Doxazosin 2mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Doxazosin 2mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains doxazosin mesylate equivalent to 2mg doxazosin.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White round flat bevelled edged tablets marked “Dxn2” on one side and scored on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension:
Doxazosin Tablets are indicated 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 may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin converting enzyme inhibitor.
Benign Prostatic Hyperplasia (BPH):
Doxazosin is indicated for the treatment of urinary outflow obstruction and symptoms associated with benign prostatic hyperplasia.
4.2 Posology and method of administration
Hypertension:
Doxazosin is normally prescribed once daily with the initial dose of 1mg. Dosage may be increased after one to two weeks of therapy to 2mg and thereafter to 4mg, where necessary. A majority of patients respond to a dose of 4mg or less. However, the dose can be increased to 8mg or to a maximum of 16mg daily, if necessary.
Benign Prostatic Hyperplasia (BPH):
Doxazosin is normally prescribed once daily with the initial dose of 1mg. Depending on the patient’s response, the dosage may be increased after one to two weeks to 2mg, and thereafter to 4mg, up to the maximum dose of 8mg. A majority of patients respond to a dose of 2mg - 4mg.
Children:
There is insufficient experience to recommend the use of Doxazosin Tablets in children.
Elderly:
Normal adult dose.
Patients with renal impairment:
Since there is no change in the pharmacokinetics in patients with impaired renal function, the usual adult dose is recommended. Doxazosin is not dialysable.
Patients with hepatic impairment:
There are only limited data with liver impairment and on the effect of drugs known to influence hepatic metabolism (e.g. cimetidine). As with any drug wholly metabolised by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution (See section 4.4 Special warnings and precautions for use).
4.3 Contraindications
Doxazosin is contraindicated in
1. Patients with a 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 (please see section 4.6)1
5. Patients with hypotension2
Doxazosin is contraindicated as monotherapy in patients with either overflow bladder or anuria with or without progressive renal insufficiency.
1 For the hypertension indication only
2 For the benign prostatic hyperplasia indication only
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 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.
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 use 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. 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 tablets contain lactose. Therefore, these 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 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.
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 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. The10% 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 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: Preclinical Safety Data).
Breastfeeding
Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (please see section 5.3: Preclinical Safety Data).
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.
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 following undesirable effects have been observed and reported during treatment with Doxazosin with the following frequencies: 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
|
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 |
|
Infections and infestations |
Respiratory tract infection, urinary tract infection | |||||
|
Blood and the lymphatic system disorders |
Leukopenia, thrombocytopenia | |||||
|
Immune system disorders |
Allergic drug reaction | |||||
|
Metabolism and nutrition disorders |
Gout, increased appetite, anorexia | |||||
|
Psychiatric disorders |
Depression, anxiety, insomnia, agitation, nervousness, | |||||
|
Nervous system disorders |
Somnolence dizziness, headache |
Cerebrovascular accident, hypoesthesia, syncope, tremor |
Dizziness postural, paresthesia | |||
|
Eye disorders |
Blurred vision |
Introperative floppy iris syndrome (see Section 4.4) | ||||
|
Ear and labyrinth disorders |
Vertigo |
Tinnitus | ||||
|
Cardiac disorders |
Palpitation, tachycardia |
Angina pectoris, myocardial |
Bradycardia, cardiac arrhythmias |
|
infarction, | ||||||
|
Vascular disorders |
Hypotension, postural hypotension |
Hot flushesh | ||||
|
Respiratory, thoracic and mediastinal disorders |
Bronchitis, cough, dyspnea, rhinitis |
Epistaxis, |
Bronchospasm | |||
|
Gastrointestinal disorders |
Abdominal pain, dyspepsia, dry mouth, nausea, |
Constipation, flatulence, vomiting, gastroenteritis, diarrhoea | ||||
|
Hepato-biliary disorders |
Abnormal liver function tests |
Cholestasis, hepatitis, jaundice, | ||||
|
Skin and subcutaneous tissue disorders |
Pruritus |
Skin rash, |
Urticaria, alopecia, purpura | |||
|
Musculoskeletal, connective tissue and bone disorders |
Back pain, myalgia |
Arthralgia, |
Muscle cramps, muscle weakness | |||
|
Renal and urinary disorders |
Cystitis, urinary incontinence |
Dysuria, micturition frequency, hematuria, |
Polyuria |
Increased diuresis, micturition disorder, nocturia, | ||
|
Reproductive system and breast disorders |
Impotence |
Gynecomastia, priapism |
Retrograde ejaculation | |||
|
General disorders and administration site conditions |
Asthenia, chest pain, influenza-like symptoms, peripheral oedema, |
Pain, facial oedema |
Fatigue, malaise | |||
|
Investigations |
Weight increase |
4.9 Overdose
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.
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
Pharmacotherapeutic group: Alpha-adrenoceptor blocking agents
ATC-CODE: C02C AC04
Doxazosin is a potent and selective post-junctional alpha-1-adrenoceptor antagonist. This action results in a decrease in systemic blood pressure. Doxazosin is appropriate for oral administration in a once daily regimen in patients with essential hypertension.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with co-existent diabetes mellitus, gout and insulin resistance.
Doxazosin is suitable for patients in co-existing asthma, left ventricular hypertrophy and in elderly patients. Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen factor.
Additionally, doxazosin improves the insulin sensitivity in patients with insulin resistance. In addition to its antihypertensive effect, doxazosin produced in long term studies 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 and capsule and in the bladder neck.
5.2 Pharmacokinetic properties
Following oral administration in humans, doxazosin is well absorbed, achieving maximum blood levels at 2 hours, and the bioavailability is approximately two thirds of the administered dose. 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. 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 hypertensive activity is, in the main, due to doxazosin.
Preclinical safety data
5.3
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
Sodium starch glycolate Microcrystalline cellulose Lactose monohydrate Magnesium stearate Sodium lauril sulphate
6.2 Incompatibilities
Not Applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30°C. Store in the original package.
6.5 Nature and contents of container
Doxazosin 2mg Tablets are packed in PVC/PVdC/Aluminium blister strips available in a pack size of 28 tablets.
Carton box containing blister strips.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Arrow Generics Limited Unit 2, Eastman Way, Stevenage, Herts,
SG1 4SZ
8 MARKETING AUTHORISATION NUMBER(S)
PL 018909/0060
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/08/2009
10
DATE OF REVISION OF THE TEXT
20/08/2012