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Benph 5mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Benph 5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

5mg:

Each tablet contains 5mg of terazosin (in the form of terazosin hydrochloride dihydrate).

Excipients with known effect:

110mg lactose monohydrate 0.01mg Sunset Yellow (E110)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM 5mg:

Tablet

Light orange, round, flat, bevel edged, tablet imprinted “E” and “453” on one side.

4.1 Therapeutic indications

Benph tablets are indicated for:

- symptomatic treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).

4.2 Posology and method of administration

Posology

Adults only:

The dose of terazosin should be managed according to each patient’s response.

Initial dose

An initial dose of 1.0mg daily should be given before bedtime. Strict compliance with this recommendation should be observed to minimise acute first-dose hypotensive episodes.

Subsequent dose

The dose may be increased by approximately doubling the dose at weekly or bi-weekly intervals to achieve the desired reduction in symptoms. The maintenance dose is usually 5 to 10mg once daily. Improvements in symptoms have been detected as early as two weeks after starting treatment with terazosin.

At present there are insufficient data to suggest symptomatic relief with doses above 10mg once daily

Transient side effects may occur at each titration step. If any side effects persist, consideration should be given to reducing the dose.

Use with thiazide diuretics and other antihypertensive agents

The dose of terazosin should be re-titrated if a thiazide diuretic or antihypertensive agent is added to a patients medication. On initiation of the new medication hypotension may be observed.

Elderly

Pharmacokinetic studies in the elderly indicate that no alteration in dosage recommendation is required.

Postural hypotension

Postural hypotension has been reported to occur in patients receiving terazosin for the symptomatic treatment of urinary obstruction caused by BPH. In these cases, the incidence of postural hypotensive agents was greater in patients aged 65 years and over (5.6%) than those aged less than 65 years (2.6%)

Patients with renal impairment

Pharmacokinetic studies indicate that patients with impaired renal function need no alteration in the recommended dosage. There is no evidence that terazosin aggravates renal dysfunction.

Paediatric population

There is no relevant use of Benph in the paediatric population.

Method of administration For oral use.

Benph tablets should be swallowed whole and not chewed and can be taken with or without food.

4.3 Contraindications

-    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to a structurally similar alpha-i-adrenergic antagonist.

-    Patients that are hypersensitive to quinazolines.

-    Congestive heart failure due to mechanical obstruction (e.g. aortic valve or mitral valve stenosis, pulmonary embolism, restrictive pericarditis).

4.4 Special warnings and precautions for use

As with other alpha adrenoceptor blocking agents, terazosin should not be administered to patients suffering from (or with a history of) micturition syncope.

In clinical trials, the incidence of postural hypotension was greater in BPH patients than those with hypertension. In these cases, the incidence of postural hypotension events was greater in patients aged 65 years and over (5.6%) than those aged less than 65 years (2.6%). ‘First dose’ effect might occur after the first terazosin dose or during the initial period of treatment. This consists of: marked reduction of blood pressure mainly as orthostatic hypotension (vertigo, unsteadiness, syncope). Volume depletion, restricted salt-intake and advanced age (i.e. 65 years or over) increase the risk of postural hypotension. It should be born in mind that this is also likely to happen when terazosin treatment is re-started after a few days break. In such case, the 1mg initial dose should be prescribed.

Syncope has been seen in one percent of patients in hypertension trials. Rapid dose increase as well as combining terazosin with a diuretic and/or another antihypertensive might result in syncope. Syncope is related to marked postural hypotension, and in some cases it is preceded by tachycardia (120-160/min). Postural hypotension is most pronounced within a short time of drug intake, while the risk of syncope is the greatest 30-90 minutes following drug administration. Dizziness, unsteadiness and syncope are most likely to be provoked by any of the following: standing up from a sitting or a supine position, long periods of standing, increased physical load, warm weather and concomitant drinking of alcoholic beverages (please also see section 4.7).

Management of syncope: the patient should be kept in a supine position with elevated lower extremities. Supportive and/or symptomatic treatment might be necessary.

Special care should be taken when giving terazosin to individuals with known susceptibility to developing orthostatic hypotension or to those suffering from: ischaemic or any other heart diseases, cerebrovascular disorders, III and/or IV degree hypertensive retinopathy, insulin dependent diabetes, hepatic and/or renal failure.

In certain patients with left ventricular failure, the decrease in left ventricular filling consequent to vigorous therapy may result in a significant fall in cardiac output and systemic blood pressure after administration of terazosin. These effects should be kept in mind when introducing therapy and continuous titration of dose used.

The usual half-life of terazosin is approximately12 hours. This may be significantly prolonged in patients with congestive cardiac failure (by up to 7-8 hours), usually with reduction on clinical improvement.

Before starting terazosin therapy for BPH, carcinoma of the prostate should be excluded. The blood pressure of patients with BPH should be measured at baseline and monitored thereafter particularly at times of dose adjustment. Possible antihypertensive treatment should also be taken into consideration. Effectiveness of Terazosin in the management of BPH should be evaluated after allowing a period of 4-6 weeks of treatment with the maintenance dose.

Since the drug is metabolised in the liver it should only be used with care in patients with existing hepatic dysfunction.

Priapism: rarely, terazosin has been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of that condition.

Concomitant use of phosphodiesterase-5-inhibitors (sildenafil, tadalafil, vardenafil) and terazosin, may lead to symptomatic hypotension in some patients. In order to minimise the risk for developing postural hypotension the patient should be stable on the alpha-blocker therapy before initiating use of phospodiesterase-5-inhibitors. In addition, phosphodiesterase-5-inhibitors should be started on the lowest dose and with a time interval (e.g. 6 hours) following terazosin administration.

‘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 adrenergic 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 and the ophthalmologist in advance of surgery.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

For 5mg & 10mg SmPCs only:

Sunset Yellow (E110) maycause allergic-type reactions including asthma. Allergy is more common

to those people who are allergic to aspirin.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and terazosin may lead to symptomatic hypotension in some patients (see section 4.4).

The drug is highly protein bound. There is a theoretical potential for interaction with such drugs as anticoagulants and nonsteroidal anti-inflammatory drugs leading to higher plasma levels of drug.

Except for angiotensin converting enzyme (ACE) inhibitors and diuretics, no clinically significant interactions have been observed with terazosin in BPH. In BPH patients the adverse events profile of patients treated concurrently with non-steroidal anti-inflammatory drugs (NSAIDs), theophylline, antianginal agents, oral hypoglycaemia agents, ACE inhibitors or diuretics was comparative to the profile in the general treated population.

In the small subset patients who were treated with terazosin and ACE inhibitors or diuretics, the percent reporting dizziness or other dizziness-related adverse events appears to be greater than in the total population of terazosin patients from doubleblind placebo-controlled studies.

Caution should be observed when terazosin is administered concomitantly with other antihypertensive agents (e.g. calcium antagonists) to avoid the possibility of significant hypotension. When adding terazosin to a diuretic or other antihypertensive agent, dosing reduction and retitration of these agents may be necessary.

Laboratory tests: Laboratory findings suggestive of haemodilution (e.g. decrease in haematocrit, haemoglobin, white blood cells, total protein and albumin) have been observed in controlled clinical trials. No significant effect on prostate specific antigen (PSA) levels was reported after terazosin treatment for up to 24 months.

4.6 Fertility, pregnancy and lactation

Although no teratogenic effects were seen in animal testing, the safety of terazosin use during pregnancy or during breast-feeding has not yet been established. Terazosin should not be used in pregnancy unless the potential benefit is considered to outweigh the risk.

4.7 Effects on ability to drive and use machines

Drowsiness, dizziness or light-headedness may occur with the initial dose or in association with missed doses and subsequent re-initiation of Benph therapy. Patients should be cautioned about these possible adverse effects and the circumstances in which they occur and advised not drive a vehicle, operate machinery or perform activities with increased risk of accidents for 12 hours after starting terazosin and 12 hours after any increase in dose. Thereafter, patients should not drive, operate machinery or perform activities with increased risk of accidents unless terazosin has been shown not to affect their physical or mental capacity.

4.8 Undesirable effects

As with other alpha adrenoceptor blocking antagonists, terazosin may cause syncope. Syncopal episodes may occur within 30-90 minutes of the initial dose of the medicinal product. Occasionally the syncopal episode may be preceded by tachycardia with heart rates of 120 to 160 beats per minute. First-dose hypotension might occur which could lead to vertigo and in severe cases syncope. To avoid hypotension, terazosin treatment should be started with a 1mg dose at bed-time (see section 4.4).

The following adverse events have been reported:

Additional adverse reactions reported in clinical trials or reported during marketing experience but not clearly associated with the use of terazosin have been listed under the frequency heading ‘Not Known’.

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 available data)

Infections and infestations

Bronchitis, flu symptoms, pharyngitis, rhinitis, cold symptoms,

Blood and lymphatic system disorders

Thrombocytopenia

Immune

system

disorders

Anaphylactic

reactions

Metabolism and nutrition disorders

gout

Psychiatric

disorders

Depression

Anxiety, insomnia

Nervous

system

disorders

Nervousness, somnolence, paraesthesia, dizziness, light-headedness headache

syncope

Eye disorders

Blurred

vision/amblyopia

Abnormal vision,

Conjunctivitis,

IFIS

(intraoperative floppy iris syndrome) see section 4.4.

Ear and

labyrinth

disorders

Tinnitus vertigo

Cardiac

disorders

Palpitations,

tachycardia,

Atrial fibrillation

Arrhythmia

Vascular

disorders

fainting

vasodilation

Respiratory, thoracic and mediastinal disorders

Dyspnoea, nasal congestion, sinusitis, epistaxis

increased cough

Gastrointestinal

disorders

Nausea, constipation, diarrhoea, vomiting

Dry mouth, dyspepsia, flatulence, abdominal pain

Skin and subcutaneous tissue disorders

Pruritus, rash

Facial oedema, sweating

Musculoskeletal and connective tissue disorders

Back pain

Neck and shoulder pain, arthralgia, arthritis, joint disorders, myalgia

Renal and urinary disorders

Urinary tract infection and urinary incontinence, (primarily reported in postmenopausal women)

Urinary frequency

Reproductive system and breast disorders

Impotence

Decreased

libido

Priapism

General disorders and administration site conditions

postural hypotension, asthenia, oedema, , pain in the

extremities chest pain, peripheral oedema

Fever

Investigations

Weight

gain

Decreases in haematocrit haemoglobin, white blood cells, total protein and albumin

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

If acute hypotension occurs as a result of terazosin treatment, cardiovascular support should be of primary importance. The patient should be kept in a supine position in order to restore blood pressure and heart rate to normal. If this measure is unsuccessful then shock should be treated with volume expansion followed by administration of vasopressors. Plasma and electrolyte balance should be restored. Renal function should be monitored and general supportive measures applied as required. Terazosin is highly protein bound, therefore, dialysis may not be of benefit.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in benign prostatic hypertrophy, ATC code: G04CA03

Studies suggest that alpha-1-adrenoreceptor antagonism is useful in improving the urodynamics in patients with chronic bladder obstruction such as in benign prostatic hyperplasia (BPH).

The symptoms of BPH are caused mainly by the presence of an enlarged prostate and by the increased smooth muscle tone of the bladder outlet and prostate, which is regulated by alpha-1-adrenergic receptors.

In in-vitro experiments, terazosin has been shown to antagonise phenylephrine-induced contractions of human prostatic tissue. In clinical trials terazosin has been shown to improve the urodynamics and symptomatology in patients with BPH.

A significant antihypertensive effect has been observed 3 hours following oral administration of terazosin. The drug’s antihypertensive effect has been reported to persist for 24 hours after oral administration.

5.2 Pharmacokinetic properties

Absorption

Terazosin is rapidly and almost completely absorbed from the gastrointestinal tract, without being affected by food intake. It has a 90% bioavailability.

Following administration of the smallest dose, mean peak serum levels were achieved within one hour. Terazosin has a half-life of approximately 12 hours. 36 hours following drug intake, terazosin could still be traced in plasma.

Distribution

Terazosin is 90-94% plasma protein-bound.

Biotransformation

It is extensively metabolised in the liver via hydrolysis, demethylation and dealkylation with five different metabolites identified.

Elimination

Mean elimination half-life of parent compound is 12 hours. 10% of the orally administered drug is excreted in the form of unchanged drug in the urine and 30% as inactive metabolites. Faecal elimination accounts for 55-60% of the oral dose. There are no reports on possible drug excretion in breast milk.

5.3 Preclinical safety data

Terazosin has been shown to produce benign adrenal medullary tumours in male rats when administered in high doses over a long period. No such occurances were observed in female rats or in

a similar study with mice. The relevance of these findings with respect to the clinical use of the drug in man is unknown.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

1mg:

Magnesium stearate Talc

Povidone

Starch, pregelatinised Lactose monohydrate

2mg:

Magnesium stearate Talc

Povidone

Starch, pregelatinised Lactose monohydrate Quinoline Yellow (E104)

5mg:

Magnesium stearate Talc

Povidone

Starch, pregelatinised Lactose monohydrate Sunset Yellow (E110)


10mg:

Magnesium stearate Talc

Povidone

Starch, pregelatinised Lactose monohydrate Sunset Yellow (E110)


6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container 1mg:

Benph 1mg tablets are provided in Aluminium foil/PVC/PVDC blister strip packs. Pack size:

Benph 1mg tablets are presented in cartons of 7, 10, 14, 20, 28, 50 and 100.

Not all pack sizes may be marketed.

2mg:

Benph 2mg tablets are provided in Aluminium foil/PVC/PVDC blister strip packs. Pack size:

Benph 2mg tablets are presented in cartons of 7, 10, 14, 20, 28, 50, 84, 98 and 100. Not all pack sizes may be marketed.

5mg:

Benph 5mg tablets are provided in Aluminium foil/PVC/PVDC blister strip packs. Pack size:

Benph 5mg tablets are presented in cartons of 14, 20, 28, 30, 50, 84, 98 and 100. Not all pack sizes may be marketed.


10mg:

Benph 10mg tablets are provided in Aluminium foil/PVC/PVDC blister strip packs. Pack size:

Benph 10mg tablets are presented in cartons of 28, 50, 84, 98 and 100.

Not all pack sizes may be marketed.


6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close Potters Bar Hertfordshire EN6 1TL United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 04569/0531

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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/10/2006

DATE OF REVISION OF THE TEXT

26/08/2015