Doxazosin 4mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Doxazosin 4 mg Tablets
2. Qualitative and Quantitative Composition
Each tablet contains 4.85 mg doxazosin mesilate equivalent to 4 mg of doxazosin.
For the full list of excipients, see 6.1.
3. PHARMACEUTICAL FORM
Tablet
4 mg: white oblong scored tablet, “D4” engraved on one side
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
Essential hypertension.
Symptomatic treatment of benign prostatic hyperplasia (BPH).
4.2 Posology and method of administration
Posology
The duration of therapy will be decided by the physician.
Hypertension:
The usual dosage limits of doxazosin lie between 1 and 8 mg per day. The maximum recommended dosage is 16 mg per day. The initial dosage is 1 mg, to be taken before retiring to bed. This dose is maintained for 1 or 2 weeks. The dose can then be increased to 2 mg once a day for another 1 or 2 weeks. If necessary the daily dose can then be gradually increased, observing equal intervals, to 4, 8 and 16 mg once a day, depending on the patient's response.
Benign prostate hyperplasia:
The initial dose of doxazosin is 1 mg (1 mg tablet) on the 1st to 8th day once daily and 2 mg (2 mg tablet) on the 9th to 14th day. Subsequently, dose should be titrated individually to 4 mg and to the maximum recommended dosage of 8 mg, depending on the urodynamic parameters and the BPH symptomatology of the patient. The recommended titration interval is 1 to 2 weeks. The usual recommended dose is 2-4 mg daily. Doxazosin is administered once a day. If the doxazosin treatment has been stopped for a number of days, the regimen should be determined again.
Use in elderly patients and use in renally impaired patients:
Because the pharmacokinetics of doxazosin remain unchanged in patients with renal insufficiency, and no evidence exists that doxazosin will exacerbate an existing renal insufficiency, the application of the usual dosages is generally advised. As in rare cases an increased sensitivity cannot be ruled out, a more cautious approach with respect to initiating the treatment in such patients may be called for. As doxazosin is highly protein bound, it is not removed by dialysis.
Use in patients with hepatic insufficiency:
The doxazosin dose should be titrated particularly carefully in patients with impaired liver function. No clinical experience is available in patients with serious hepatic dysfunction (cf. 4.4 ‘Warnings and precautions for use’).
Use in children:
The safety and efficacy of Doxazosin mesilate in children and adolescents have not been established.
Method of adminstration
The tablets should be taken with a sufficient amount of water once daily.
4.3 Contraindications
Doxazosin is contraindicated in:
- patients with hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1 or other quinazolines (e.g. prazosin, terazosin).
- patients with history of orthostatic hypotension
- patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infection or bladder stones
- during lactation when being treated for hypertension (see section 4.6)
- BPH patients with hypotension.
Doxazosin is contraindicated as monotherapy in patients with overflow bladder, anuria or progressive renal insufficiency.
4.4 Special warnings and precautions for use
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 antihypertensive 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
Use in hepatically impaired patients:
As with any drug wholly metabolised by the liver, doxazosin should be administered with particular caution to patients with evidence of impaired hepatic function. Since there is no clinical experience in patients with severe hepatic impairment, using doxazosin in these patients is not recommended.
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.
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 cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.
Doxazosine tablets contain lactose. Therefore it should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients (see section 4.4).
Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin 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 administration of a single 1 mg dose of doxazosin on day 1 of a four-day regiment 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 high doses.
Lactation
Doxazosin is contraindicated during lactation as 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.
Breast-feeding
Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (see section 5.3).
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
Frequencies used are as follows:
- 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)
|
System organ class |
Frequency |
Undesirable effects |
|
Infections and infestations |
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 |
Uncommon |
Anorexia Gout Increased appetite |
|
Psychiatric disorders |
Uncommon |
Anxiety Insomnia Nervousness Agitation Depression |
|
Nervous system disorders |
Common |
Dizziness Headache Somnolence |
|
Uncommon |
Cerebrovascular accident Hypoesthesia Syncope Tremor | |
|
Very rare |
Dizziness postural Paresthesia | |
|
Eye disorders |
Very rare |
Blurred vision |
|
Not known |
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 |
Hypotension Postural hypotension |
|
Very rare |
Hot flushes | |
|
Respiratory, thoracic and mediastinal disorders |
Common |
Bronchitis Cough Dyspnoea Rhinitis |
|
Uncommon |
Epistaxis | |
|
Very rare |
Bronchospasm aggravated | |
|
Gastrointestinal disorders |
Common |
Abdominal pain Dyspepsia Dry mouth Nausea |
|
Uncommon |
Constipation Diarrhoea Flatulence Vomiting Gastroenteritis | |
|
Hepatobiliary disorders |
Uncommon |
Abnormal liver function tests |
|
Very rare |
Cholestasis Hepatitis Jaundice | |
|
Skin and subcutaneous tissue disorders |
Common |
Pruritus |
|
Uncommon |
Skin rash | |
|
Very rare |
Alopecia Purpura Urticaria | |
|
Musculoskeletal and connective tissue disorders |
Common |
Back pain Myalgia |
|
Uncommon |
Arthralgia | |
|
Rare |
Muscle cramps Muscle weakness | |
|
Renal and urinary disorders |
Common |
Cystitis Urinary incontinence |
|
Uncommon |
Dysuria Micturition frequency increased Hematuria | |
|
Rare |
Polyuria | |
|
Very rare |
Increased diuresis Micturition disorder Nocturia | |
|
Reproductive system and breast disorders |
Uncommon |
Impotence |
|
Very rare |
Gynaecomastia Priapism |
|
Not known |
Retrograde ejaculation | |
|
General disorders and administration site conditions |
Common |
Asthenia Chest pain Influenza-like symptoms Peripheral oedema |
|
Uncommon |
Pain Facial oedema | |
|
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 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 immediately be 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.
If this measure is inadequate, shock should be first treated with volume expanders. If necessary, vasopressor agents should then be used. Renal function should be monitored and supported as needed.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha-adrenoceptor antagonists, ATC-code: C02CA04,
Doxazosin is a selective and competitive antagonist of postsynaptic alpha-1-adrenergic receptors.
Administration of doxazosin will cause a significant reduction in blood pressure due to decreased peripheral vascular resistance. Following once-daily administration a clinically significant reduction in the blood pressure is maintained for up to 24 hours. After administration a gradual reduction in blood pressure will come about; orthostatic effects at the start of the treatment may occur. Maximum reduction in blood pressure will be achieved about 2-6 hours after administration.
In hypertensive patients the blood pressure during the doxazosin therapy is similar in a lying and in a standing position.
During therapy with doxazosin regression of left ventricular hypertrophy has been reported.
Unlike the non-selective alpha adrenergic receptor blocking agents, no tolerance has been observed after a prolonged doxazosin therapy. An increase in the plasma renin activity and tachycardia have only infrequently been observed after a continued therapy.
In clinical studies doxazosin caused a slight reduction in the plasma concentrations of triglycerides, total cholesterol and the LDL fraction. A slight increase in HDL/total cholesterol ratio (approximately 4% to 13% of baseline) has been observed. The clinical significance of these findings remains to be established.
Administration of doxazosin to patients with symptomatic BPH results in an improvement of urodynamic symptoms. The effect is reported to be due to selective blockade of the alpha-adrenoreceptors in the smooth muscle of bladder neck, prostate capsule and urethra.
After an interim analysis of ALLHAT (Antihypertensive and lipid-lowering treatment to prevent heart attack trial) the doxazosin treatment arm based on comparisons with chlorthalidone was discontinued. There was a significantly higher (25%) incidence of combined cardiovascular disease events and in particular congestive heart failure (CHF) compared with the chlorthalidone group. The risk of CHF was almost doubled. There were also negative trends for stroke and for combined coronary heart disease (CHD). The total mortality did not differ between the doxazosin and chlorthalidone arms.
5.2 Pharmacokinetic properties
Following oral administration, doxazosin is absorbed well. Maximum plasma levels are reached after 2 hours and the absolute bioavailability is approximately 63%. Doxazosin is to large extent bound to plasma protein (about 98%). The plasma elimination is biphasic; the terminal half-life is 16-30 hours so that once-daily administration is possible. Doxazosin is metabolised in the liver to a large extent and mainly excreted in the faeces (63-65%), with less than 5% of the dose excreted as unchanged doxazosin. 6-hydroxy-doxazosin is a potent and selective alpha-blocker and in man accounts for 5% of the oral dose. Therefore it contributes little to the antihypertensive effect of doxazosin.
Pharmacokinetic tests in the elderly and in patients with renal insufficiency have not shown any important pharmacokinetic differences in comparison with patients with a normal renal function. There are only limited data on the use of doxazosin 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 patients with mild hepatic insufficiency, the area under the plasma concentration-time curve (AUC) was increased by 43%, and clearance after single oral dosing was reduced by 40%.
5.3 Preclinical safety data
Doxazosin accumulates in milk of lactating rats. There is no information about the excretion of the drug into the milk of lactating women. Alternatively, the use of doxazosin is contraindicated during lactation.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Microcrystalline cellulose, lactose anhydrous, starch sodium glycollate (type A), magnesium stearate, sodium laurylsulfate, colloidal anhydrous silica.
6.2. Incompatibilities
Not applicable
6.3. Shelf-Life
5 years
6.4. Special Precautions for Storage
Do not store above 30°C.
6.5. Nature and Content of Container
PVC/PVDC-Aluminium blister strips, 2, 3, 5, 10, 20 or 50 x 10 tablets or 1, 2 or 7 x 14 tablets.
6.6. Instructions for Use, Handling and Disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Ltd Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG United Kingdom
MARKETING AUTHORISATION NUMBER(S)
8.
PL 00289/0359
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/11/2010
10 DATE OF REVISION OF THE TEXT
04/09/2015