4.1. Therapeutic indications

Apresoline Tablets are indicated in adults for the treatment of moderate to severe hypertension as an adjunct to other anti-hypertensive agents.

Due to the complementary mechanism of action the combination of hydralazine with b-blockers and diuretics may enable antihypertensive efficacy at lower dose levels and counteract accompanying hydralazine effects such as reflex tachycardia and oedema.

Apresoline Tablets are indicated as supplementary medication for use in combination with long-acting nitrates in moderate to severe chronic congestive cardiac failure in patients in whom optimal doses of conventional therapy have proved insufficient.

4.2. Posology and method of administration

Posology

Paediatric population

Apresoline Tablets are not recommended for paediatric use.

Older people (over 65 years)

No studies in the elderly have been performed. The safety and efficacy of Apresoline is not established in the elderly population

Elderly:

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.

Adults:

Hypertension:

The dose should be adjusted to the individual requirements of the patient. Treatment should begin with low doses of Apresoline which, depending on the patient's response should be increased stepwise to achieve optimal therapeutic effect whilst keeping unwanted effects to a minimum.

Initially 25 mg twice a day. This can be increased gradually to a dose not exceeding 200 mg daily. The dose should not be increased beyond 100 mg daily without first checking the patient's acetylator status. The maximum dose in women should not exceed 100 mg (see section 4.4).

Chronic congestive heart failure: Treatment with Apresoline should always be initiated in hospital, where the patient's individual haemodynamic values can be reliably determined with the help of invasive monitoring. It should then be continued in hospital until the patient has become stabilised on the requisite maintenance dose. Doses vary greatly between individual patients and are generally higher than those used for treating hypertension. After progressive titration (initially 25 mg three times a day or four times a day increasing every second day) the maintenance dosage averages 50-75 mg four times a day.

Paediatric population:

Not recommended

Special Populations

Renal impairment and hepatic impairment (all indications)

In patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min or serum creatinine concentration > 2.5 mg/100 mL or 221 mol/L) or hepatic dysfunction, the dosage or the dosing interval must be adapted according to the clinical response to avoid accumulation of the “apparent” active substance (see section 4.4).

Method of administration

For Oral use only.

4.3. Contraindications

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

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 constrictive pericarditis). Isolated right ventricular failure due to pulmonary hypertension. Porphyria

Dissecting aortic aneurysm

4.4. Special warnings and precautions for use

Cardiovascular system

The overall 'hyperdynamic' state of the circulation induced by hydralazine may accentuate certain clinical conditions. Myocardial stimulation may provoke or aggravate angina pectoris. Hydralazine can cause anginal attacks and ECG changes indicative of myocardial ischaemia. It must therefore be used with caution in patients with suspected coronary artery disease or with cerebrovascular disease. Patients with suspected or confirmed coronary artery disease should therefore be given Apresoline Tablets only under beta-blocker cover 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 Tablets.

When undergoing surgery, patients treated with Apresoline/Hydralazine Tablets 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.

Patients who have survived a myocardial infarction should not receive Apresoline Tablets until a post-infarction stabilisation phase has been achieved. When initiating therapy in heart failure, particular caution should be exercised and the patient kept under surveillance and/or haemodynamic monitoring for early detection of postural hypotension or tachycardia. Where discontinuation of therapy in heart failure is indicated, Apresoline/Hydralazine Tablets should be withdrawn gradually (except in serious situations, such as SLE-like syndrome or blood dyscrasias) in order to avoid precipitation and/or exacerbation of heart failure.

Immune system

Prolonged treatment with hydralazine may provoke a systemic lupus erythematosus (SLE)-like syndrome. First symptoms are likely to be similar to rheumatoid arthritis (arthralgia, sometimes associated with fever, anaemia, leucopenia, thrombocytopenia and rash) and are reversible after withdrawal of the drug. In its more severe form it resembles acute SLE (similar manifestations as the milder form plus pleurisy, pleural effusions and pericarditis), and in rare cases renal and ocular involvement have been reported. Early detection and a timely diagnosis with appropriate therapy (i.e. treatment discontinuation and possibly long-term treatment with corticosteroids may be required to reverse these changes) are of utmost importance in this life-threatening illness to prevent more severe complications, which may sometimes be fatal.

Treatment with hydralazine may induce systemic vasculitis. There have also been a small number of reported cases of suspected antineutrophil cytoplasmic antibody ANCA (+) vasculitis in some patients also receiving hydralazine, leading to pulmonary renal syndrome which is a combination of diffuse alveolar haemorrhage and rapidly progressive glomerulonephritis. Patients may present with severe respiratory and/or renal failure and require early diagnosis, discontinuation of the medicine and prompt hospital treatment. The syndrome is characterised by a fulminant course if left untreated, and may sometimes be fatal.

Since such reactions tend to occur more frequently the higher the dose and the longer its duration, and since they are also 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 SLE-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 SLE like syndrome.

During long term treatment with Apresoline Tablets 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. A complete blood count and ANF titre determination is indicated before and periodically during prolonged therapy with hydralazine even if the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, persistent malaise, or other unexplained signs or symptoms. A positive ANF titre requires that the physician carefully weighs the implications of the test results against the benefits of continued therapy with hydralazine

Nervous system

Isolated cases of peripheral neuritis in the form of paraesthesia has been reported, and may respond to pyridoxine administration or drug withdrawal.

Haematological effects

Adverse haematological effects, such as a reduction in haemoglobin and red cell count, leucopoenia, agranulocytosis and purpura, have been reported in a very few cases. If such abnormalities develop, therapy should be discontinued.

Genetic effects

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.

Skin

Skin rash, febrile reactions and change in blood count occur rarely and the drug should be withdrawn.

Driving and using machines

Dizziness or hypotension may occur with Apresoline with established mechanism of action, it is therefore advisable to exercise caution when driving or operating machinery.

This medicine contains sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

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

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

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

Concurrent administration of Apresoline/Hydralazine Tablets with betablockers subject to a strong first pass effect (e.g. propranolol) may increase their bioavailability. Downward adjustment of these drugs may be required when they are given concomitantly with Apresoline/Hydralazine Tablets.

There is potential for the hypotensive effect of hydralazine to be antagonised when used concomitantly with oestrogens, corticosteroids or non-steroidal anti-inflammatory drugs.

Concurrent intake of food has been found to decrease the bioavailability of hydralazine and also to reduce its vasodilator effect.

4.6. Fertility, pregnancy and lactation

Women of child-bearing potential

Women planning to become pregnant should not take Apresoline. When pregnancy is confirmed in women taking Apresoline, the treatment should be discontinued immediately (see subsection Pregnancy).

Pregnancy

Use of Apresoline in pregnancy, before the third trimester should be avoided but the drug may be employed in later pregnancy if there is no safer alternative or when the disease itself carries serious risks for the mother or child e.g. preeclampsia and or eclampsia.

No serious adverse effects in human pregnancy have been reported to date with Apresoline, although experience in the third trimester is extensive. However, studies have shown teratogenic potential in mice but not in other animal species. Hydralazine crosses the placenta.

Breast-feeding

Hydralazine passes into breast milk but reports available so far have not shown adverse effects on the infant Mothers in whom use of Apresoline is unavoidable may breast feed their infant provided that the infant is observed for possible adverse effects.

Fertility

No data available.

4.7. Effects on ability to drive and use machines

Dizziness or hypotension may occur with Apresoline, it is therefore advisable to exercise caution when driving or operating machinery.

4.8. Undesirable effects

Adverse drug reactions from multiple sources including clinical trials and spontaneous reports are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10); 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 the available data), isolated cases (< 0.001%).

Some of the adverse effects listed below e.g. tachycardia, palpitations, angina symptoms, flushing, headache, dizziness, nasal congestion and gastrointestinal 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.

System Organ Class

Frequency

Adverse effects

Blood and lymphatic system disorders

Rare

Anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura. eosinophilia

Isolated cases

Haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis

Immune system disorders

Not known

Vasculitis including pulmonary renal syndrome

Metabolism and nutrition disorders

Rare

Decreased appetite

Psychiatric disorders

Rare

Agitation, anxiety

Isolated cases

Depression, hallucinations

Nervous system disorders

Very common

Headache

Rare

Dizziness

Isolated cases

Peripheral neuritis, polyneuritis, paraesthesia (these unwanted effects may be reversed by administering pyridoxine).

Not known

Tremor

Eye disorders

Rare

Conjunctivitis, lacrimation increased

Isolated cases

Exophthalmos

Cardiac disorders

Very common:

Tachycardia, palpitations

Common

Anginal pectoris

Rare

heart failure

Vascular disorder

Common

Flushing, hypotension

Isolated cases:

Paradoxical pressor responses

Respiratory, thoracic and mediastinal disorders

Rare

Nasal congestion, Dyspnoea, pleuritic pain

Gastrointestinal disorders

Common

Gastrointestinal disturbances, diarrhoea, nausea, vomiting

Isolated cases

Paralytic ileus.

Hepatobiliary

Rare

Jaundice, hepatomegaly,

disorders

abnormal liver function sometimes in association with hepatitis.

Not known

Hepatosplenomegaly (more common when associated with SLE-like symptoms

Skin and subcutaneous tissue disorders

Common

SLE-like syndrome (sometimes resulting in a fatal outcome see section 4.4 Special warnings and precautions for use)

Rare

Hypersensitivity reactions such as pruritus, urticaria, vasculitis, rash

Musculoskeletal and connective tissue disorders

Common

Arthralgia, joint swelling, myalgia

Renal and urinary disorders

Rare

Proteinuria, Blood creatinine increased, haematuria sometimes in association with glomerulonephritis.

Isolated cases

Acute kidney failure, urinary retention.

General disorders and administration site conditions

Rare

Pyrexia, malaise, Oedema

Investigations

Rare

Weight decrease

Reporting 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

The chief manifestations are cardiovascular disorders such as pronounced tachycardia and hypotension, which are accompanied by nausea, dizziness, and sweating, and which can result in circulatory collapse; also possible are myocardial ischaemia with angina pectoris and cardiac arrhythmias. Further signs and symptoms may include impairment of consciousness, headache, and vomiting, as well as possibly tremor, convulsions, oliguria, and hypothermia.

Management

Since no specific antidote is known, - in addition to attempts to eliminate the drug from the gastrointestinal tract (early induction of vomiting, later gastric lavage; administration of activated charcoal and possibly laxatives) - treatment should be supportive including use of a plasma expander or intravenous fluids as indicated .If hypotension is present, an attempt should be made to raise the blood pressure without increasing the tachycardia. Adrenaline should therefore be avoided.