SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Hypovase Tablets 1mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Prazosin Hydrochloride Ph Eur equivalent to 1mg Prazosin based on a potency of 93.1% base activity.

3. PHARMACEUTICAL FORM

Tablet.

White oblong tablets scored on both sides and engraved “M6” on one side.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension

Hypovase is indicated in the treatment of all grades of essential (primary) hypertension and of 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

Hypovase may 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

Hypovase is indicated for the symptomatic treatment of patients with Raynaud’s Phenomenon and Raynaud’s Disease.

Benign Prostatic Hyperplasia

Hypovase 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

Hypovase tablets are for oral administration only.

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 Hypovase alone of up to 15 mg daily in divided doses. Maximum recommended daily dosage: 20 mg in divided doses.

Patients receiving other antihypertensive therapy but with inadequate control: The dosage of the other drug should be reduced to a maintenance level and Hypovase 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 Hypovase 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 cardiac failure: The recommended starting dose is 500 micrograms two, three or four times daily, increasing to 4 mg 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 4 mg to 20 mg daily in divided doses. Adjustment of dosage may be required in the course of Hypovase therapy in some patients to maintain optimal clinical improvement.

Usual daily maintenance dosage: 4 mg to 20 mg 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 2 mg twice daily. This dose should not be exceeded unless the patient requires Hypovase as antihypertensive therapy. Patients with benign prostatic hyperplasia receiving hypertensive therapy, should be administered Hypovase 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 Hypovase 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 Hypovase, 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 Hypovase in this patient group, however, since Hypovase 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.

Use in children: Hypovase is not recommended for the treatment of children under the age of 12 years since safe conditions for its use have not been established.

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

4.3 Contraindications

Hypovase is contraindicated in patients with known sensitivity to Hypovase, other quinazolines, prazosin or any of the excipients.

4.4 Special warnings and precautions for use

In patients with benign prostatic hyperplasia: Hypovase is not recommended for patients with a history of micturition syncope.

Hypovase 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, Hypovase may augment the efficacy of antihypertensive therapy, consequently, close observation is especially recommended for patients taking medications that are known to lower blood pressure.

Hypovase should not normally be administered to patients already receiving another alpha-1 -antagonist.

In patients with congestive cardiac failure: Hypovase 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 Hypovase 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 Hypovase followed by gradual dosage increase is particularly important.

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

Use with Phosphodiesterase-5 Inhibitors (PDE-5 Inhibitors): Concomitant use of PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) and prazosin hydrochloride 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 PDE-5 inhibitors.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Hypovase 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: chlordiazapoxide, 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.

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

PDE-5 Inhibitors: Concomitant use of PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) and prazosin hydrochloride 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 Hypovase.

4.6 Pregnancy and lactation

Although no teratogenic effects were seen in animal testing, the safety of Hypovase during pregnancy has not yet been established. The use of Hypovase 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 Hypovase was continued for as long as 14 weeks.

Hypovase 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 Hypovase.

Studies to date are inadequate to establish the safety of Hypovase in pregnancy, accordingly, it should be used only when, in the opinion of the physician, potential benefit outweighs potential risk. Hypovase has been shown to be excreted in small amounts in human milk. Caution should be exercised when Hypovase 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 Hypovase therapy (i.e. driving or operating machinery).

4.8 Undesirable effects

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

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

	Uncommon	Diaphoresis, pruritis,
		urticaria
	Rare	Alopecia, lichen planus
Musculoskeletal and	Uncommon	Arthralgia
Connective Tissue
Disorders
Renal and Urinary Disorders	Common	Urinary frequency
	Rare	Incontinence
Reproductive System and Breast Disorders	Uncommon	Impotence
	Rare	Gynaecomastia, priapism
General Disorders and	Common	Oedema, lack of energy,
Administration Site		weakness
Conditions	Rare	Fever, pain
Investigations	Rare	Positive ANA titer

The frequency of side-effects observed in patients being managed for left ventricular failure with Hypovase 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	Dry mouth, nausea
	Uncommon	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.

4.9 Overdose

Should over-dosage lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary vasopressors including angiotensin should then be used. Renal function should be monitored and supported as needed. Laboratory data indicate Hypovase is not dialysable because it is protein bound.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Hypovase 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 Hypovase therapy.

The therapeutic efficacy of Hypovase 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 Hypovase in congestive heart failure does not provoke a reflex tachycardia and blood pressure reduction is minimal in normotensive patients.

Hypovase 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-1-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 Hypovase therapy is not associated with adverse changes in the serum lipid profile.

5.2 Pharmacokinetic properties

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. Hypovase is highly bound to plasma protein. Studies indicate that Hypovase 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 Hypovase can be used with safety in hypertensive patients with impaired renal function.

5.3 Preclinical safety data

None stated

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Calcium phosphate dibasic anhydrous Maize starch

Microcrystalline cellulose Magnesium stearate Sodium lauryl sulphate

6.2    Incompatibilities

None stated.

6.3    Shelf life

36 Months

Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

PVC/Aluminium blisters.

Original packs of 60 tablets, (in blister strips of 4 x 15 tablets).

6.6. Special precaution for disposal

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich, Kent, CT13 9NJ United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00057/0106R

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/06/2010

10    DATE OF REVISION OF THE TEXT

04/06/2010