Doxzogen Xl 4 Mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Doxzogen XL 4 mg prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One 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 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 maximum recommended dose is 8 mg doxazosin once daily.
Essential hypertension:
Adult patients:
Usually 4 mg doxazosin once daily. If necessary, the dosage may be increased to 8 mg doxazosin once daily.
Doxzogen XL 4 mg prolonged-release 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:
Adult patients:
Usually 4 mg doxazosin once daily. If necessary, the dosage may be increased to 8 mg doxazosin once daily.
Doxzogen XL 4 mg prolonged-release 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 patients :
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.
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).
Paediatric population:
The safety and efficacy of doxazosin in children below 18 years of age has not yet been established. Doxzogen XL 4 mg prolonged-release tablets are not recommended for patients under the age of 18 years.
Method of administration
Doxzogen 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.
4.3 Contraindications
Hypersensitivity to the active substance or any of the excipients listed in section 6.1 or quinazolines (e.g. prazosin, terazosin)
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 history of gastro-intestinal obstruction, oesophageal obstruction or any degree of decreased lumen diameter of the gastrointestinal tract.1 During lactation(see section 4.6)2
3
Patients with hypotension
Doxzogen is contraindictaed as monotherapy in patients with either overflow bladder or anuria with or without progressive renal insufficiency.
1For patients taking the sustained release tablets only.
2
For the hypertension indication only
3
For the benign prostatic hyperplasia indication only
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 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 heart diseases:
• pulmonary oedema as a result of aortic or mitral stenosis
• heart failure at high output
• right sided heart failure as a result of pulmonary embolism or pericardiac effusion and
• left sided ventricular heart insufficiency with low filling pressure.
In hypertensive patients with one or more additional risk factors for cardiovascular disease, doxazosin 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.
On initiation of therapy or increasing of dose the patient should be monitored to minimise the potential for postural effects, e.g. hypotension and syncope. In patients treated for benign prostatic hyperplasia and without hypertension mean blood pressure changes are small, but hypotension, dizziness, fatigue occur in 10 - 20% of the patients and oedema and dyspnoea occur in less than 5% of patients. Special care should be taken with hypotensive patients or patients with known orthostatic dysregulation taking doxazosin to treat benign prostatic hyperplasia (BPH). They should be informed about the potential risk form injuries and measures of precaution to minimize orthostatic symptoms.
Use in Hepatically Impaired Patients:
As with any drug wholly metabolised by the liver, doxazosin should be administered with particular caution in patients with evidence of hepatic impairment (see section 5.2). Since there is no clinical experience in patients with severe hepatic impairment, use in these patients is not recommended.
Caution is also recommended when doxazosin is administered concomitantly with medicinal products, which may influence hepatic metabolism (e.g. cimetidine).
Doxazosin should be used with care in patients with Diabetic Autonomic Neuropathy
Doxazosin may influence plasma renin activity and urinary excretion of vanillylmandelic acid. This should be considered when interpreting laboratory data.
Use with PDE-5 inhibitors:
Concomitant administration of doxzosin with phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) should be done with caution as both drugs have vasodilating effects and may lead to symptomatic hypotension in some patients. In order to minimize the risk for developing orthostatic hypotension the patient should be haemodynamically stabilised 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.
In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.
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.
4.5
Interaction with other medicinal products and other forms of interaction
Conventional 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. Doxazosin has been administered together with thiazide diuretics, furosemide, beta-blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic agents, uricosuric agents, or anticoagulants without adverse drug interactions. However, data from formal drug/drug interaction studies are not present.
Doxazosin potentiates the blood pressure lowering effect 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 phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxzosin may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with doxazosin prolonged release formulations.
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
Pregnancy
For the hypertension indication:
As there are no adequate data 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. Animal studies have shown reduced foetal survival at extremely high doses (see section 5.3). Doxzogen XL 4 mg prolonged-release tablets should not be used during pregnancy unless clearly needed.
Lactation
Doxzogen XL 4 mg prolonged-release tablets are contraindicated during lactation as the medicinal product accumulates in the milk of lactating rats (see section 5.3) and there is no information about the excretion of the medicinal product into the milk of lactating women.
Alternatively, breast-feeding should be stopped, if treatment with Doxzogen XL 4 mg prolonged-release tablets is necessary (see section 5.3) .
For benign prostatic hyperplasia indication: This section is not applicable
4.7 Effects on ability to drive and use machines
Doxzogen XL 4 mg prolonged-release tablets may impair the ability to drive and use machines, especially at the beginning of therapy.
4.8 Undesirable effects
The occurrence of adverse reactions is 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 following undesirable effects have been observed and reported during treatment with Doxzogen 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) and not known (frequency cannot be estimated from the available data).
|
System Organ Class |
Common |
Uncommon |
Rare |
Very Rare |
Not known |
|
Infections and |
Respiratory tract |
|
infestations |
infection, urinary tract infection | ||||
|
Blood and lymphatic system disorders |
Leukopenia, thrombocytopenia, erythrocytopenia | ||||
|
Immune system disorders |
Allergic drug reaction | ||||
|
Metabolism and nutrition disorders |
Anorexia, gout, increased appetite, hypokalaemia, thirst |
hypoglycaemia |
Increase in serum urea. | ||
|
Psychiatric disorders |
apathy |
Anxiety, depression, insomnia, nightmares, amnesia, emotional stability |
Agitation, nervousness | ||
|
Nervous system disorders |
Dizziness, headache, somnolence, |
Cerebrovascul ar accident, hypoesthesia, syncope, tremor, |
Dizziness postural, paraesthesia | ||
|
Eye disorders |
accommodation disturbances |
lacrimation, photophobia |
Blurred vision |
Intraoperative floppy iris syndrome (see Section 4.4) | |
|
Ear and labyrinth disorders |
Vertigo |
Tinnitus | |||
|
Cardiac disorders |
Palpitation, tachycardia |
Angina pectoris, myocardial infarction |
Bradycardia, cardiac arrhythmias | ||
|
Vascular disorders |
Hypotension, postural hypotension, oedema, |
Peripheral ischaemia, |
Flush, | ||
|
Respiratory, thoracic and mediastinal disorders |
Bronchitis, cough, dyspnoea, rhinitis |
Epistaxis, pharyngitis |
Oedema of larynx |
Bronchospasm | |
|
Gastrointestinal disorders |
Abdominal pain, dyspepsia, dry mouth, nausea |
Constipation, diarrhoea, flatulence, vomiting, gastroenteritis, taste disturbances | |||
|
Hepatobiliary disorders |
Abnormal liver function tests |
Cholestasis, hepatitis, jaundice, icterus, increased liver values | |||
|
Skin and subcutaneous tissue disorders |
Pruritus |
Skin rash |
Alopecia, purpura, urticaria | ||
|
Musculoskeletal, and connective tissue disorders |
Back pain, myalgia, muscle cramps |
Arthralgia, muscle stiffness |
Muscle cramps, muscle weakness |
|
Renal and urinary disorders |
Cystitis, urinary incontinence, , |
Dysuria, haematuria, micturition frequency, |
Micturition disorder, nocturia, polyuria, increased diuresis, increase of serum creatinine | ||
|
Reproductive system and breast disorders |
Delayed ejaculation |
Impotence |
Gynecomastia, priapism |
Retrograde ejaculation | |
|
General disorders and administration site conditions |
Asthenia, chest pain, influenzalike symptoms, peripheral oedema |
Pain, facial oedema, fever/shiver, paleness, general oedema |
Fatigue, malaise, low body temperature in elderly | ||
|
Investigations |
Weight increase |
Particular caution:
Postural hypotension and in rare cases syncope may occur at the beginning of therapy, especially at very high doses but also when treatment is recommenced after a break.
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. 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 Doxzogen XL 4 mg prolonged-release 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 4 mg Doxzogen XL 4 mg prolonged-release tablets. In patients with hypertension, the decrease in blood pressure during treatment with Doxzogen XL prolonged-release tablets was similar in both the sitting and standing position.
Patients treated with immediate release doxazosin tablets against hypertension can be transferred to Doxzogen 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 (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 Doxzogen XL 4 mg prolonged-release 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, Doxzogen XL 4 mg prolonged-release tablets 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 in Doxzogen XL
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 Doxzogen XL 4 mg prolonged release tablets lead to a minor variation in plasma levels. Peak/trough ratio of Doxzogen XL 4 mg prolonged release tablets is less than half that of immediate release doxazosin tablets.
At steady-state, the relative bioavailability of doxazosin from Doxzogen XL 4 mg prolonged-release tablets 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).
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 82mg/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 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
Tablet core:
Macrogol
Cellulose, microcrystalline Povidone K 29-32 Butylhydroxytoluene (E321) a-Tocopherol Silica, colloidal anhydrous Sodium stearyl fumarate
Tablet coat:
Methacrylic acid - ethyl acrylate copolymer (1:1) Dispersion 30 per cent Silica, colloidal anhydrous 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 blisters
Pack sizes: 10, 20, 28, 30, 50, 56, 60, 90, 98, 100, 140 (10 x 14) tablets Calendar packs of 28 and 98
Unit dose 50 x 1
HDPE tablet container Pack sizes: 100, 250 tablets
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0743
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/05/2007
10 DATE OF REVISION OF THE TEXT
15/02/2013