doxazosin 1,2 &4mg tablets pl 36390 0002-4par

MHRA-UKPAR –Doxazosin 1mg, 2mg & 4 mg Tablets PL 36390/0002-4 - 1 -

DOXAZOSIN 1 MG TABLETS DOXAZOSIN 2 MG TABLETS DOXAZOSIN 4 MG TABLETS

PL 36390/0002-4

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

1

Steps taken after authorisation – summary

Page 12

Summary of Product Characteristics Page 13

Patient Information Leaflet

Page 28

Labelling Page 30



PL 36390/0002-4

LAY SUMMARY The Medicines and Healthcare products Regulatory Agency granted STD Chemicals Ltd, Marketing Authorisations for the medicinal products, Doxazosin 1 mg, 2 mg and 4 mg Tablets (PL 36390/0002-4) on 10 October 2011. These are prescription-only medicines. Doxazosin is a one of a group of medicines called alpha blockers. Doxazosin Tablets are used for the treatment of a condition called benign prostatic hyperplasia (BPH) which is common in older men. BPH is caused by the prostate gland growing too big and obstructing the flow of urine from the bladder more frequently and/or a sudden need to pass water. Doxazosin can relax the muscle of the prostate gland and bladder exite to help relieve these symptoms. Doxazosin is also used to treat hypertension (high blood pressure) as it relaxes arteries so that blood passes through them more easily. This has the effect of helping to reduce the blood pressure. This application is considered to be identical to a previously granted licence for Doxazosin 1 mg, 2 mg and 4 mg Tablets (PL 08137/0078-80) on 17 June 2002 to NeoLab Ltd. Holder. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Doxazosin 1 mg, 2 mg and 4 mg Tablets (PL 36390/0002-4) outweigh the risks; hence Marketing Authorisations have been granted.



PL 36390/0002-4

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-Clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk benefit assessment Page 10


INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted STD Chemicals Ltd., Marketing Authorisations for the medicinal products, Doxazosin 1 mg, 2 mg and 4 mg Tablets (PL 36390/0002-4), on 10 October 2011. The products are POM licensed medicine. These simple, abridged, ‘informed consent’ applications submitted according to Article 10(c) of EC Directive 2001/83 (as amended), cross-referencing the Marketing Authorisaion for Doxazosin 1 mg, 2mg and 4 mg Tablets (PL 08137/0078-80), licensed to Neolab Ltd on 17 June 2002. The reference products have been authorised in the EEA for over 10 years. Doxazosin is an antihypertensive; adrenoceptor blocking agent, that is peripherally acting. Doxazosin is a potent, competitive and selective antagonist of postjunctional alpha-1-adrenoceptors. It causes a decrease in systemic blood pressure and is suitable for oral administration in a once daily dosage regimen for patients with essential hypertension. Doxazosin is indicated for the treatment of hypertension. It is also indicated for the treatment of urinary outflow obstruction and the symptoms associated with benign prostatic hyperplasia (BPH). No new data were submitted nor were they necessary for these simple applications, as the data is identical to that of the previously granted cross-reference product. As the cross-reference product was granted prior to the introduction of current legislation, no Public Assessment Report (PAR) has been generated for it.


PHARMACEUTICAL ASSESSMENT LICENCE NO: PL 36390/0002-4 PROPRIETARY NAME: Doxazosin 1 mg, 2 mg and 4 mg Tablets ACTIVE: Doxazosin mesilate COMPANY NAME: STD Chemicals Ltd E.C. ARTICLE: Article 10c of Directive 2001/83/EC LEGAL STATUS: POM 1. INTRODUCTION These are simple, informed consent applications for Doxazosin 1 mg, 2 mg and 4 mg Tablets submitted under Article 10c of Directive 2001/83/EC. The proposed Marketing Authorisation Holder is STD Chemicals Ltd, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW, UK. The application cross-refers to Doxazosin 1 m g, 2 mg and 4 mg Tablets (PL 08137/0078-80) authorised to Neolab Ltd since 17 June 2002. The current applications are considered valid. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name The proposed name of the product is for Doxazosin 1 mg, 2 mg and 4 mg tablets. The products have been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes Each tablet contains 1 mg, 2 mg or 4 mg of the active ingredient doxazosin, equivalent to 1.21 mg, 2.42 mg and 4.85 mg of doxazosin mesilate respectively.. The tablets are licensed for marketing in polyethylenevinylcholride (PVC)/aluminium blister strips, which are packed with the Patient Information Leaflet (PIL) into cardboard outer cartons, in pack sizes of 28 or 30 tablets. The Marketing Authorisation Holder (MAH) has stated that not all pack sizes may be marketed. The container closure systems and pack sizes are identical to those for the reference products.

The approved shelf-life (24 months) and with no special storage requirements for these products are identical to the details registered fot he reference products.

2.3 Legal status POM- The products are available subject to a medical prescription. 2.4 Marketing authorisation holder/Contact Persons/Company The proposed Marketing Authorisation Holder is STD Chemicals Ltd, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW, UK The Quality Person (QP) responsible for pharmacovigilance is stated and their curriculum vita has been included. 2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference product and evidence of GMP compliance has been provided.


2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the cross-reference product. 2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference product and the maximum batch size is stated. 2.8 Finished product/shelf-life specification The proposed finished product specification is in-line with the details registered for the cross-reference product. 2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross-reference product. 2.10 TSE Compliance With the exception of lactose monohydrate none of the other excipients used contain material derived from animal or human origin. The applicant has provided a declaration that milk used in the production of lactose is sourced from healthy animals under the same conditions as that for human consumption. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients. This is consistent with the cross-reference products. 3. EXPERT REPORT A satisfactory quality overall summary has been prepared by an appropriately qualified expert. The CV of the expert was provided. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The 1 mg tablets are white, round, biconvex tablets; the 2 mg tablets are white, capsule-shaped tablets with a break-line on one side and 4 mg tablets are white, capsule-shaped, bioconvex tablets plain on both sides.The appearance of the products is identical to that of the cross-reference product. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The approved SmPCs are consistent with the details registered for the cross-reference products. 6. PATIENT INFORMATION LEAFLET (PIL)/CARTON PIL The approved PIL is satisfactory and in line with the approved SmPCs. It ahs been prepared according to the Quality Review of Documents (QRD) template and is consistent with the details registered for the cross-reference products. PIL user testing has been accepted based on bridging to the successful user-testing of the PIL for the reference products, Doxazosin 1mg, 2 mg and 4 mg Tablets (PL 08137/0078-80). The text, content and layout of the proposed PIL are essentially identical to the approved PIL for the reference products. The bridging report is accepted.


Carton and label Mock-ups of the labelling have been provided and are satisfactory. The approved artwork is comparable to the artwork registered for the cross-reference product and complies with statutory requirements. In line with current legislation the applicant has included the name of the product in Braille on the outer packaging. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for currently unmarketed pack sizes to the MHRA for approval before those packs are commercially marketed. 7. CONCLUSIONS The data submitted with these applications is acceptable. Marketing Authorisations were, therefore, granted.


NON-CLINICAL ASSESSMENT These are simple, abridged, ‘informed consent’ applications made under Article 10c of EC Directive 2001/83 (as amended). These applications are identical to the reference products Doxazosin 1 m g, 2 mg and 4 mg Tablets (PL 08137/0078-80) authorised to Neolab Ltd since 17 June 2002 in the UK, therefore, no new non-clinical data has been supplied with these applications and none are required. A non-clinical overview report has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied. The marketing authorisation holder has provided adequate justification for not submitting an Environment Risk Assessment (ERA). As this application is identical to an already authorised reference product, it is not expected that the environmental exposure to doxazosin mesilate will increase following the marketing approval of the proposed product.


CLINICAL ASSESSMENT

These are simple, abridged, ‘informed consent’ applications made under Article 10(c) of EC Directive 2001/83 (as amended), cross-referring to Doxazosin 1 m g, 2 mg and 4 mg Tablets (PL 08137/0078-80) authorised to Neolab Ltd since 17 June 2002 in the UK. No new clinical data has been supplied with this application and none are required. A clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the clinical expert has been supplied. The marketing authorisation holder (MAH) has provided adequate justification for not submitting a Risk Management Plan (RMP). As this application is identical to an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profile of the active is well-established. The MAH has provided a suitable pharmacovigilance system that fulfils the requirements and provides adequate evidence that the MAH has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The data for these applications are consistent with those previously assessed for the cross-reference products and as such has been judged to be satisfactory. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY These applications are considered identical to the previously granted licence for Doxazosin 1 m g, 2 mg and 4 mg Tablets (PL 08137/0078-80) authorised to Neolab Ltd since 17 June 2002 in the UK. No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The approved SmPCs, PIL and labelling are satisfactory, and consistent with those for the cross-reference products. PIL user-testing has been accepted based on bridging to the successful user-testing of the PIL for the reference products, Doxazosin 1 m g, 2 mg and 4 mg Tablets (PL 08137/0078-80). The approved labeling artwork complies with statutory requirements. In-line with current legislation, the name of the product in Braille appears on the outer packaging and sufficient space has been included for a standard UK pharmacy dispensing label. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for unmarketed pack sizes to the MHRA for approval before those packs ar marketed. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s product is identical to the cross-reference product. The risk benefit is, therefore, considered to be positive.



PL 36390/0002-4

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 25 May 2011.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 15 June 2011

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 14 July 2011 and 16 September 2011.

4 The applicant responded to the MHRA’s requests, providing further information on 15 August 2011 and 4 October 2011.

5 The application was determined on 10 Ocotber 2011.



PL 36390/0002-4

STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome



PL 36390/0002-4

SUMMARY OF PRODUCT CHARACTERISTICS

The UK Summary of Product Characteristics (SmPC) for Doxazosin 1 mg Tablets (PL 36390/0002) is as follows: 1 NAME OF THE MEDICINAL PRODUCT

Doxazosin 1mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Doxazosin mesilate 1.21 mg equivalent to 1 mg doxazosin.

For a full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White, round, biconvex tablets. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Treatment of hypertension. As a mono-agent Doxazosin Tablets can control blood pressure in most hypertensive patients. In patients inadequately controlled on single antihypertensive therapy, doxazosin can be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist, or an angiotensin- converting enzyme inhibitor. Doxazosin Tablets are also indicated for the treatment of urinary outflow obstruction and the symptoms associated with benign prostatic hyperplasia (BPH).

4.2 Posology and method of administration

Adults: Hypertension: Doxazosin is taken in a once daily regimen. The initial dose is 1 mg. After one to two weeks of therapy, the dose may be increased to 2 mg and thereafter to 4mg. Most patients who will respond to doxazosin will do so at a dose of 4 mg daily or less. If necessary, the daily dosage can be further increased to 8 mg or to the maximum daily dose of 16 mg. Benign prostatic hyperplasia: Initial dose is 1mg once daily. The dosage may then be increased, according to the individual patient’s response, to 2 mg and thereafter to 4mg and up to the maximum daily dose of 8mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4 mg daily.

Elderly : Normal adult dosage Children: There is not enough experience to recommend the use of Doxazosin Tablets in children. Patients with renal impairment: There is no change in pharmacokinetics of doxazosin in patients with impaired renal function. Normal adult dosage is therefore recommended. Doxazosin is not dialysable. Patients with hepatic impairment: Since doxazosin is wholly metabolised by the liver, it should be used with caution in such patients. Method of administration: For oral administration.


4.3 Contraindications

Doxazosin is contra-indicated in 1) Patients with a known hypersensitivity to quinazolines (e.g. praxosin, 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 overflow bladder, anuria or progressive renal insufficiency. 1 For the hypertension indication only 2 For 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 use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk of developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors. 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 1mg Tablets contains 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 indicates that doxazosin has no effect on protein binding of warfarin, digoxin, 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. 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

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). 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. (Please see section 5.3)

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 and < 1/10, Uncommon > 1/1000 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 Leucopenia, thrombocytopenia

Immune System Disorders Uncommon Allergic drug reaction Metabolism and Nutrition Disorders Common

Uncommon Anorexia 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, hypoesthesia,

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 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, dyspnea, 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 Hepatobiliary Disorders Uncommon Abnormal liver function tests Very Rare Cholestasis, hepatitis, jaundice, abnormal

liver function tests Skin and Subcutaneous Tissue Disorders

Common Pruritus

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 Dysruria, 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

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

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

The ATC code of doxazosin is C02CA04. The ATC-classification is: Cardiovascular system; antihypertensives; adrenergic agents, peripherally acting; alpha-adrenoceptor blocking agents. Doxazosin is a potent, competitive and selective antagonist of postjunctional alpha-1-adrenoceptors. It causes a decrease in systemic blood pressure and is suitable for oral administration in a once daily dosage regimen for patients with essential hypertension. Doxazosin does not cause adverse metabolic side effects and it is therefore suitable for patients with coexistent insulin resistance, gout and coexistent diabetes mellitus. Doxazosin is also suitable for patients with coexistent left ventricular hypertrophy, asthma and in elderly patients. Doxazosin treatment has been demonstrated to reduce left ventricular hypertrophy, inhibit platelet aggregation and enhances activity of tissue plasminogen activator. Doxazosin also improves insulin sensitivity in patients with insulin resistance. Long term studies have shown that doxazosin also produces a modest reduction in total plasma cholesterol, LDL cholesterol and triglyceride concentrations. It may therefore be of benefit for hypertensive patients with concomitant hyperlipidaemia.


Doxazosin significantly improves symptoms such as hesitancy, impaired urinary stream, nocturia and urgency in patients with symptomatic BPH. Its action in BPH is thought to be due to the selective blockade of the alpha adrenoceptors in the prostatic muscular stroma, capsule and bladder neck.

5.2 Pharmacokinetic properties

Doxazosin is well absorbed after oral administration with peak blood levels reached between 2 and 4 hours and with a bioavailability of about 65%. The average plasma elimination half-life is 22 hours, thus making the drug suitable to be taken as a once daily regimen. Doxazosin is highly metabolised in both humans and in animal species tested. It is mainly excreted in the faeces. Following oral administration of doxazosin, the plasma concentrations of metabolites are low. The 6’ hydroxy metabolite is the most active metabolite and is present in humans at one fortieth of the plasma concentration of the parent compound. Hence doxazosin is the main antihypertensive component.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Lactose monohydrate; magnesium stearate; microcrystalline cellulose; sodium lauryl sulphate; sodium starch glycolate (Type A).

6.2 Incompatibilities

Not applicable

6.3 Shelf life 24 Months.

6.4 Special precautions for storage

No special requirements.

6.5 Nature and contents of container PVC/aluminium blister packs containing 28 or 30 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements

7 MARKETING AUTHORISATION HOLDER

STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10/10/2011 10 DATE OF REVISION OF THE TEXT

10/10/2011


The UK Summary of Product Characteristics (SmPC) for Doxazosin 2 mg Tablets (PL 36390/0003) is as follows: SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Doxazosin 2mg Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin mesilate 2.42 mg equivalent to 2 mg doxazosin.

For a full list of excipients, see 6.1. 3 PHARMACEUTICAL FORM

Tablet. White, capsule shaped tablets with a break line on one side.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications


4.2 Posology and method of administration Adults: Hypertension: Doxazosin is taken in a once daily regimen. The initial dose is 1 mg. After one to two weeks of therapy, the dose may be increased to 2 mg and thereafter to 4mg. Most patients who will respond to doxazosin will do so at a dose of 4 mg daily or less. If necessary, the daily dosage can be further increased to 8 mg or to the maximum daily dose of 16 mg. Benign prostatic hyperplasia: Initial dose is 1mg once daily. The dosage may then be increased, according to the individual patient’s response, to 2 mg and thereafter to 4mg and up to the maximum daily dose of 8mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4 mg daily.




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 overflow bladder, anuria or progressive renal insufficiency. 1 For the hypertension indication only 2 For 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 initiation of 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 use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk of developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors. 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 2 mg 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 is protein bound. In vitro data in human plasma indicates that doxazosin has no effect on protein binding of warfarin, digoxin, 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. The 10% increase in the


mean AUC for doxazosin with cimetidine is within intersubject variation (27%) of the mean AUC for doxazosin with placebo.


Animal studies have shown no evidence of teratogenicity after doxazosin treatment. Foetal survival rates however, were reduced in animals at extremely high doses. There is only limited experience with the use of doxazosin during pregnancy in humans. Doxazosin is not therefore recommended for use during pregnancy unless the physician considers that the potential benefit to the mother outweighs potential risk to the foetus. In animal studies doxazosin accumulated in breast milk. Since the clinical safety of doxazosin during lactation has not been established, the drug is contra-indicated in breast-feeding women.

4.7 Effects on ability to drive and use machines

The ability to drive or operate machinery may be reduced, particularly at the start of the therapy (See 4.8).




















Common Pruritus

Uncommon Skin rash, alopecia, purpura


Very Rare Urticaria Musculoskeletal and Connective Tissue Disorders






Uncommon Impotence




4.9 Overdose



The ATC-code of doxazosin is C02CA04. The ATC-classification is: Cardiovascular system; antihypertensives; antiadrenergic agents, peripherally acting; alpha-adrenoceptor blocking agents. Doxazosin is a potent, competitive and selective antagonist of postjunctional alpha-1-adrenoceptors. It causes a decrease in systemic blood pressure and is suitable for oral administration in a once daily dosage regimen for patients with essential hypertension. Doxazosin does not cause adverse metabolic side effects and it is therefore suitable for patients with coexistent insulin resistance, gout and coexistent diabetes mellitus. Doxazosin is also suitable for patients with coexistent left ventricular hypertrophy, asthma and in elderly patients. Doxazosin treatment has been demonstrated to reduce left ventricular hypertrophy, inhibit platelet aggregation and enhances activity of tissue plasminogen activator. Doxazosin also improves insulin sensitivity in patients with insulin resistance. Long term studies have shown that doxazosin also produces a modest reduction in total plasma cholesterol, LDL cholesterol and triglyceride concentrations. It may therefore be of benefit for hypertensive patients with concomitant hyperlipidaemia. Doxazosin significantly improves symptoms such as hesitancy, impaired urinary stream, nocturia and urgency in patients with symptomatic BPH. Its action in BPH is thought to be due to the selective blockade of the alpha adrenoceptors in the prostatic muscular stroma, capsule and bladder neck.

5.2 Pharmacokinetic properties

Doxazosin is well absorbed after oral administration with peak blood levels reached between 2 and 4 hours and with a bioavailability of about 65%. The average plasma elimination half-life is 22 hours, thus making the drug suitable to be taken as a once daily regimen. Doxazosin is highly metabolised in both humans and in animal species tested. It is mainly excreted in the faeces.


Following oral administration of doxazosin, the plasma concentrations of metabolites are low. The 6’ hydroxy metabolite is the most active metabolite and is present in humans at one fortieth of the plasma concentration of the parent compound. Hence doxazosin is the main antihypertensive ingredient.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.



6.2 Incompatibilities Not applicable

6.3 Shelf life

24 Months. 6.4 Special precautions for storage


6.5 Nature and contents of container PVC/aluminium blister packs containing 28 or 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements 7 MARKETING AUTHORISATION HOLDER

STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW


PL 36390/0003 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10/10/2011 10 DATE OF REVISION OF THE TEXT

10/10/2011


The UK Summary of Product Characteristics (SmPC) for Doxazosin 4 mg Tablets (PL 36390/0004) is as follows: SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Doxazosin 4mg Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Doxazosin mesilate 4.85 mg equivalent to 4 mg doxazosin.

For a full list of excipients, see 6.1. 3 PHARMACEUTICAL FORM

Tablet. White, capsule shaped, biconvex tablets plain on both sides.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications


4.2 Posology and method of administration

Adults: Hypertension: Doxazosin is taken in a once daily regimen. The initial dose is 1 mg. After one to two weeks of therapy, the dose may be increased to 2 mg and thereafter to 4mg. Most patients who will respond to doxazosin will do so at a dose of 4 mg daily or less. If necessary, the daily dosage can be further increased to 8 mg or to the maximum daily dose of 16 mg. Benign prostatic hyperplasia: Initial dose is 1mg once daily. The dosage may then be increased, according to the individual patient’s response, to 2 mg and thereafter to 4mg and up to the maximum daily dose of 8mg. The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4 mg daily.




or any of the excipients 2) Patients with a history of orthostatic hypotension 3) Patients with a 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 contra-indicated as monotherapy in patients with overflow bladder anuria or progressive renal insufficiency.

1 For the hypertension indication only 2 For 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 initiation of 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 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 use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and doxazosin may lead to symptomatic hypotension in some patients. In order to minimise the risk of developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phosphodiesterase-5-inhibitors. 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 4mg 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 indicates that doxazosin has no effect on protein binding of warfarin, digoxin, phenytoin and indometacin. Conventional doxazosin has bee 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 signigicant 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.


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). 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. (Please see section 5.3)

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.





















Common Pruritus

Uncommon Skin rash, alopecia, purpura Very Rare Urticaria Musculoskeletal and Connective Tissue Disorders






Uncommon Impotence




4.9 Overdose



The ATC-code of doxazosin is C02CA04. The ATC-classification is: Cardiovascular system; antihypertensives; antiadrenergic agents, peripherally acting; alpha-adrenoceptor blocking agents. Doxazosin is a potent, competitive and selective antagonist of postjunctional alpha-1-adrenoceptors. It causes a decrease in systemic blood pressure and is suitable for oral administration in a once daily dosage regimen for patients with essential hypertension. Doxazosin does not cause adverse metabolic side effects and it is therefore suitable for patients with coexistent insulin resistance, gout and coexistent diabetes mellitus. Doxazosin is also suitable for patients with coexistent left ventricular hypertrophy, asthma and in elderly patients. Doxazosin treatment has been demonstrated to reduce left ventricular hypertrophy, inhibit platelet aggregation and enhances activity of tissue plasminogen activator. Doxazosin also improves insulin sensitivity in patients with insulin resistance. Long term studies have shown that doxazosin also produces a modest reduction in total plasma cholesterol, LDL cholesterol and triglyceride concentrations. It may therefore be of benefit for hypertensive patients with concomitant hyperlipidaemia Doxazosin significantly improves symptoms such as hesitancy, impaired urinary stream, nocturia and urgency in patients with symptomatic BPH. Its action in BPH is thought to be due to the selective blockade of the alpha adrenoceptors in the prostatic muscular stroma, capsule and bladder neck.

5.2 Pharmacokinetic properties Doxazosin is well absorbed after oral administration with peak blood levels reached between 2 and 4 hours and with a bioavailability of about 65%. The average plasma elimination half-life is 22 hours, thus making the drug suitable to be taken as a once daily regimen.


Doxazosin is highly metabolised in both humans and in animal species tested. It is mainly excreted in the faeces. Following oral administration of doxazosin, the plasma concentrations of metabolites are low. The 6’ hydroxy metabolite is the most active metabolite and is present in humans at one fortieth of the plasma concentration of the parent compound. Hence doxazosin is the main antihypertensive component.

5.3 Preclinical safety data There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.



6.2 Incompatibilities Not applicable

6.3 Shelf life 24 Months.

6.4 Special precautions for storage


6.5 Nature and contents of container PVC/aluminium blister packs containing 28 or 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW


PL 36390/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10/10/2011 10 DATE OF REVISION OF THE TEXT

10/10/2011


DOXAZOSIN 1 MG, 2 MG & 4MG TABLETS

PL 36390/0002-4 PATIENT INFORMATION LEAFLET


DOXAZOSIN 1 MG, 2 MG & 4MG TABLETS PL 36390/0002-4

LABELLING CARTON

BLISTER FOIL


CARTON

BLISTER FOIL