Slocinx Xl 4mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Slocinx XL 4mg prolonged-release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 4 mg doxazosin (as mesilate).
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
Essential hypertension
Symptomatic treatment of benign prostatic hyperplasia.
4.2 Posology and method of administration
Slocinx XL 4 mg prolonged-release Tablets 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.
The maximum recommended dose is 8 mg doxazosin once daily.
Essential hypertension:
Adults
Usually 4 mg doxazosin once daily. If necessary, the dosage may be increased to 8 mg doxazosin once daily.
Slocinx XL 4mg Tablets 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.
Slocinx XL 4 mg Tablets 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 prolonged release tablets aggravates existing renal impairment, the usual dose can be used in these patients.
Patients with hepatic impairment
Slocinx XL 4 mg Tablets 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 prolonged release tablets is not recommended (see section 4.4).
Paediatric population
The safety and efficacy of doxasozin mesilate in children and adolescents has not been established.
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 infections or bladder stones
• Patients with a history of oesophageal obstruction, gastrointestinal obstruction or any degree of decreased lumen diameter of the gastrointestinal tract (for patients taking the sustained release tablets only)
• During lactation (for the hypertension indication only, please 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 4mg 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 drug 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 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.
In hypertensive patients with one or more additional risk factors for cardiovascular disease, doxazosin prolonged release tablets should not be used as a single agent for the first-line treatment of hypertension due to a possible increased risk for development of heart failure.
Use in Hepatically Impaired Patients:
As with any drug wholly metabolised by the liver, Slocinx XL 4mg Tablets should be administered with particular caution in patients with signs of impaired hepatic function. Since no clinical experience from patients with severe hepatic impairment exists, use in these patients is not recommended.
Caution is also recommended when doxazosin prolonged release tablets is administered concomitantly with medicinal products which may influence hepatic metabolism (e.g. cimetidine).
Use with PDE-5-inhibitors
Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and Slocinx XL 4mg should be done with caution as both drugs have vasodilating effects and may lead to symptomatic hypotension in some patients. In order to minimise the risk for developing postural hypotension the patients should be stable on the alpha-blocker therapy 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 formulation.
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.
Use in patients with Diabetic Autonomic Neuropathy:
Slocinx XL 4mg Tablets should be used with care in patients with Diabetic Autonomic Neuropathy.
Influence on plasma rennin activity and urinary excretion of vanillylmandelic acid: Slocinx XL 4mg Tablets may influence plasma renin activity and urinary excretion of vanillylmandelic acid. This should be considered when interpreting laboratory data.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and Slocinx XL 4mg 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 digoxin, warfarin, phenytoin or indomethacin.
Conventional doxazosin has been administered together with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic agents, uricosuric agents, and anticoagulants without any adverse drug interaction in clinical experience. 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.
Concomitant administration of doxazosin with a PDE-5 inhibitor (e.g. sildenofil, tadalafil, vardenafil) intended for erectile dysfunction should be used with caution as it may lead to symptomatic hypotension in some patients (see section 4.4)
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
Slocinx XL 4mg Tablets are contraindicated during lactation as the active ingredient accumulates in the milk of lactating rats (see section 5.3) and there is no information about the excretion of the active ingredient into human breast milk. Alternatively, breast-feeding must be stopped, if treatment with Slocinx XL 4mg Tablets is unavoidable.
For the benign prostatic hyperplasia indication: This section is not applicable.
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 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.
The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency. Frequencies are defined as very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10 000 to < 1/1000); 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, paresthesia | |
|
Eye Disorders |
Common |
Accomodation 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, dyspnea, 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 | |
|
Unknown |
Taste disturbances | |
|
Hepato-biliary Disorders |
Uncommon |
Abnormal liver function tests |
|
Very rare |
Cholestasis, hepatitis, jaundice | |
|
Rare |
icterus | |
|
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, hematuria, micturition frequency | |
|
Very rare |
Micturition disorder, nocturia, polyuria, increased diuresis, increase of serum creatinine | |
|
Reproductive |
Uncommon |
Impotence |
|
System and Breast Disorders |
Very rare |
Gynecomastia, priapism |
|
Unknown |
Retrograde ejaculation | |
|
General Disorders and Administration Site Conditions |
Common |
Asthenia, chest pain, influenza-like symptoms, peripheral edema |
|
Uncommon |
Pain, flushing, fever/shiver, facial oedema | |
|
Rare |
Low body temperature in elderly | |
|
Very rare |
Fatigue, malaise | |
|
Investigations |
Uncommon |
Weight increase |
Reporting 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
4.9 Overdose
Symptoms:
Headache, dizziness, unconsciousness, syncope, dyspnoea, hypotension, palpitation, tachycardia, arrhythmia. Nausea, vomiting. Possibly hypoglycaemia, hypokalaemia.
Treatment:
Should overdosage lead to hypotension, the patient should be immediately placed in a supine head down position. Symptomatic treatment. Close control of blood pressure. Since doxazosin is strongly bound to plasma proteins dialysis is not indicated.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha-adrenoceptor antagonists,
ATC code: C02CA04
Hypertension:
Administration of Slocinx XL 4 mg Tablets 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 Slocinx XL 4 mg prolonged-release Tablets. In patients with hypertension, the decrease in blood pressure during treatment with Slocinx XL 4 mg Tablets was similar in both the sitting and standing position.
Patients treated with immediate release doxazosin tablets against hypertension can be transferred to Slocinx XL 4 mg prolonged release tablets 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 (approx. 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 Slocinx XL 4 mg Tablets 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, Slocinx XL 4 mg prolonged-release Tablets 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 in Slocinx XL 4mg 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 Slocinx XL 4mg Tablets leads to a minor variation in plasma levels. Peak/trough ratio of Slocinx XL 4mg Tablets is less than half that of immediate release doxazosin tablets.
At steady-state, the relative bioavailability of doxazosin from Slocinx XL 4mg Tablets compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.
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.
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.).
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.
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
a-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
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Ltd
1 Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
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
11/06/2015