Document: spc-doc_PL 43870-0002 change

• spc-doc_PL 00289-0365
• spc-doc_PL 20075-0093
• spc-doc_PL 43870-0002

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Terazosin 5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Active    mg/tablet

Terazosin    5.0

as hydrochloride dihydrate

Excipients with known effect:

Lactose

Red iron oxide (E172)

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Red, round, bevelled edged uncoated tablets embossed with the identifying code “S152” on one face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Orally administered terazosin is indicated:

(i)    for the symptomatic treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). Terazosin is a selective post synaptic alpha-1-adrenoreceptor antagonist. Antagonism of alpha-1-receptors on prostatic and urethral smooth muscle has been shown to improve urinary tract flow and relieve the urinary obstruction caused by BPH.

(ii)    in the treatment of mild to moderate hypertension. It may be used in combination with thiazide diuretics and/or other antihypertensive drugs or as sole therapy where other agents are inappropriate or ineffective. The hypotensive effect is most pronounced on the diastolic pressure. Although the exact mechanism of the hypotensive action of terazosin is not established, the relaxation of peripheral blood vessels appears to be produced mainly by competitive antagonism of post-synaptic alpha ₁- adrenoreceptors. Terazosin

usually produces an initial gradual decrease in blood pressure followed by a sustained antihypertensive action.

4.2 Posology and method of administration Adults Only:

The dose of terazosin should be adjusted according to the patient's response. The following is a guide to administration:

Initial dose

1 mg before bedtime is the starting dose for all patients and should not be exceeded. Strict compliance with this recommendation should be observed to minimise acute first-dose hypotensive episodes. Therefore use of an alternative preparation will be necessary for initiation of therapy.

Subsequent dose

In the treatment of BPH:

The dose may be increased by approximately doubling at weekly or bi-weekly intervals to achieve the desired reduction in symptoms. The maintenance dose is usually 5 to 10 mg 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 additional symptomatic relief with doses above 10 mg once daily.

In the treatment of hypertension:

The single daily dosage may be increased by approximately doubling the dosage at weekly intervals to achieve the desired blood pressure response. The usual maintenance dose is 2mg to 10mg once daily. Doses over 20mg rarely improve efficacy and doses over 40mg have not been studied.

Use with thiazide diuretics and other antihypertensive agents

When adding a thiazide diuretic or another antihypertensive agent to a patient's regimen the dose of terazosin should be reduced and retitration carried out if necessary. Caution should be observed when terazosin is administered with thiazides or other antihypertensive agents as hypotension may develop.

Use in renal insufficiency

Pharmacokinetic studies indicate that patients with impaired renal function need no alteration in the recommended dosages.

Use in Children

Use in children is not applicable.

Use in the 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 events was greater in patients aged 65 years and over (5.6%) than those aged less than 65 years (2.6%)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known sensitivity to other alpha-adrenoceptor blockers.

Patients with a history of micturition syncope.

4.4 Special warnings and precautions for use

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. A similar effect can be anticipated if therapy is interrupted for more than a few doses and then re-started. 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.

In clinical trials, the incidence of postural hypotension was greater in BPH patients than in 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%). If administration is discontinued for more than several days, therapy should be re-instituted using the initial dosing regimen.

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.

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.

Laboratory Tests:

Small but statistically significant decreases in haematocrit, haemoglobin, white blood cells, total protein and albumin were observed in controlled clinical trials. These laboratory findings suggest the possibility of haemodilution. Treatment with terazosin for up to 24 months had no significant effect on Prostate Specific Antigen (PSA) levels. Caution is also recommended, when terazosin is administered concomitantly with drugs, which may influence hepatic metabolism.

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, verdenafil) 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 phophodiesterase-5-inhibitors.

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-adrenoceptor blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during cataract operation current or past use of alpha- adrenoceptor blockers should be made known to the ophthalmic surgeon in advance of surgery.

Terazosin 5mg Tablets contain lactose

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Caution should be observed when terazosin is administered with other antihypertensive agents, to avoid the possibility of significant hypotension. When adding terazosin to a diuretic or other antihypertensive agent, dosage reduction and retitration may be necessary.

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

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

4.6 Fertility, Pregnancy and lactation Pregnancy

Terazosin hydrochloride 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 during pregnancy and lactation 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 therefore in pregnancy unless the potential benefit outweighs 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. Dizziness, light-headedness or drowsiness may occur with the initial dose or in association with missed doses and subsequent reinitiation of terazosin therapy. Patients should be cautioned about these possible adverse events and the circumstances in which they may occur and advised to avoid driving or hazardous tasks for approximately 12 hours after the initial dose or when the dose is increased.

4.8 Undesirable effects

Terazosin, in common with other alpha-adrenoreceptor antagonists, may cause syncope. Syncopal episodes have occurred within 30 to 90 minutes of the initial dose of the drug. 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 has been preceded by a bout of tachycardia with heart rates of 120 to 160 beats per minute.

If syncope occurs the patient should be placed in a recumbent position and given supportive treatment 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 re-occurrence.

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 events reported with terazosin from multiple sources including clinical trials and spontaneous reports:

Blood and lymphatic system disorder Thrombocytopenia Immune system disorders Anaphylactoid reaction Psychiatric disorders

Depression, nervousness, anxiety, insomnia Nervous system disorders

Dizziness, somnolence, headache, paraesthesia, vertigo Eye disorders

Blurred vision, amblyopia, visual impairment, conjunctivitis

Ear and labyrinth disorders Tinnitus

Cardiac disorders

Palpitations, tachycardia, arrhythmia, atrial fibrillation Vascular disorders

Postural hypotension, syncope, vasodilatation Respiratory, thoracic and mediastinal disorders

Nasal congestion, rhinitis, dyspnoea, sinusitis, bronchitis, epistaxis, flu symptoms, pharyngitis, cold symptoms, cough Gastrointestinal system disorders

Nausea, abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, flatulence, vomiting

Skin and subcutaneous tissue disorders Pruritus, rash, hyperhidrosis, angioedema Musculoskeletal and connective tissue disorders

Back pain, pain in extremity, neck pain, shoulder pain, gout, arthralgia, arthritis, joint

disorders, myalgia

Renal and urinary disorders

Pollakiuria, urinary tract infection and urinary incontinence (primarily reported in post-menopausal women).

Reproductive system and breast disorders

Libido decreased, erectile dysfunction, priapism

General disorders and administration site conditions

Asthenia, peripheral oedema, oedema, chest pain, face oedema, pyrexia

Investigations

Weight increased. Decreased haematocrit, decreased haemoglobin, decreased white blood cell count, decreased total protein and decreased blood 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, website www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms Acute hypotension

Management

Cardiovascular support is of first importance. Restoration of blood pressure and normalisation of heart rate may be accomplished by keeping the patient in a supine position. If this measure is inadequate, shock should first be treated with volume expanders and, if necessary, vasopressors could then be used. Renal function should be monitored and general supportive measures applied as required. Dialysis may not be of benefit since laboratory data indicate that terazosin is highly protein bound.

5.1 Pharmacodynamic properties

ATC Code: G04CA03

Pharmacotherapeutic group: alpha-adrenoreceptor antagonists 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 LDL_C + VLDL_C 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.

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. The plasma concentration of the parent drug has a maximum 1 hour post administration and declines with a half-life of approximately 12 hours. Food has little or no effect on bioavailability.

Distribution

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

Biotransformation

Main metabolites of terazosin are caused by demethylation and conjugation. Elimination

Approximately 10% and 20% of orally administered terazosin is excreted as unchanged active substance in urine and in faeces, respectively. Approximately 40% of the administered dose is eliminated in the urine and 60% in the faeces. The drug is highly bound to plasma proteins.

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).

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 findings 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

Lactose monohydrate, Croscarmellose sodium, Cellactose 80,

Magnesium stearate (E572) Red iron oxide (E172).

6.2    Incompatibilities

Not applicable.

10 DATE OF REVISION OF THE TEXT

02/08/2016