin is contraindicated in:

• Patients with a known hypersensitivity to the active substance, 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.

• 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

Information to be given to the patient

Patients should be informed that Slocinx XL should be swallowed whole. Patients should not chew, divide or crush the tablets (see section 4.2).

For some prolonged-release formulations the active compound is surrounded by an inert, non- absorbable shell that has been specially designed to control the release of the drug over a prolonged period. After transit through the gastrointestinal tract, the empty tablet shell is excreted. Patients should be advised that they should not 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.

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. 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.

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.

Hepatic impairment

As with any drug wholly metabolised by the liver, Slocinx XL should be administered with particular caution in patients with evidence of impaired hepatic function (see sections 4.2 and 5.2). 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 the risk of orthostatic hypotension it is recommended to initiate 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. No studies have been conducted with doxazosin prolonged-release formulations.

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 alpha1 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 alpha1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

Screening for prostate cancer

Carcinoma of the prostate causes many of the symptoms associated with BHP and the two disorders can co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin for treatment with BPH symptoms.

Patients with diabetic autonomic neuropathy

Slocinx XL should be used with care in patients with diabetic autonomic neuropathy.

Influence on plasma rennin activity and urinary excretion of vanillylmandelic acid

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

Priapism

Prolonged erections and priapism have been reported with alpha1 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.

Warning about excipients

This medicine 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

Phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil)

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

Doxazosin is highly bound to plasma proteins (98%). In vitro data in human plasma indicate that doxazosin has no effect on protein binding of the drug tested (digoxin, warfarin, phenytoin or indomethacin).

Conventional doxazosin has been administered without any adverse drug interactions in clinical experience with thiazide diuretics, furosemide, beta-blocking agents, non-steroidal 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.

Non-steroidal antirheumatics or estrogens may reduce the antihypertensive effect of doxazosin. Sympathomimetics may reduce the antihypertensive effect of doxazosin; doxazosin may reduce blood pressure and vascular reactions to dopamine, ephedrine, epinephrine, metaraminol, methoxamine and phenylephrine.

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 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 ability to drive or use machinery may be impaired, especially when initiating therapy.

4.8 Undesirable effects

The occurrence of adverse reactions are mainly due to the pharmacological properties of the medicinal product. The majority of the adverse reactions were transient.

The adverse reaction profile in clinical trials with patients with benign prostatic hyperplasia corresponded to the one seen in hypertension.

In clinical trials, the most common reactions associated with doxazosin therapy were of a postural type (rarely associated with fainting) or non-specific.

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); not known (cannot be estimated from the available data.

MedDRA

System Organ Class

Frequency

Undesirable Effects

Infections and infestations

Common

Respiratory tract infection, urinary tract infection

Blood and lymphatic system disorders

Very rare

Reduction of erythrocytes, leukopenia, thrombocytopenia

Immune system disorders

Uncommon

Allergic drug reaction

Metabolism and nutrition disorders

Uncommon

Thirst, hypokalaemia, anorexia, gout, increased appetite

Rare

Hypoglycaemia

Very Rare

Increase in serum urea

Psychiatric disorders

Common

Apathia

Uncommon

Nightmares, amnesia, anxiety, depression, insomnia, emotional instability

Very rare

Agitation, nervousness

Nervous system disorders

Common

Dizziness, headache, somnolence

Uncommon

Cerebrovascular accident, hypoesthesia, syncope, tremor

Very rare

Dizziness postural, paraesthesia

Eye disorders

Common

Accommodation disturbances

Uncommon

Lacrimation, photophobia

Very rare

Blurred vision

Unknown

Intraoperative floppy iris syndrome (see section 4.4)

Ear and labyrinth disorders

Common

Vertigo

Uncommon

Tinnitus

Cardiac disorders

Common

Palpitation, tachycardia

Uncommon

Angina pectoris, myocardial infarction

Very rare

Bradycardia, cardiac arrhythmias

Vascular disorders

Common

Giddiness, hypotension, postural hypotension, oedema, orthostatic dysregulation

Uncommon

Peripheral ischaemia

Very rare

Flush

Respiratory, thoracic and mediastinal disorders

Common

Bronchitis, cough, dyspnoea, rhinitis

Uncommon

Epistaxis, pharyngitis

Rare

Oedema of larynx

Very rare

Bronchospasm

Gastrointestinal disorders

Common

Abdominal pain, dyspepsia, dry mouth, nausea

Uncommon

Constipation, diarrhoea, flatulence, vomiting, gastroenteritis

Rare

Gastrointestinal obstruction

Not known

Taste disturbances

Hepato-biliary disorders

Uncommon

Abnormal liver function tests

Rare

Icterus

Very rare

Cholestatis, hepatitis

Skin and subcutaneous tissue disorders

Common

Pruritus

Uncommon

Skin rash, general oedema

Very rare

Alopecia, purpura, urticaria

Musculoskeletal and connective tissue disorders

Common

Back pain, myalgia

Uncommon

Arthralgia

Very rare

Muscle cramps, muscle weakness

Renal and urinary disorders

Common

Cystitis, urinary incontinence

Uncommon

Dysuria, haematuria, micturition frequency

Very rare

Micturition disorder, nocturia, polyuria, increased diuresis, increase or serum creatinine

Reproductive system and breast disorders

Uncommon

Impotence

Very rare

Gynecomastia, priapism

Not known

Retrograde ejaculation

General disorders and administration site conditions

Common

Asthenia, chest pain, influenza-like symptoms, peripheral oedema

Uncommon

Pain, flushing, fever/shiver, facial oedema

Rare

Low body temperature in elderly

Very rare

Fatigue, malaise

Investigations

Uncommon

Weight increase

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows the 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 the Google Play or Apple App Store.

4.9 Overdose

Symptoms:

Headache, dizziness, unconsciousness, syncope, dyspnoea, hypotension, palpitation, tachycardia, arrhythmia. Nausea, vomiting. Possibly hypoglycaemia, hypokalaemia.

Management

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Symptomatic treatment. Close control of blood pressure. 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-adrenoreceptor antagonists,

ATC code: C02CA04.

Mechanism of action

Doxazosin is a potent and selective post-junctional alpha1 adrenoreceptor antagonist.

Administration of doxazosin 4 mg 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 alpha1-adrenoreceptors 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. In patients with hypertension, the decrease in blood pressure during treatment with doxazosin 4 mg was similar in both the sitting and standing position.

Subjects treated with immediate release doxazosin tablets can be transferred to doxazosin 4 mg and the dose titrated upwards as needed.

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.

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 4 mg to patients with symptomatic BPH result 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 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 have 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 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 in doxazosin leads to a minor variation in plasma levels. Peak/trough ratio of doxazosin 4 mg prolonged-release tablets is less than half that of immediate release doxazosin tablets.

At steady-state, the relative bioavailability of doxazosin 4 mg prolonged-release-tablets compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.

Pharmacokinetic studies with doxazosin 4 mg prolonged-release tablets in the elderly have shown no significant alterations compared to younger patients.

Distribution

Approx. 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.

Hepatic 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.).

5.3 Preclinical safety data

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 (Cmax 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.

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 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.

6. Pharmaceutical particulars
6.1 List of excipients

Polyethylene oxide

Microcrystalline cellulose

Povidone

α-tocopherol

Butylhydroxytoluene (E321)

Colloidal anhydrous silica

Sodium stearyl fumarate

Methacrylic acid copolymer (Eudragir L30 D-55)

Macrogol 1300-1600

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC/aluminium blister pack.

Pack sizes: 28, 30 and 100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Zentiva Pharma UK Limited

12 New Fetter Lane

London

EC4A 1JP

United Kingdom

8. Marketing authorisation number(s)

PL 17780/0259

9. Date of first authorisation/renewal of the authorisation

30/09/2007

10. Date of revision of the text

26/06/2020