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APRESOLINE AMPOULES 20MG

Active substance(s): HYDRALAZINE HYDROCHLORIDE / HYDRALAZINE HYDROCHLORIDE / HYDRALAZINE HYDROCHLORIDE

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1.

NAME OF THE MEDICINAL PRODUCT
Apresoline Ampoules 20 mg
Hydralazine 20mg Powder for Concentrate for Solution for Injection/Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is 1-hydralainophthalazine hydrochloride (hydralazine hydrochloride). Each
2 ml ampoule contains 20mg hydralazine hydrochloride.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Ampoules

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

4.2.

1.

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

2.

Treatment of hypertension with renal complications

Posology and Method of Administration
Adults:
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. Hydralazine 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.
Hydralazine for infusion can also be used with 5% sorbitol solution or isotonic inorganic
infusion solutions such as Ringers solution.
Children:
Not recommended

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.

4.3.

Contraindications
Known hypersensitivity to hydralazine or dihydralazine or to any of the excipients.
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 (cor pulmonale).
Dissecting aortic aneurysm.
Porphyria

4.4.

Special Warnings and Special 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 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 Hydralazine .
Patients who have survived a myocardial infarction should not receive Hydralazine until a
post-infarction stabilisation phase has been achieved.

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 sever
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 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 Hydralazine 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.
Hydralazine 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 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.
4.5.

Interactions 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, 1nitrates or drugs exerting central depressant actions (including
alcohol).
Administration of Hydralazine shortly before or after diazoxide may give rise to marked
hypotension.
MAO inhibitors should be used with caution in patients receiving Hydralazine.
Concurrent administration of Hydralazine 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 Hydralazine.
There is potential for the hypotensive effect of hydralazine to be antagonised when used
concomitantly with oestrogens or non-steroidal anti-inflammatory drugs.

4.6.

Pregnancy and Lactation
Use of Hydralazine in pregnancy, before the third trimester should be avoided but the
drug maybe 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.

1

PL 06464/1239-0014; 06/11/2009

Hydralazine passes into breast milk but reports available so far have not shown adverse
effects on the infant. Mothers in whom use of Hydralazine proves 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.
(The following frequency estimates are used: frequent> 10 %, occasional 1-10% rare
0.001-1% isolated cases < 0.001%)
Cardiovascular system:
Frequently: tachycardia, palpitations.
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, paraesthesia (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.
Gastrointestinal tract:

Occasionally: gastrointestinal 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.
Psychiatric reactions:
Rarely: agitation, anorexia, anxiety.
Isolated cases: depression, hallucinations.
Sense organs:
Rarely: increased lacrimination, conjunctivitis, nasal congestion.
Hypersensitivity reactions:
Occasionally: SLE-like syndrome (sometimes resulting in a fatal outcome see section 4.4
Special warnings and precautions for use)
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.
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
Signs and Symptoms
Symptoms include hypotension, tachycardia, myocardial ischaemia dysrhythmias and coma.
Treatment
Supportive measures including intravenous fluids are also indicated. If hypotension is present, an
attempt should be made to raise the blood pressure without increasing the tachycardia. Adrenaline
should therefore be avoided.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group
Hydralazine is a peripheral vasodilator.
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
None stated
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%.
Biotransformation
None stated
Elimination
Plasma half-life averages 2-3 hours but is prolonged up to 16 hours in severe renal failure
(creatinine clearance less than 20 ml / min) and shortened to approximately 45 minutes in
rapid acetylators.
Characteristics in patients
None stated

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 20-120mg/kg i.e. 20-30 times
the maximum human daily dose. It was not teratogenic in rats or rabbits.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Hydrochloric acid

6.2

Incompatibilities
Dextrose infusion solutions are not compatible because contact between hydralazine and glucose
causes hydralazine to be rapidly broken down.

6.3

Shelf life
Five years.

6.4

Special precautions for storage
The ampoules should be protected from light and stored below 30°C. Single use only. Use
immediately after reconstitution.
Medicines should be kept out of reach of children.

6.5

Nature and contents of container
Colourless Type I glass 2ml ampoule. Five ampoules are packed in a cardboard printed carton.

6.6

Special precautions for disposal
None.

7

MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited
Regency House
Miles Gray Road
Basildon
Essex
SS14 3AF
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 20072/0230

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15 November 2001

10

DATE OF REVISION OF THE TEXT
24/06/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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