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Document: spc-doc_PL 06831-0093 change

• spc-doc_PL 00289-0359
• spc-doc_PL 04569-0458
• spc-doc_PL 06464-1126
• spc-doc_PL 06831-0093
• spc-doc_PL 11311-0130
• spc-doc_PL 14017-0034
• spc-doc_PL 16363-0290
• spc-doc_PL 17907-0257
• spc-doc_PL 20417-0037
• spc-doc_PL 21880-0036

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1.    NAME OF THE MEDICINAL PRODUCT

Doxazosin 4 mg Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin 4 mg contains 4.85 mg of doxazosin mesilate to the equivalent of 4 mg of the active constituent doxazosin.

For excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Tablets.

Pink biconvex uncoated tablets, scored with a division mark on both sides and embossed with “DZS 4” on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of hypertension.

Doxazosin can be used as a mono-agent in the treatment of hypertension or in patients inadequately controlled on single antihypertensive therapy. Doxazosin tablets may be used in combination with thiazide diuretics, beta-adrenoceptor blocking agents, calcium antagonists or angiotensin converting enzyme inhibitors.

4.2    Posology and method of administration

Doxazosin is used in a once daily regimen. The dose of Doxazosin should be adjusted according to the patient's response. The initial dose of Doxazosin should be 1 mg per day. Dosage may then be increased in intervals of 1 or 2 weeks to 2 mg and thereafter to 4 mg. If necessary, dosage can be further increased to 8 mg or the maximum recommended dose of 16 mg. Dosage may be increased until the desired blood pressure level is achieved, or until undesirable effects occur.

Paediatric population:

The safety and efficacy of Doxazosin in children and adolescents have not been established.

Elderly:

Normal adult dosage is recommended.

Renal insufficiency:

There is no change in pharmacokinetics of Doxazosin in patients with impaired renal function. Normal adult dosage is recommended. Doxazosin is not dialysable.

Hepatic insufficiency:

Up to now no studies have been performed with Doxazosin in patients with liver impairment. Since Doxazosin is extensively metabolised in the liver, it should be used with care in such patients.

4.3 Contraindications

Doxazosin is contraindicated in:

•    patients with a known hypersensitivity to quinazolines (e.g. prazosin, terazosin, doxazosin), or any of the excipients

•    patients with a 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 (see section 4.6 Pregnancy and Lactation).

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

Initiation of Therapy: in relation to 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 experiences 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 (e.g. 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 thermodynamically stabilised 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.

Excipients: Doxazosin tablets contain lactose. Therefore, they should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

The excipient E110 is known to cause allergic reactions, including asthma. Allergy is more common in persons who are allergic to aspirin. This excipient is only used in the 2mg and 4mg tablets.

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 interactions studies are not present.

Doxazosin potentiates the blood pressure lowering activity of other alpha-blockers and other antihypertensives.

In an open-label, randomised, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1mg dose of doxazosin on day 1 of a four-day regiment of oral cimetidine (400mg 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 of doxazosin with placebo.

4.6 Pregnancy and lactation

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).

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. Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (see section 5.3 Preclinical Safety Data).

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.

Undesirable effects

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 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	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, paraesthesia, somnolence
	Uncommon	Cerebrovascular accident, hypoaesthesia, syncope, tremor
Eye disorders	Very rare	Blurred vision
	Unknown	Intraoperative Floppy Iris Syndrome (see section 4.4)
Ear and labyrinth disorders	Common	Vertigo
	Uncommon	Tinnitus
Cardiac disorders	Common	Palpitations, 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, cough
	Very rare	Bronchospasm aggravated
Gastrointestinal disorders	Common	Abdominal pain, dyspepsia, dry mouth, nausea, diarrhoea
	Uncommon	Constipation, flatulence, vomiting, gastroenteritis
	Unknown	Taste disturbances

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 overdose 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, the patient should first be treated with volume expanders. If necessary, vasopressor should then be used. Renal function should be monitored and supported as needed.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The ATC code of Doxazosin is C02CA04. The ATC classification is: Cardiovascular system; antihypertensives; antiadrenergic agents, peripherally acting; alpha adrenergic blocking agents.

Doxazosin is a selective postsynaptic a1-adrenoceptor antagonist. Blockade of this receptor causes vasodilation, decrease in peripheral resistance and decrease in blood pressure. Doxazosin therapy is accompanied by little or no reflex tachycardia.

Maximal hypotensive effects occur after approximately 2 to 6 hours. With once daily dosing, clinically significant reductions in blood pressure are maintained throughout the day and at 24 hours post dose.

After initiation of therapy increase in heart rate can occur, as well as changes in vasoactive hormones. After long term treatment these effects are abolished.

Doxazosin has a favourable effect on blood lipids: it decreases the LDL cholesterol, the total cholesterol and triglyceride levels. It increases the HDL/total cholesterol ratio.

Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with obstructive airway disease, non insulin dependent diabetes mellitus and left ventricular hypertrophy.

5.2. Pharmacokinetic Properties

Following oral administration of therapeutic doses of Doxazosin, peak plasma levels are reached after 2 to 4 hours. The bioavailability is approximately 63%. Doxazosin is 98% bound to plasma protein. Plasma elimination half-life is approximately 22 hours, providing the basis for once daily dosing. Doxazosin is extensively metabolized in the liver with less than 5% of the unchanged drug excreted in the faeces. The metabolites are mainly excreted via the faeces.

5.3. Preclinical Safety Data

There are no preclinical data of relevance to the prescriber other than those mentioned in previous sections.

6.1    List of excipients

The following inactive ingredients are used in the tablets: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, magnesium stearate, sodium lauryl sulphate and colloidal silicon dioxide.

6.2.    Incompatibilities

Not applicable.

6.3. Shelf Life

The shelf life of the product is 3 years for all tablet strengths. The expiry date is printed on the package and on the blister ("EXP"). The first two digit numbers represent the month and the last four digit numbers represent the year. Do not use after this expiry date.

6.4. Special Precautions for Storage

Doxazosin tablets should be stored in the original package in a dry place. Do not store above 25°C.

Keep all medicines out of the reach of children.

6.5. Nature and Contents of Container

PVC/PVDC-Al. blisters of 28 or 56 tablets in lithographed carton boxes together with a patient information leaflet.

Glass (type III) bottles or HDPE containers, with child resistant closures (PP), with patient information leaflets attached.

6.6. Instruction for Use/Handling

Not applicable.

7.    MARKETING AUTHORISATION HOLDER

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals Linthwaite Huddersfield HD7 5QH, UK

8. MARKETING AUTHORISATION NUMBER(S)

PL 06831/0093

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/03/2009

10 DATE OF REVISION OF THE TEXT

14/07/2015