This information is intended for use by health professionals

1. Name of the medicinal product

HYDRALAZINE 50mg TABLETS BP

2. Qualitative and quantitative composition

Each tablet contains 50mg Hydralazine Hydrochloride.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Pink, circular, biconvex, film-coated tablets impressed “C” on one face and the identifying letters “HZ” on the reverse.

4. Clinical particulars
4.1 Therapeutic indications

Hydralazine is indicated for:

1) Moderate to severe hypertension (in conjunction with a beta-adrenoceptor blocking agent or diuretic) and hypertensive crisis.

2) The management of moderate to severe congestive cardiac failure (reduces afterload), where optimal doses of diuretics and cardiac glycosides prove insufficient. In patients with high left ventricular filling pressure, it is recommended to combine hydralazine with a nitrate.

4.2 Posology and method of administration

Posology

Adults

Dosage should not be increased beyond 100mg daily without first checking the patient's acetylator status.

Hypertension

The dose should be adjusted to the individual requirements of the patient. Treatment should begin with low doses of hydralazine which, depending on the patient's response should be increased stepwise to achieve optimal therapeutic effect whilst keeping unwanted effects to a minimum. Initially 50mg once daily. This can be increased gradually to a dose not exceeding 200mg daily.

Chronic congestive heart failure:

Treatment with hydralazine should always be initiated in hospital, where the patients 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 50mg twice daily) the maintenance dosage averages 50mg four times daily.

Paediatric population

Not recommended for this age group.

Elderly

Clinical evidence indicates 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.

Method of administration

For oral administration.

4.3 Contraindications

• Hypersensitivity to hydralazine, dihydralazine or to any of the excipients listed in section 6.1.

• Patients with tachycardia and also in cases of left ventricular failure due to severe aortic or mitral stenosis or in constrictive pericarditis.

• In heart failure associated with high output (ie in thyrotoxicosis).

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

• Idiopathic system lupus erythematosus (SLE) and related diseases.

• Dissecting aortic aneurism.

• Porphyria.

4.4 Special warnings and precautions for use

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 Hydralazine 50mg Tablets BP only under cover of 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 Hydralazine 50mg Tablets BP.

Patients who have survived a myocardial infarction should not receive Hydralazine 50mg Tablets BP until a post-infarction stabilisation state has been achieved.

Prolonged treatment with hydralazine (i.e. usually for more than 6 months) may provoke a systemic lupus erythematosus (SLE)-like syndrome, especially where doses exceed 100 mg daily. 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.

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 LE like syndrome.

During long term treatment with Hydralazine 50mg Tablets BP 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.

Precautions

In patients with renal impairment (creatinine 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.

Hydralazine 50mg Tablets BP 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 Hydralazine 50mg Tablets BP 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.

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, Hydralazine 50mg Tablets BP 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.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption 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), muscle relaxants (baclofen and tizonidine), anaesthetics, tricyclic antidepressants, major tranquillisers, nitrates or drugs exerting central depressant actions (including alcohol).

Administration of Hydralazine 50mg Tablets BP shortly before or after diazoxide may give rise to marked hypotension.

MAO inhibitors should be used with caution in patients receiving Hydralazine 50mg Tablets BP.

Concurrent administration of Hydralazine 50mg Tablets BP with beta-blockers 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 Hydralazine 50mg Tablets BP.

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

Reduction in effects

Concomitant treatment with sympathomimetics, tricyclic antidepressants, NSAIDs, corticosteroids.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use of Hydralazine 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. pre-eclampsia and or eclampsia.

No serious adverse effects in human pregnancy have been reported to date with Hydralazine, although experience in the third trimester is extensive.

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 Hydralazine is unavoidable may breast feed their infant provided that the infant is observed for possible adverse effects.

4.7 Effects on ability to drive and use machines

Hydralazine may impair the patient's reactions especially at the start of the treatment.

The patient should be warned of the hazard when driving or operating machinery.

4.8 Undesirable effects

Some of the adverse effects listed below e.g. tachycardia, palpitations, 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.

System organ class

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)

Blood and lymphatic system disorders

anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura

haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis

Psychiatric disorders

agitation, anorexia, anxiety

depression, hallucinations

Nervous system disorder

headache

dizziness

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

Eye disorders

increased lacrimation, conjunctivitis

Cardiac disorders

tachycardia, palpitations

flushing, hypotension, anginal symptoms

oedema, heart failure

paradoxical pressor responses, fluid retention

Respiratory, thoracic and mediastinal disorders

nasal congestion, dyspnoea, pleural pain

Gastrointestinal disorders

gastro-intestinal disturbances, diarrhoea, nausea, vomiting

jaundice, liver enlargement, abnormal liver function sometimes in association with hepatitis

paralytic ileus

Skin and subcutaneous tissue disorders

rash

Musculoskeletal and connective tissue disorders

arthralgia, joint swelling, myalgia

Renal and Urinary disorders

proteinuria, increased plasma creatinine, haematuria sometimes in association with glomerulonephritis

acute renal failure, urinary retention, glomerulonephritis

General disorders and administration site conditions

SLE-like syndrome (sometimes resulting in a fatal outcome. See section 4.4)

hypersensitivity reactions such as pruritus, urticaria, vasculitis, eosinophilia, hepatitis, fever, weight decrease, malaise, anti-neutrophil cytoplasmic antibody positive vasculitis

exophthalmos, rheumatoid arthritis

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 including hypotension, tachycardia, myocardial ischaemia, dysrrhythmias and coma.

Gastric lavage or, in the absence of coma, emetic treatment should be given as soon as possible. If hypotension is present, an attempt should be made to raise blood pressure without increasing tachycardia, hence adrenaline (epinephrine) should be avoided. Supportive measures such as intravenous fluids and elevation of foot of bed are also indicated. Cautious administration of angiotensin or noradrenaline (norepinephrine) intravenously may be of use.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hydralazine hydrochloride is a vasodilator and antihypertensive agent.

ATC code: C02D B02

Mechanism of action

Hydralazine is a direct acting vasodilator which exerts its effects principally on the arterioles. Its precise mode of action is not known. Administration of hydralazine produces a fall in peripheral resistance and a decrease in arterial blood pressure, effects which induce reflex sympathetic cardiovascular responses. The concomitant use of a beta-blocker will reduce these reflex effects and enhance the anti-hypertensive effect. The use of hydralazine can result in sodium and fluid retention, producing oedema and reduced urinary volume. These effects can be prevented by concomitant administration of a diuretic.

5.2 Pharmacokinetic properties

Absorption

Orally administered Hydralazine is rapidly and completely absorbed but is subject to a dose dependent first pass effect (systemic bioavailability: 26-55%) which is dependent upon the individual's acetylator status. Peak plasma concentrations are attained after 0.5 to 1.5 hours.

Distribution

Hydralazine is rapidly distributed in the body and displays a particular affinity for the blood vessel walls. Plasma protein binding is of the order of 90%. Within 24 hours after an oral dose, the quantity recovered in the urine averages 80% of the dose.

Biotransformation

Nil.

Elimination

Hydralazine appears in the plasma chiefly in the form of a readily hydrolysable conjugate with pyruvic acid. Plasma half-life averages 2-3 hours but is prolonged up to 16 hours in severe renal failure (creatinine clearance less than 20 ml/mm) and shortened to approximately 45 minutes in rapid acetylators.

The bulk of the dose is excreted as acetylated and hydroxylated metabolites, some of which are conjugated with glucoronic acid.

Characteristics in patients

None relevant.

5.3 Preclinical safety data

Hydralazine has been found to be teratogenic in mice producing a small incidence of cleft palate and certain other bony malformations, in oral doses ranging from 20-120 mg / kg i.e. 20-30 times the maximum human daily dose. It was not teratogenic in rats or rabbits.

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.

6. Pharmaceutical particulars
6.1 List of excipients

The tablet core contains: polyvidone, disodium edetate, microcrystalline cellulose (E460), magnesium stearate.

The coating contains: hypromellose (E464), titanium dioxide (E171), polyethylene glycol, carmoisine aluminium lake azorubine (E122).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Polypropylene and polyethylene containers

Do not store above 25°C. Store in the original container.

Blister packs

Do not store above 25°C. Keep container in the outer carton.

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene containers and snap-on polyethylene lids.

The product may also be supplied in blister packs and cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: 250µm white rigid PVC. Surface printed 20µm hard temper aluminium foil with 5-6g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s.

Polyethylene container with a polypropylene lid.

Pack size: 56s

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7. Marketing authorisation holder

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing authorisation number(s)

PL 00142/0500

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 6th March 2001

Date of latest renewal: 19th March 2009

10. Date of revision of the text

26th August 2016