SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Prazosin 0.5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Prazosin Hydrochloride BP equivalent to 0.5 mg prazosin Excipient(s) with known effect:

Lactose

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension

Prazosin is used in the treatment of all grades of primary hypertension and all grades of secondary hypertension of varied aetiology. It can be used as the initial and sole agent or it may be employed in a treatment regimen in conjunction with a diuretic and/or other antihypertensive drug as needed for proper patient response.

Congestive heart failure

Prazosin can be used alone or added to the therapeutic regimen in those patients with congestive heart failure who are resistant or refractory to conventional therapy with diuretics and/or cardiac glycosides.

Raynaud's Phenomenon and Raynaud's Disease

Prazosin is indicated for the symptomatic treatment of patients with Raynaud's Phenomenon and Raynaud's Disease.

Benign Prostatic Hyperplasia

Prazosin is indicated as an adjunct in the symptomatic treatment of urinary obstruction caused by benign prostatic hyperplasia. It may therefore be of value in patients awaiting prostatic surgery.

4.2 Posology and method of administration

Posology

Hypertension

The dosage range is from 500 micrograms - 20 mg daily.

It is recommended that therapy be initiated at the lowest dose, 500 micrograms, twice or three times daily for three to seven days, with the starting dose administered in the evening. This dose should be increased to 1mg twice or three times daily for a further three to seven days. Thereafter, the daily dose should be increased gradually as determined by the patient’s response to the blood pressure lowering effect. Most patients are likely to be maintained on a dosage regimen of prazosin alone of up to 15 mg daily in divided doses. Maximum recommended daily dosage: 20 mg in divided doses. May be given in conjunction with a thiazide diuretic, in which case the dosage should be halved, with later adjustment if necessary.

Patients receiving other antihypertensive therapy but with inadequate control

The dosage of the other drug should be reduced to a maintenance level and prazosin initiated at 500 micrograms in the evening, then continuing with 500 micrograms twice or three times daily. Subsequent dosage increases should be made gradually depending upon the patient’s response.

There is evidence that adding prazosin to angiotensin converting enzyme inhibitor, beta-adrenergic antagonist or calcium antagonist therapy may bring about a substantial reduction in blood pressure. Therefore, the low initial dosage regimen is recommended.

Congestive heart failure

The recommended starting dose is 500 micrograms two, three or four times daily, increasing to 4mg in divided doses. Dosage should be adjusted according to the patient's clinical response, based on careful monitoring of cardiopulmonary signs and symptoms, and when indicated, haemodynamic studies. Dosage may be adjusted as often as every two to three days in patients under close medical supervision. In severely ill, decompensated patients, rapid dosage adjustment over one to two days may be indicated and is best done when haemodynamic monitoring is available. In clinical studies the therapeutic dosages ranged from 4mg to 20mg daily in divided doses. Adjustment of dosage may be required in the course of prazosin therapy in some patients to maintain optimal clinical improvement.

Usual daily maintenance dose is 4-20mg daily in divided doses.

Raynaud's Phenomenon and Raynaud's Disease

The recommended starting dosage is 500 micrograms twice daily given for a period of three to seven days and should be adjusted according to the patient's clinical response. Usual maintenance dosage is 1mg or 2mg twice daily.

Benign prostatic hyperplasia

The recommended dosage is 500 micrograms twice daily for a period of 3 to 7 days, with the initial dose administered in the evening. The dosage should then be adjusted according to clinical response. The usual maintenance dosage is 2mg twice daily. This dose should not be exceeded unless the patient requires prazosin as antihypertensive therapy. Patients with benign prostatic hyperplasia receiving hypertensive therapy, should be administered prazosin only under the supervision of the practitioner responsible for treating the patient's hypertension.

Patients with moderate to severe grades of renal impairment.

Evidence to date shows that prazosin does not further compromise renal function when used in patients with renal impairment. As some patients in this category have responded to small doses of prazosin, it is recommended that therapy be initiated at 500 micrograms daily and that dosage increases be instituted cautiously.

Patients with hepatic dysfunction

No information is available on the use of prazosin in this patient group, however, since prazosin normally undergoes substantial first pass metabolism and subsequent metabolism and excretion by the liver, it is recommended that therapy be initiated at 500 micrograms daily and that dosage increases be instituted cautiously.

Paediatric population Children

Prazosin is not recommended for the treatment of children under the age of 12 years.

Use in Elderly

Since the elderly may be more susceptible to hypotension, therapy should be initiated with the lowest possible dose.

Method of administration

Prazosin Tablets are for oral administration only.

Prazosin tablets should be swallowed with a glass of water.

4.3 Contraindications

Hypersensitivity to the active substances, other quinazolines or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Use with Phosphodiesterase-5 Inhibitors (PDE-5 Inhibitors):

Concomitant use of phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) and prazosin 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 phosphodiesterase-5-inhibitors.

In patients with benign prostatic hyperplasia

Prazosin is not recommended for patients with a history of micturition syncope.

Prazosin decreases peripheral vascular resistance and since many patients with this disorder are elderly, careful monitoring of blood pressure during initial administration and during adjustment of dosage is recommended. The possibility of postural hypotension, or rarely, loss of consciousness, as reported in other patient groups should be borne in mind. Close observation is especially recommended. For patients taking medications that are known to lower blood pressure, prazosin may augment the efficacy of antihypertensive therapy, consequently, close observation is especially recommended for patients taking medications that are known to lower blood pressure. Prazosin should not normally be administered to patients already receiving another alpha-1-antagonist.

Sudden collapse may follow the initial dose of prazosin.

In patients with congestive cardiac failure

Prazosin is not recommended in the treatment of congestive cardiac failure due to mechanical obstruction such as aortic valve stenosis, mitral valve stenosis, pulmonary embolism and restrictive pericardial disease. Adequate data are not yet available to establish efficacy in patients with heart failure due to recent myocardial infarction.

When prazosin is initially administered to patients with congestive cardiac failure who have undergone vigorous diuretic or other vasodilator treatment, particularly in higher than the recommended starting dose, the resultant decrease in left ventricular filling pressure may be associated with a significant fall in cardiac output and systemic blood pressure. In such patients, observance of the recommended starting dose of prazosin followed by gradual dosage increase is particularly important.

The clinical efficacy of prazosin in congestive cardiac failure has been reported to diminish after several months of treatment, in a proportion of patients. In these patients there is usually evidence of weight gain or peripheral oedema indicating fluid retention. Since spontaneous deterioration may occur in such severely ill patients, a causal relationship to prazosin therapy has not been established. Thus, as with all patients with congestive cardiac failure, careful adjustment of diuretic dosage according to the patient's clinical condition is required to prevent excessive fluid retention and consequent relief of symptoms.

In those patients without evidence of fluid retention, when clinical improvement has diminished, an increase in the dosage of prazosin will usually restore clinical efficacy.

In patients with hypertension

A very small percentage of patients may respond in an abrupt and exaggerated manner to the initial dose of prazosin. Postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness, has been reported, particularly with the commencement of therapy, but this effect is readily avoided by initiating treatment with a low dose of prazosin and with small increases in dosage during the first one to two weeks of therapy. The effect when observed is not related to the severity of hypertension, is self-limiting and in most patients does not recur after the initial period of therapy or during subsequent titration steps.

Raynaud’s phenomenon and Raynaud’s disease

Because prazosin decreases peripheral vascular resistance, careful monitoring of blood pressure during initial administration and during subsequent dosage increments of prazosin is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure.

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.

Lactose intolerance

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

Prazosin has been administered without any adverse drug interaction in clinical experience to date with the following:

Cardiac glycosides: digitalis and digoxin.

Hypoglycaemic agents: insulin, chlorpropamide, phenformin, tolazamide and tolbutamide.

Tranquillizers and sedatives: chlordiazepoxide, diazepam and phenobarbital. Agents for treatment of gout: allopurinol, colchicine and probenecid. Anti-arrhythmic agents: procainamide and quinidine.

Analgesic, antipyretic and anti-inflammatory agents: dextropropoxyphene, aspirin, indomethacin and phenylbutazone.

The hypotensive effects of prazosin are enhanced by thiazide diuretics.

There is evidence that adding Prazosin to beta-adrenergic antagonist or calcium antagonist therapy may produce a substantial reduction in blood pressure. Therefore the low initial dosage regimen is recommended.

Adrenaline should not be given to antagonise the hypotensive effects of prazosin in overdosage since it may enhance any cardiac-accelerating effects which may occur.

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

Drug/Laboratory Test Interactions

False positive results may occur in screening tests for phaeochromocytoma urinary vanillylmandelic acid (VMA) and methoxyhydroxyphenyl glycol (MHPG) metabolites of norepinephrine (noradrenaline) in patients who are being treated with prazosin.

4.6 Fertility, pregnancy and lactation

Pregnancy

Although no teratogenic effects were seen in animal testing, the safety of prazosin during pregnancy has not yet been established. The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant women revealed no drug-related foetal abnormalities or adverse effects. Therapy with prazosin was continued for as long as 14 weeks.

Prazosin has also been used alone or in combination with other hypotensive agents in severe hypertension of pregnancy. No foetal or neonatal abnormalities have been reported with the use of prazosin.

Studies to date are inadequate to establish the safety of prazosin in pregnancy; accordingly, it should be used only when, in the opinion of the physician, potential benefit outweighs potential risk.

Breast-feeding

Prazosin has been shown to be excreted in small amounts in human milk. Caution should be exercised when prazosin is administered to nursing mothers.

4.7 Effects on ability to drive and use machines

When instituting therapy with any effective antihypertensive agent, the patient should be advised on how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of prazosin therapy (i.e. driving or operating machinery).

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with Prazosin 0.5 mg Tablets with the following frequencies: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

In patients with hypertension

The following side-effects have been associated with prazosin therapy:

MedDRA System Organ Class	Frequency	Undesirable effects
Immune System Disorders	Rare	Allergic reaction
Psychiatric Disorders	Common Uncommon Rare	Depression, nervousness Insomnia Hallucinations
Nervous System Disorders	Common Uncommon Rare	Dizziness, drowsiness, headache, faintness, syncope Paraesthesia Worsening of pre-existing narcolepsy
Eye Disorders	Common Uncommon	Blurred vision Eye pain, reddened sclera
Ear and Labyrinth	Common	Vertigo
Disorders	Uncommon	Tinnitus
Cardiac Disorders	Common Uncommon Rare	Palpitations Angina pectoris, tachycardia Bradycardia
Vascular Disorders	Rare	Flushing, orthostatic hypotension, vasculitis
Respiratory, Thoracic and Mediastinal Disorders	Common Uncommon	Dyspnoea, nasal congestion Epistaxis
Gastrointestinal Disorders	Common Uncommon Rare	Constipation, diarrhoea, dry mouth, nausea, vomiting Abdominal discomfort and/or pain Pancreatitis
Hepato-biliary Disorders	Rare	Liver function abnormalities
Skin and Subcutaneous	Common	Rash
Tissue Disorders	Uncommon	Diaphoresis, pruritus, urticaria

MedDRA System Organ Class	Frequency	Undesirable effects
	Rare	Alopecia, lichen planus
Musculoskeletal and Connective Tissue Disorders	Uncommon	Arthralgia
Renal and Urinary	Common	Urinary frequency
Disorders	Rare	Incontinence
Reproductive System and	Uncommon	Impotence
Breast Disorders	Rare	Gynaecomastia, priapism
General Disorders and	Common	Oedema, lack of energy,
Administration Site		weakness
Conditions	Rare	Fever, pain
Investigations	Rare	Positive ANA titre

In patients with congestive cardiac failure

The frequency of side-effects observed in patients being managed for left ventricular failure with prazosin when used in conjunction with cardiac glycosides and diuretics is shown below:

MedDRA System Organ Class	Frequency	Undesirable effects
Nervous System Disorders	Common Uncommon Rare	Dizziness Headache Drowsiness
Eye Disorders	Common	Blurred vision
Cardiac Disorders	Rare	Palpitations
Vascular Disorders	Common	Postural hypotension
Respiratory, Thoracic and Mediastinal Disorders	Rare	Nasal congestion
Gastrointestinal Disorders	Common Uncommon	Dry mouth, nausea Diarrhoea
Reproductive System and Breast Disorders	Common	Impotence
General Disorders and Administration Site Conditions	Rare	Oedema

In most instances these occurrences have been mild to moderate in severity and have resolved with continued therapy or have been tolerated with no decrease in drug dosage.

In patients with Raynaud's phenomenon and Raynaud's disease and benign prostatic hypertrophy

The most common, although infrequently reported side-effect, is mild dizziness.

Literature reports exist associating prazosin therapy with a worsening of preexisting narcolepsy. A causal relationship is uncertain in these cases.

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

Treatment of adverse effects: If overdosage occurs the stomach should be emptied by aspiration and lavage. Should overdose lead to hypotension, support of the cardiovascular system is of prime importance. Restoration of blood pressure and normalisation of heart rate may be accomplished by keeping the patient in supine position. If this measure is adequate, shock should be first treated with volume expanders. If necessary the cautious use of vasopressors (including angiotensin and metaraminol) should then be used. Adrenaline should not be given to antagonise the hypotensive effects of prazosin in overdosage since it may enhance any cardiac-accelerating effects which may occur.

Renal function should be monitored and supported as needed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Prazosin causes a decrease in total peripheral vascular resistance through selective inhibition of postsynaptic alpha-1-adrenoreceptors in vascular smooth muscle. The results of forearm plethysmographic studies in humans demonstrate that the resultant peripheral vasodilation is a balanced effect on both resistance vessels (arterioles) and capacitance vessels (veins).

In hypertensive patients, blood pressure is lowered in both the supine and standing positions; this effect is more pronounced on the diastolic blood pressure. Tolerance to the antihypertensive effect has not been observed in long-term clinical use; relatively little tachycardia or change in renin levels has been noted. Rebound elevation of blood pressure does not occur following abrupt cessation of prazosin therapy.

The therapeutic efficacy of prazosin in patients with congestive heart failure is ascribed to a reduction in left ventricular filling pressure, reduction in cardiac impedance and an augmentation of cardiac output. The use of prazosin in congestive heart failure does not provoke a reflex tachycardia and blood pressure reduction is minimal in normotensive patients.

Prazosin has been found to successfully reduce the severity of the signs, symptoms, frequency and duration of attacks, in patients with Raynaud’s disease.

In low dosage, antagonism of alpha-i-receptors on pro static and urethral smooth muscle has been shown to improve the urinary pressure profile in men and to improve symptoms of benign prostatic hypertrophy.

Clinical studies have shown that prazosin therapy is not associated with adverse changes in the serum lipid profile.

5.2 Pharmacokinetic properties

Prazosin is readily absorbed from the gastro-intestinal tract and excreted mainly in the form of metabolites. Less than 10% is excreted unchanged in the urine. Following oral administration in normal volunteers and hypertensive patients plasma concentrations of prazosin reach a peak in one to two hours with a plasma half-life of two to three hours. Pharmacokinetic data in a limited number of patients with congestive heart failure, most of whom showed evidence of hepatic congestion, indicates that peak plasma concentrations are reached in 2.5 hours and plasma half life is approximately 7 hours. Prazosin is highly bound to plasma protein. Studies indicate that prazosin is extensively metabolised, primarily by demethylation and conjugation, and excreted mainly via bile and faeces.

Renal blood flow and glomerular filtration rate are not impaired by long term oral administration and thus prazosin can be used with safety in hypertensive patients with impaired renal function.

Comparison of our product and Hypovase on 0.5 mg tablets gave the following results:_

	Prazosin	Hypovase
AUC	32.10	32.70
Tmax	1.00	1.18
V life (hours)	3.59	3.38

No statistically significant difference was found between the two preparations. A full report is included in the application.

5.3 Preclinical safety data

None stated

6.1 List of excipients

Lactose BP

Pre-gelatinised Starch BP Povidone BP Isopropanol BP Sodium Starch Glycollate BP Magnesium Stearate BP

6.2 Incompatibilities

None known other than those stated in above.

6.3 Shelf life

Shelf-life of the product as packaged for sale

3 years from date of manufacture in polypropylene containers and 2 years from date of manufacture in PVdC coated PVC blister packs.

6.4 Special precautions for storage

Store in a cool dry place Protect from light and moisture

6.5 Nature and contents of container

Polypropylene container with a low density polyethylene lid incorporating a tear-off sealing band or high density polyethylene tampertainers with tamper-evident closures

Pack sizes: 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 250, 500 and 1000 tablets.

₂

PVdC coated PVC/aluminium blister packs (60g/m PVdC on 250p PVC 20p Al) Pack sizes 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112, and 120 tablets.

6.6 Special precautions for disposal and other handling

No special instructions.