Vasodilators.

The active ingredient is 1-hydralainophthalazine hydrochloride (hydralazine hydrochloride). Each 2 ml ampoule contains 20mg hydralazine hydrochloride.

Ampoules.

Treatment of hypertensive emergencies, particularly those associated with pre-eclampsia and toxaemia of pregnancy. Treatment of hypertension with renal complications.

Initially 5 to 10 mg by slow intravenous injection, to avoid precipitous decreases in arterial pressure with a critical reduction in cerebral or utero-placental perfusion. If necessary a repeat injection can be given after an interval of 20-30 minutes, throughout which blood pressure and heart rate should be monitored. A satisfactory response can be defined as a decrease in diastyloic blood pressure to 90/100 mmHg.

The contents of the vial should be reconstituted by dissolving in 1 ml of water for injection BP. This should then be further diluted with 10 ml of Sodium Chloride injection BP 0.9% and be administered by slow intravenous injection. The injection must be given immediately and any remainder discarded. Apresoline may also be given by continuous intravenous infusion, beginning with a flow rate of 200-300µg/min.

Maintenance flow rates must be determined individually and are usually within the range 50-150µg/min. The product reconstituted as for direct iv injection may be added via the infusion container to 500 ml of Sodium Chloride Injection BP 0.9% and given by continuous infusion. The addition should be made immediately before administration and the mixture should not be stored. Apresoline for infusion can also be used with 5% sorbitol solution or isotonic inorganic infusion solutions such as Ringers solution.

Not recommended.

Clinical evidence would indicate that no special dosage regime is necessary. Advancing age does not affect either blood concentration or systemic clearance. Renal elimination may however be affected in so far as kidney function diminishes with age.

Known hypersensitivity to hydralazine of dihydralazine.

Idiopathic systemic lupus erythematosus (SLE) and related diseases.

Severe tachycardia and heart failure with a high cardiac output (e.g. in thyrotoxicosis).

Myocardial insufficiency due to mechanical obstruction (e.g. in the presence of aortic or mitral stenosis or constructive pericarditis).

Isolated right ventricular failure due to pulmonary hypertension (cor pulmonale).

Dissecting aortic aneurysm.

Warnings

The overall 'hyperdynamic' state of the circulation induced by hydralazine may accentuate certain clinical conditions. Myocardial stimulation may provoke or aggravate angina pectoris. Patients with suspected or confirmed coronary artery disease should therefore be given Apresoline only under cover beta-blocker or in combination with other suitable sympatholytic agents. It is important that the beta-blocker medication should be commenced a few days before the start of treatment with Apresoline.

Patients who have survived a myocardial infarction should not receive Apresoline until a post-infarction stabilisation phase has been achieved.

Prolonged treatment with hydralazine (i.e. usually for more than 6 months) may provoke a lupus erythematosus (LE) like syndrome, especially where doses exceed 100 mg daily. First symptoms are likely to be arthralgia, sometimes associated with fever and rash and are reversible after withdrawal of the drug. In its more severe form it resembles acute SLE, and in rare cases renal and ocular involvement have been reported. Long-term treatment with corticosteroids may be required to reverse these changes. Since such reactions tend to occur more frequently the higher the dose and the longer its duration, and since they are more common in slow acetylators, it is recommended that for maintenance therapy the lowest effective dose should be used. If 100 mg daily fails to elicit an adequate clinical effect, the patient's acetylator status should be evaluated. Slow acetylators and women run greater risk of developing the LE like syndrome and every effort should therefore be made to keep the dosage below 100 mg daily and a careful watch kept for signs and symptoms suggestive of this syndrome. If such symptoms do develop the drug should be gradually withdrawn. Rapid acetylators often respond inadequately even to doses of 100 mg daily and therefore the dose can be raised with only a slightly increased risk of an LE-like syndrome.

During long term treatment with Apresoline it is advisable to determine the antinuclear factors and conduct urine analysis at intervals of approximately 6 months. Microhaematuria and / or proteinuria, in particular together with positive titres of ANF, may be initial signs of immune-complex glomerulonephritis associated with the SLE like syndrome. If overt clinical signs or symptoms develop, the drug should be withdrawn immediately.

Skin rash, febrile reactions and change in blood count occur rarely and drug should be withdrawn. Peripheral neuritis in the form of paraesthesia has been reported, and may respond to pyridoxine administration or drug withdrawal.

In high (cyto-) toxic concentrations, hydralazine induces gene mutations in single cell organisms and in mammalian cells in vitro. No unequivocally mutagenic effects have been detected in vivo in a great number of test systems.

Hydralazine in lifetime carcinogenicity studies, caused, towards the end of the experiments, small but statistically significant increases in lung tumours in mice and in hepatic and testicular tumours in rats. These tumours also occur spontaneously with fairly high frequency in aged rodents.

With due consideration of these animals and in-vitro toxicological findings, hydralazine in therapeutic doses does not appear to bear risk that would necessitate a limitation of its administration. Many years of clinical experience have not suggested that human cancer is associated with hydralazine use.

Precautions

In patients with renal impairment (creatine clearance < 30 ml/min or serum creatinine concentrations> 2.5 mg / 100 ml or 221 µmol / l) and in patients with hepatic dysfunction the dose or interval between doses should be adjusted according to clinical response, in order to avoid accumulation of the 'apparent' active substance.

Apresoline should be used with caution in patients with coronary artery disease (since it may increase angina) or cerebrovascular disease.

When undergoing surgery, patients treated with Apresoline may show a fall in blood pressure, in which case one should not use adrenaline to correct the hypotension, since it enhances the cardiac-accelerating effects of hydralazine.

Potentiation of effects: Concurrent therapy with other antihypertensives (vasodilators, calcium antagonists, ACE inhibitors, diuretics), anaesthetics tricyclic antidepressants, major tranquillisers or drugs exerting central depressant actions (including alcohol).

Administration of Apresoline shortly before or after diazoxide may give rise to marked hypotension.

MAO inhibitors should be used with caution in patients receiving Apresoline.

Concurrent administration of Apresoline with beta-blockers subject to a strong first pass effect (e.g. propranolol) may increase their bioavailability. Download adjustment of these drugs may be required when they are given concomitantly with Apresoline.

Some of the adverse effects listed below e.g. tachycardia, palpitation, angina symptoms, flushing, headache, dizziness, nasal congestion and gastro-intestinal disturbances are commonly seen at the start of treatment, especially if the dose is raised quickly. However such effects generally subside in the further course of treatment.

(The following frequency estimates are used: frequent> 10 %, occasional 1-10% rare 0.001-1% isolated cases < 0.001%)

Cardiovascular system:

Frequently: tachycardia, palpitation.

Occasionally: flushing, hypotension, anginal symptoms.

Rarely: oedema, heart failure.

Isolated cases: paradoxical pressor responses.

Central and peripheral nervous system:

Frequently: headache.

Rarely: dizziness.

Isolated cases: peripheral neuritis, polyneuritis, paraesthesiae (these unwanted effects may be reversed by administering pyridoxine).

Musculo-skeletal system:

Occasionally: arthralgia, joint swelling, myalgia.

Skin and appendages:

Rarely: rash.

Urogenital system:

Rarely: proteinuria, increased plasma creatinine, haematuria sometimes in association with glomerulonephritis.

Isolated cases: acute renal failure, urinary retention.

Gastro-intestinal tract:

Occasionally: gastro-intestinal disturbances, diarrhoea, nausea, vomiting. Rarely: jaundice, liver enlargement, abnormal liver function sometimes in association with hepatitis.

Isolated cases: paralytic ileus.

Blood:

Rarely: anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura.

Isolated cases: haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis.

Psyche:

Rarely: agitation, anorexia, anxiety.

Isolated cases: depression, hallucinations.

Sense organs:

Rarely: increased lacrimination, conjunctivitis, nasal congestion.

Hypersensitivity reactions:

Occasionally: SLE-like syndrome (see under 'Warnings')

Rarely: hypersensitivity reactions such as pruritus, urticaria, vasculitis, eosinophilia, hepatitis.

Respiratory tract:

Rarely: dyspnoea, pleural pain.

Miscellaneous:

Rarely: fever, weight decrease, malaise.

Isolated cases: exophthalmos.

Sovereign

(POM)

29 June 2009