This information is intended for use by health professionals

1. Name of the medicinal product

Benph 1mg Tablets

Benph 2mg Tablets

Benph 5mg Tablets

Benph 10mg Tablets

2. Qualitative and quantitative composition

1mg:

Each tablet contains 1mg of terazosin (in the form of terazosin hydrochloride dihydrate).

Excipient with known effect:

55mg lactose monohydrate

For the full list of excipients, see section 6.1.

2mg:

Each tablet contains 2mg of terazosin (in the form of terazosin hydrochloride dihydrate).

Excipient with known effect:

110mg lactose monohydrate

For the full list of excipients, see section 6.1.

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.

10mg:

Each tablet contains 10mg of terazosin (in the form of terazosin hydrochloride dihydrate).

Excipients with known effect:

110mg lactose monohydrate

0.1mg Sunset Yellow (E110)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

1mg:

Tablet

White, round, flat, bevel edged, tablet imprinted “E” and “451” on one side.

2mg:

Tablet

Yellow, round, flat, bevel edged, tablet imprinted “E” and “452” on one side.

5mg:

Tablet

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

10mg:

Tablet

Orange, round, flat, bevel edged, tablet imprinted “E” and “454” on one side.

4. Clinical particulars
4.1 Therapeutic indications

Benph tablets are indicated in adults 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. The following is a guide to administration.

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%)

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.

Hepatic impairment

The terazosin dose should be titrated with particular caution in patients with impaired liver function since terazosin undergoes extensive hepatic metabolism and is mainly excreted by the biliary tract. As no clinical experience is available in patients with severe hepatic impairment, the use of terazosin is not recommended in these patients.

Paediatric population

Benph is not recommended for use in children. Safety and efficacy in children has not been established.

Method of administration

For oral use. Response to treatment should be reviewed at four weeks of the treatment.

If administration is discontinued for more than several days, therapy should be re-instituted using the initial titration regimen.

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 other alpha-adrenoceptor blockers.

- Patients that are hypersensitive to quinazolines.

- Patients with a history of micturition syncope.

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

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%).

Terazosin hydrochloride, like other alpha-adrenoceptor blockers, can cause marked lowering of blood pressure, especially postural hypotension and syncope in association with the first dose or first few doses of therapy. '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. A similar effect can be anticipated if therapy is interrupted for more than a few doses and then re-started. If administration is discontinued for more than several days, therapy should be re-instituted using the initial dosing regimen.

Syncope has also been reported with other alpha-adrenoceptor blockers in association with rapid dosage increases or the introduction of another antihypertensive drug. Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120 to 160 beats per minute.

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.

Due to the vasodilatory effect of terazosin, it should be administered with caution if the following cardiac conditions are present:

• Pulmonary oedema due to aortic or mitral valve stenosis

• High output cardiac insufficiency

• Right-sided cardiac insufficiency due to pulmonary embolism or pericardial effusion

• Left-sided cardiac insufficiency with low filling pressure

In patients with severe coronary heart disease, a very rapid or excessive decrease in blood pressure can lead to an exacerbation of angina pectoris.

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 treating the symptoms of benign prostatic hyperplasia (BPH) with alpha-blockers, other causes of impaired urinary flow or urinary symptoms should be excluded. Also where the diagnosis of BPH has been established, it should be confirmed that there is no concomitant obstruction of the upper urinary tract or any signs of infection before treating with terazosin. Patients with benign prostatic hyperplasia, who simultaneously suffer from congestion of the upper urinary tract, chronic urinary tract infection or bladder stones, should not be treated with terazosin.

Terazosin should not be given to patients with bladder overflow, anuria or advanced renal failure.

Due to the risk of an excessive decrease in blood pressure, caution is advised for the concomitant administration of terazosin and thiazides or other antihypertensive medications. If a thiazide diuretic or another antihypertensive medication is added during treatment with terazosin, the terazosin dose must be reduced or the drug discontinued. A new dose-titration is essential. When administering terazosin in addition to other antihypertensives, the dose of the other antihypertensives should be reduced before commencement of therapy and adjusted after discontinuation of terazosin.

Since the drug is metabolised in the liver it should only be used with care in patients with existing hepatic dysfunction. Caution is also recommended, when terazosin is administered concomitantly with drugs, which may influence hepatic metabolism.

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 (e.g. 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-adrenoreceptor 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- adrenoreceptor 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-adrenoreceptor should be made known to the ophthalmic surgeon and the ophthalmologist in advance of surgery.

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.

Benph tablets contain lactose. 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) may cause 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

Phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) (see section 4.4).

In patients receiveing terazosin plus ACE inhibitors or diuretics, the proportion reporting dizziness or related side effects wasgreater than in the total population of terazosin patients from clinical trials.

Caution should be observed when terazosin is administered concomitantly with other antihypertensive agents to avoid the possibility of significant hypotension. When adding terazosin to a diuretic or other antihypertensive agent, dosing reduction and re-titration of these agents may be necessary.

Terazosin has been given without interaction with analgesics/anti-inflammatories, cardiac glycosides, hypoglycemics, antiarrhythmics, anxiolytics/sedatives, antibacterials, hormones/steroids and drugs used for gout.

4.6 Fertility, pregnancy and lactation

Pregnancy

Terazosin was not teratogenic in either rats or rabbits when administered at oral doses up to 1330 and 165 times, respectively, the maximum recommended human dose. Fetal resorptions occurred in rats dosed with 480mg/kg/day, approximately 1330 times the maximum recommended human dose. Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 165 times the maximum recommended human dose. These findings (in both species) were most likely secondary to maternal toxicity.

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. Furthermore, data from animal studies show that terazosin may increase the duration of pregnancy or inhibit labour. Therefore, terazosin should not be used in pregnancy unless the potential benefit is considered to outweigh the risk.

Breast-feeding

It is not known whether terazosin hydrochloride is excreted in breast milk. Because many drugs are excreted in breast milk, caution should be exercised when terazosin hydrochloride is administered to a nursing woman.

4.7 Effects on ability to drive and use machines

Terazosin tablets have a major influence on the 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 blockers, terazosin may cause syncope. Syncopal episodes may occur within 30 to90 minutes of the initial dose of the medicinal product. Syncope has occasionally occurred in association with rapid dosage increases or the introduction of another antihypertensive agent.

In clinical trials in hypertension, the incidence of syncopal episodes was approximately one percent. In most cases this was believed to be due to an excessive postural hypotensive effect although occasionally the syncopal episode may be preceded by tachycardia with heart rates of 120 to 160 beats per minute.

If syncope occurs the patient should be placed in a recumbent position and supportive treatment applied as necessary.

Dizziness, light-headedness or fainting may occur when standing up quickly from a lying or sitting position. Patients should be advised of this possibility and instructed to lie down if these symptoms appear and then sit for a few minutes before standing to prevent their recurrence.

These adverse effects are self-limiting and in most cases do not recur after the initial period of therapy or during subsequent re-titration.

Adverse drug effects reported with terazosin from multiple sources including clinical trials and spontaneous reports:

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 post-menopausal women)

Urinary frequency

(Pollakiuria)

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 oedema

Fever

Investigations

Weight gain

Decreases in haematocrit haemoglobin, white blood cells, total protein and albumin (suggestive of haemodilution) treatment with terazosin for up to 24 months had no significant effect on prostate specific antigen (PSA) levels.

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

Symptoms

Acute hypotension

Management

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. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: alpha-adrenoreceptor antagonists ATC code: G04CA03

Mechanism of action

Although the exact mechanism of the hypotensive action is not established, the relaxation of peripheral blood vessels appears to be produced mainly by competitive antagonism of post-synaptic alpha-adrenoceptors. Terazosin usually produces an initial gradual decrease in blood pressure followed by a sustained antihypertensive action.

Pharmacodynamic effects

Clinical experience indicates that a 2-5% decrease in total cholesterol plasma concentration and a 3-7% decrease in the combined LDLC + VLDLC fraction plasma concentration from pretreatment values are associated with the administration of therapeutic doses of terazosin.

In clinical trials, plasma concentrates of total cholesterol and combined low density and very low density lipoproteins were found to be slightly reduced following terazosin administration. Additionally, the increase in total cholesterol seen with other hypertensive agents did not occur when these were used in combination with terazosin.

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 well absorbed (80-100%). Terazosin has a minimal “first pass” effect and almost the complete dose of terazosin is systematically available.

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

Approximately of 90-94% terazosin is bound to plasma protein.. Protein binding is independent of total active substance concentrations.

Biotransformation

It is extensively metabolised in the liver via hydrolysis. Main metabolites of terazosin are caused by demethylation and conjugation.

Elimination

Mean elimination half-life of parent compound is 12 hours. Approximately 10% and 20 % of the orally administered terazosin is excreted as unchanged active substance the urine and in faeces, respect. Approximately 40% as inactive metabolites. Faecal elimination accounts for 55-60% of the oral dose. There are no reports on possible drug excretion in breast milk.

Linearity / non-linearity of pharmacokinetics

After oral dosing of terazosin AUC and Cmax increase in proportion with dose over the recommended dose range (2-10 mg).

5.3 Preclinical safety data

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology.

No evidence of a genotoxic effect of terazosin has been reported from in vitro and in vivo investigations of the mutagenic potential of the substance.

Decreased fertility and testicular atrophy were seen in rats at repeated administration of doses ≥ 20-30 times higher than the maximum recommended human dose. Foetal resorptions, decreased foetal weights, increased number of supernumerary ribs and decreased post-natal survival were noted in reproductive toxicity studies in rats and rabbits at maternally toxic doses (60 – 280 times the maximum recommended human dose).

In male rats, terazosin induced benign adrenal medullary tumours at the highest administered dose corresponding to 175 times the maximum human dose.

Carcinogenicity:

In male rats, terazosin induced benign adrenal medullary tumours at the highest administered dose corresponding to 175 times the maximum human dose. No such occurrences were seen in female rats or in a similar study in 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 and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 04569/0532

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 31/10/2006

Date of latest renewal: 18/03/2011

10. Date of revision of the text

September 2017