Doxazosin 4mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Doxazosin 4mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 4mg doxazosin equivalent to 4.85mg doxazosin mesilate.
Excipients with known effect: Each tablet contains 177.55 mg lactose (as lactose monohydrate)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablets
Oblong, biconvex, white tablets with no marking scored on one side with diameter of 11.8 - 12.2 mm x 5.8 - 6.2 mm
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension: Doxazosin Tablets is indicated for the treatment of essential 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 4 mg Tablets may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.
Benign prostatic hyperplasia: doxazosin Tablets is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia (BPH). Doxazosin Tablets may be used in BPH patients who are either hypertensive or normotensive.
4.2 Posology and method of administration
Posology
Unless prescribed otherwise, the following dosage regimen is recommended: Hypertension:
Doxazocin Tablets is used as a once daily regimen. The initial dose is 1 mg to minimise the potential for postural hypotension and/or syncope (see section 4.4). Dosage may then be increased to 2 mg after an additional one to two weeks of therapy thereafter, if necessary, to 4 mg, The majority of patients who respond to doxazosin will do so at a dose of 4mg or less.Dosage can be further increased if necessary to 8 mg of doxazosin or the maximum recommended dose: 16 mg of doxazosin.
Benign prostatic hyperplasia: The recommended initial dosage of Doxazocin 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 urodynamics and BPH symptomatology 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.
Paediatric population: The safety and efficacy of doxazosin in children and adolescents have not been established.
Older people: Normal adult dosage.
Use in the older people and in patients with renal insufficiencySince there is no change in pharmacokinetics in patients with impaired renal function, the usual adult dose of doxazosin is recommended. Doxazosin is not dialysable.
Patients with hepatic insufficiency
There is limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (eg cimetidine). As with any drug wholly metabolised by the liver, Doxazocin Tablets should be administered with caution to patients with evidence of impaired liver function (see section 4.4 and section 5.2).
Method of administration
For oral administration. The tablets should be taken with sufficient fluid in the morning. The attending doctor will decide upon the duration of treatment.
4.3 Contraindications
Doxazosin Tablets is contraindicated in:
1) Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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, see section 4.6 Pregnancy and lactation)
5) Patients 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 precautions for use
Postural Hypotension/Syncope:
Initiation of Therapy: In relation with the alpha-blocking properties of doxazosin patients may experience postural hypotension (orthostatic dysregulation) 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 monitor blood pressure on initiation of therapy to minimise the pontential 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.
Patients on sodium-low diet or treated with diuretics seem more sensitive for the potential for postural effects.
Use in patients with Acute Cardiac Conditions:
As with any other vasodilatory anti-hypertensive agent, it is prudent medical practice to advise that caution when administering doxazosin to patients with the following acute cardiac conditions:
- pulmonary oedema caused by aortic or mistral stenosis
- high output cardiac failure
- right sided (ventricular) heart failure caused by pulmonary embolism or pericardial effusion - left ventricular heart failure with low filling pressure
In patients with serious coronary suffering, a too quick or too distinct lowering of the blood pressure can result in worsening of anginal complaints.
Use in patients with hepatic insufficiency
As with any drug wholly metabolised by the liver, doxazosin should be used with particular caution in patients with impaired hepatic function (see section 4.2). Since there is no clinical experiencein patients with severe hepatic impairment, use in these patients is not recommended.
Paediatric population
Due to the lack of relevant experience, Doxazosin Tablets cannot be recommended for use in children.
Use with PDE-5 Inhibitors:
Concomitant administration of doxazosin with phosphodiesterase-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.
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 precautions for use). No studies have been conducted with doxazosin prolonged release formulations.
Doxazosin is highly bound to plasma proteins (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, betablocking 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 pontentiate the blood pressure lowering effect of other alpha-blockers and other antihypertensive drugs.
As for other antihypertensive agents, non-steroidal antirheumatics or estrogens may reduce the antihypertensive effect of doxazosin.
Sympathomimetics may reduce the anthypertensive effect of doxazosin; doxazosin may reduce blood pressure and vascular reactions to dopamine, ephedrine, epinephrine, metaramizol, methoxamine and phenylephrine.
Doxazosin may increase plasma renin activity and urinary excretion of vanillylmandelic acid. This should be considered when interpreting laboratory data.
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, safe use of Doxazosin 4 mg tablets during pregnancy has not been established. Accordingly, during pregnancy Doxazosin Tablets 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). These doses were approximately 300 times the maximum recommended human doses.
Breast-feeding:
Doxazosin is contraindicated during lactation as animal studies have shown that doxazosin 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 Doxaosin Tablet during lactation has not been established.Consequently, Doxazosin Tablets is contra-indicated 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 drive or use machinery 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 doxazosin 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.
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).
|
System Organ Class |
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) |
Unknown |
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Infections and infestations |
Respiratory tract infection, urinary tract infection | |||||
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Blood and the lymphatic system disorders |
Leukopenia, thrombocytopenia | |||||
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Immune system disorders |
Allergic drug reaction | |||||
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Metabolism and nutrition disorders |
Gout, increased appetite, anorexia | |||||
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Psychiatric disorders |
Agitation, depression, anxiety, |
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insomnia, nervousness | ||||||
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Nervous system disorders |
Somnolence dizziness, headache |
Cerebrovascular accident, hypoesthesia, syncope, tremor |
Dizziness postural, paresthesia | |||
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Eye disorders |
Blurred vision |
Introperative floppy iris syndrome (see Section 4.4) | ||||
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Ear and labyrinth disorders |
Vertigo |
Tinnitus | ||||
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Cardiac disorders |
Palpitation, tachycardia |
Angina pectoris, myocardial infarction, |
Bradycardia, cardiac arrhythmias | |||
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Vascular disorders |
Hypotension, postural hypotension |
Hot flushes | ||||
|
Respiratory, thoracic and mediastinal disorders |
Bronchitis, cough, dyspnea, rhinitis |
Epistaxis, |
Bronchospasm, | |||
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Gastrointestinal disorders |
Abdominal pain, dyspepsia, dry mouth, nausea, |
Constipation, flatulence, vomiting, gastroenteritis diarrhoea | ||||
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Hepato-biliary disorders |
Abnormal liver function tests |
Cholestasis, hepatitis, jaundice, | ||||
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Skin and subcutaneous tissue disorders |
Pruritus |
Skin rash, |
Urticaria, alopecia, purpura | |||
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Musculoskeletal, connective tissue and bone disorders |
Back pain, myalgia |
Arthralgia, |
Muscle cramps, muscle weakness | |||
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Renal and urinary disorders |
Cystitis, urinary incontinence |
Dysuria, micturition frequency, hematuria, polyuria |
Polyuria |
Increased diuresis, micturition disorder, nocturia | ||
|
Reproductive system and breast disorders |
Impotence |
Gynecomastia, priapism |
Retrograde ejaculation |
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General disorders and administration site conditions |
Asthenia, chest pain, influenzalike symptoms, peripheral oedema |
Pain, facial oedema |
Fatigue, malaise | |||
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Investigations |
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Should overdose 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 vaso pressors should be administered. Renal function should be monitored and, if necessary, supported. As doxazosin is highly bound to plasma proteins, dialysis is not indicated as a therapeutic measure.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha-adrenoceptor antagonists ATC code: CO2CA04
Doxazosin causes peripheral vasodilatation through a selective and competitive blockade of the postsynaptic alpha -1-adrenoceptors. The use of doxazosin in hypertensive patients causes a fall in blood pressure due to a reduction in peripheral vascular resistance.
Doxazosin is appropriate for oral administration in a once daily regimen in patients with essential hypertension. If the medication is taken once daily, the effect can still be observed 24 hours after administration. During the onset of therapy, a gradual reduction in blood pressure occurs, and orthostatic reactions are possible. Maximum reduction in blood pressure usually occurs 2 - 6 hours after dosing.
During therapy with doxazosin blood pressure values in hypertensive patients are similar in both supine and standing positions.
No tolerance development has yet been reported in connection with the antihypertensive effect in long-term therapy with doxazosin. Occasionally, during continued use, increased plasma renin activity and tachycardia occur.
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 older people. 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 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 muscular stroma and capsule of the prostate, and in the bladder neck.
5.2 Pharmacokinetic properties Absorption:
Following oral administration in humans (young male adults or elderly in either sex), doxazosin is well absorbed and approximately two thirds of the dose is bioavailable.
Biotransformation/Elimination:
Doxazosin is 98.3 % bound to plasma proteins.
Doxazosin is extensively metabolised (O-demethylation and hydroxylation) in man and in the animal species tested with the faeces, being the pre-dominant route of excretion, < 5 % is excreted in unchanged form in the faeces.
The mean plasma elimination is biphasic, the terminal half-life is 22 hours, thereby allowing once daily administration.
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. Doxazosin is a potent and selective alpha- blocker and in man accounts for 5 % of an oral dose. Therefore, 6’hydroxy-Doxazosin contributes little to the antihypertensive activity of doxazosin.
Studies in older people and patients with renal insufficiency have shown no relevant pharmacokinetic differences.
There is only limited data are available with liver impairment and on the effects of medications known to influence hepatic metabolism (e.g. cimetidine).
In one clinical trial with 12 patients with moderate hepatic insufficiency, single dose administration of doxaosin resulted in an increase in the area under the curve (AUC) of 43 % and a decrease in apparent oral clearance of 40 %.
As with any drug wholly metabolised by the liver doxazosin should be used administered with caution in patients with impaired liver function (see also 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, Microcrystalline Cellulose, Sodium starch Glycollate (Type A), Sodium laurylsulfate, Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
PVC/ Aclar/ Aluminium blisters:
Pack size: 28 tablets.
6.6 Special precautions for disposal and other handling
No special requirements for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Rd Eaton Socon. St. Neots Cambs PE19 3ET, UK
8. MARKETING AUTHORISATION NUMBER
PL 11311/0130
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 03 August 2000 Date of latest renewal: 10 January 2006
10 DATE OF REVISION OF THE TEXT
15/10/2015