Doxazosin 4mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Doxazosin 4mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Doxazosin 4mg (as mesilate) For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablets for oral administration.
Doxazosin 4mg: round, white, flat bevelled edge tablets, diameter 9mm and marked ‘DXN 4’ on one side.
4.1 Therapeutic indications
Hypertension: Doxazosin tablets are medicated 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, Doxazosin tablets may be used in combination with a thiazide diuretic, beta- adrenoreceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.
Benign prostatic hyperplasia: Doxazosin tablets are indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH). Doxazosin may be used in BPH patients who are either hypertensive or normotensive.
4.2 Posology and method of administration
Doxazosin may be administered in the morning or the evening.
Posology
Hypertension: Doxazosin tablets are used in a once daily regimen: the initial dose is lmgto minimise the potential for postural hypotension and/or syncope (see section 4.4). Dosage may then be increased after one or two weeks of therapy to 2mg and thereafter, if necessary to 4mg. The majority of patients who respond to Doxazosin tablets will do so at a dose of 4mg or less. Dosage can be further increased if necessary to 8mg or the maximum recommended dose of 16mg.
Benign prostatic hyperplasia: The initial dosage of Doxazosin tablets is 1mg given once daily to minimise the potential for postural hypotension and/or syncope (see section 4.4). Depending on the individual patient’s response dosage may then be increased to 2mg and thereafter to 4mg and up to the maximum recommended dose of 8mg.The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4mg daily.
Children: The safety and efficacy of Doxazosin tablets in children and adolescents have not been established
Elderly: Normal adult dosage.
Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function the usual adult dose of Doxazosin is recommended. Doxazosin is not dialysable.
Patient with hepatic impairment: There have been no pharmacokinetic studies in patients with liver impairment, nor in patients taking drugs known to influence hepatic metabolism (e.g. cimetidine). Doxazosin tablets should be used with care in such patients.
Method of administration
Oral use.
4.3 Contraindications
Doxazosin is contra indicated in:
(1) Patients with known hypersensitivity to quinazolines (e.g. prazosin, terazosin, doxazosin), or any of the excipients
(2) Patients with a history of orthostatic hypotension
(3) Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones.
(4) During lactation ((for the hypertension indication only please see section 4.6)
(5) Patient with hypotension (for 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 special precautions for use
• 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 (see section 4.2.). 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.
• Use in patients with Acute Cardiac Conditions: As with any other vasodilatory anti-hypertensive agent it is prudent medical practice to advice caution when administering doxzosin 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 Hepatically Impaired Patients: As with any drug wholly metabolized by the liver, doxazosin should be administered with particular caution to patients with evidence of impaired hepatic function (see section 4.2). 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 phosphodiestearase-5-inhibitors (eg 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 the 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.
• 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.
• Doxazosin 2mg tablet contains lactose. Therefore, it should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
• ‘‘Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and non-selective alpha-blockers 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 phosphodiestearse-5-inhibitors.’’
4.5 Interaction with other medicinal products and other forms of interaction
Phosphodiesterase-5-inhibitors (eg. sildenafil, tadalafil, vardenafil)
Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see Section 4.4, Special warnings and Special Precautions for Use). No studies have been conducted with doxazosin prolonged release formulations.
Doxazosin is highly bound to plasma protein (98%). In vitro data in human plasma indicates that doxazosin has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin 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 administraration 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:
Use during 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 high doses (see section 5.3: Preclinical Safety Data). These doses were approximately 300 times the maximum recommended human dose.
Use during lactation:Doxazosin is contraindicated during lactation as animal studies have shown that 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. The clinical safety of Doxazosin during lactation has not been established, consequently it is contraindicated in nursing mothers.
Use during breast-feeding: Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (Please see section 5.3: Preclinical Safety Data).
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 opening machinery or operating a motor vehicle may be impaired, especially when initiating therapy.
4.8 Undesirable effects
Hypertension: In clinical trials involving patients with hypertension, the most common reactions associated with DoxazosinDoxazosin therapy were of a postural type (rarely associated with fainting) or non-specific.
Benign prostatic hyperplasia: Experience in controlled clinical trials in BPH indicates a similar adverse event profile to that seen in hypertension.
Frequencies used are as follows: very common > 1/10, Common> 1/100 and < 1/10, Uncommon > 1/1,000 and < 1/100, Rare > 1/10,000 and < 1/1,000, Very rare< 1/10,000
|
MedDRA System Organ Class |
Frequency |
Undesirable Effects |
|
Infections and infestation |
Common |
Respiratory tract infection, urinary tract infection |
|
Blood and lymphatic system disorders |
Very Rare |
Leukopenia, thrombocytopenia |
|
Immune System Disorders |
Uncommon |
Allergic drug reaction |
|
Metabolism and Nutrition Disorders |
Common |
Anorexia |
|
Uncommon |
Gout, increased appetite | |
|
Psychiatric Disorders |
Common |
Anxiety, insomnia, nervousness |
|
Uncommon |
Agitation, depression | |
|
Nervous System Disorders |
Very common |
Dizziness, headache |
|
Common |
Dizziness postural, paresthesia, somnolence | |
|
Uncommon |
Cerebrovascular accident, hypoesthesia, syncope, tremor | |
|
Eye Disorders |
Very Rare |
Blurred vision |
|
Unknown |
Introperative 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, cardiac arrhythmias | |
|
Very Rare |
Bradycardia | |
|
Vascular Disorders |
Common |
Hypotension, postural hypotension |
|
Uncommon |
Hot flushes | |
|
Respiratory, Thoracic and Mediastinal Disorders |
Common |
Bronchitis, cough, dyspnoea, rhinitis |
|
Uncommon |
Epistaxis, | |
|
Very Rare |
Bronchospasm | |
|
Gastrointestinal Disorders |
Common |
Abdominal pain, dyspepsia, dry mouth, nausea, diarrhoea |
|
Uncommon |
Constipation, flatulence, vomiting, gastroenteritis | |
|
Unknown |
Taste disturbances | |
|
Hepatobiliary Disorders |
Uncommon |
Abnormal liver function tests |
|
Very Rare |
Cholestatis, hepatitis, jaundice, | |
|
Skin and Subcutaneous Tissue Disorders |
Common |
Pruritis |
|
Uncommon |
Skin rash, alopecia, purpura | |
|
Very Rare |
Urticaria | |
|
Musculoskeletal and Connective Tissue Disorders |
Common |
Back pain, myalgia |
|
Uncommon |
Arthralgia, muscle cramps, muscle weakness | |
|
Renal and Urinary Disorders |
Common |
Cystitis, urinary incontinence |
|
Uncommon |
Dysuria, micturition frequency, hematuria, polyuria, urinary incontinence | |
|
Very Rare |
Increased diuresis, micturition disorder, nocturia | |
|
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 oedema, fatigue, malaise |
|
Uncommon |
Pain, facial oedema | |
|
Investigations |
Uncommon |
Weight increase |
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 at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures may be appropriate in individual cases.
If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressor should then be used. Renal function should be monitored and supported as needed.
Since doxazosin is highly protein bound, dialysis is not indicated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotheraputic group: alpha-andrenoreceptor antagonists ATC Code: C02C A04
Doxazosin is a potent and selective post-junctional alpha-1-adrenoreceptor antagonist. This action results in a decrease in systemic blood pressure. Doxazosin tablets are appropriate for oral ‘administration in a once daily regimen in patients with essential hypertension.
Doxazosin tablets have been shown to be free of adverse metabolic effects and are suitable for use in patients with co-existent diabetes mellitus, gout and insulin resistance.
Doxazosin tablets are suitable for use in patients with co-existant asthma, left ventricular hypertrophy and in elderly patients. Treatment with Doxazosin tablets has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen factor.
Additionally, Doxazosin tablets improve insulin sensitivity in patients with impairment.
Doxazosin tablets in addition to their antihypertensive effect have 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 tablets to patients with symptomatic BPH results 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.
5.2 Pharmacokinetic properties
Absorption: Following oral administration in humans (young male adults or the elderely of either sex), doxazosin is well absorbed, achieving maximum blood levels at 2 hours, and approximately two thirds of the dose is bioavailable.
Biotransformation/Elimination: Approximately 98% of doxazosin is protein bound in plasma.
Plasma elimination is biphasic with a mean plasma half life of 22 hours thus making the drug suitable for once daily administration.
Doxazosin is extensively metabolised in man and in the animal species tested, with the faeces being the predominant route of excretion.
The mean plasma elimination half life is 22 hours thus making the drug suitable for once daily administration.
In man, approximately 5% of the administered dose is excreted in the faeces as unchanged drug.
After oral administration of Doxazosin the plasma concentrations of the metabolites are low. The most active (6’hydroxy) metabolite is present in man at one fortieth of the plasma concentration of the parent compound, which suggests that the antihypertensive activity is, in the main, due to doxazosin. There are only limited data in patients with liver impairment and on the effects of drugs 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 in AUC of 43% and a decrease in apparent oral clearance of 40%. As with any drug wholly metabolised by the liver, Doxazosin should be administered with caution to patients with impaired liver function (see section 4.4).
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 and carcinogenicity. For further information see section 4.6.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium carboxymethyl starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate and sodium lauryl sulphate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 30°C.
Keep container in the outer carton.
6.5 Nature and contents of container
Blister PVC (250pm)-PVDC (40g.m2)/Aluminium (20pm). Pack size: 28 tablets
6.6 Special precautions for disposal
No special requirements.
7. Marketing Authorisation Holder
Medreich Plc Warwick House Plane Tree Crescent Feltham TW13 7HF
8 MARKETING AUTHORISATION NUMBER(S)
PL 21880/0036
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/03/2009
10 DATE OF REVISION OF THE TEXT
28/08/2015