Consumer medicine information

Apresoline

Hydralazine hydrochloride

BRAND INFORMATION

Brand name

Apresoline

Active ingredient

Hydralazine hydrochloride

Schedule

What is in this CMI

This CMI answers some common questions about Apresoline. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of giving you Apresoline against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this information. You may need to read it again.

What Apresoline is used for

Apresoline is an injection that is used when your blood pressure is very high and needs to be brought down quickly. Apresoline is used to reduce very high blood pressure especially during late pregnancy.

Apresoline belongs to a group of medicines called vasodilators. It acts by relaxing and widening (dilating) the walls of blood vessels. This action helps to reduce blood pressure and increase blood and oxygen supply to the heart, brain, spleen and kidneys.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

Apresoline is only available with a doctor's prescription. It is not addictive.

Before you are given Apresoline

When you must not have it

You must not be given Apresoline if you have ever had an allergic reaction to:

hydralazine, the active ingredient in Apresoline
dihydralazine
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

You must not have Apresoline if you have any of these medical conditions:

Systemic lupus erythematosus (SLE) or a related disease
recent heart attack or other severe heart problems, e.g. due to inflammation around the heart, narrowing of blood vessels or heart valves, or related to increased demand on the heart in diseases such as thyrotoxicosis (overactive thyroid gland)
right heart failure due to pulmonary hypertension (high pressure in blood vessels supplying the lungs)
swelling and weakening of part of a large blood vessel (called an aneurysm)
a rare blood pigment disorder known as porphyria

If you are not sure whether any of the above conditions apply to you, ask your doctor.

Apresoline must not be given to children. There is not enough information to recommend its use in children.

Before you have it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

chest pain (angina) or other heart problems whether or not severe
previous heart attack
problems with blood flow to the brain, e.g. stroke, mini-stroke or transient ischaemic attack (TIA)
kidney problems
liver problems

Your doctor may want to take special precautions if you have any of these conditions.

Tell your doctor if you are pregnant or plan to become pregnant. Apresoline may affect your developing baby if you have it while you are pregnant, although it is often used near the end of pregnancy to lower very high blood pressure. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding. The active ingredient of Apresoline passes into breast milk and could affect your baby if you breastfeed.

If you have not told your doctor about any of these things, tell him/her before you have Apresoline.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Apresoline may interfere with each other. These include:

other medicines used to treat high blood pressure, such as vasodilators (e.g. diazoxide), calcium antagonists, ACE inhibitors or beta-blockers (e.g. propranolol, metoprolol)
diuretics (fluid tablets), medicines used to reduce water retention and treat high blood pressure
some medicines used to treat heart problems
monoamine oxidase inhibitors (MAOIs), used to treat depression or Parkinson's Disease
some other medicines used to treat depression, such as tricyclic antidepressants
central depressants, sometimes referred to as sedatives and tranquillisers (medicines to help you sleep, reduce anxiety, induce anaesthesia or treat psychosis)
non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation
adrenaline (epinephrine), used to raise blood pressure, e.g. due to a heart attack or serious allergic reaction
oestrogens, e.g. used in the contraceptive pill and in hormone replacement therapy (HRT)

These medicines may be affected by Apresoline or they may affect how well it works. You may need to take different amounts of your medicines or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are receiving Apresoline.

How Apresoline is given

How much you need

Your doctor will decide how much you need and how often the injections will be given. The first dose of Apresoline is usually 5 to 10 mg. After 20 or 30 minutes, another dose can be given, if necessary, to bring your blood pressure down.

How it is given

Apresoline is usually given in hospital. It can be given by slow injection directly from the syringe into a vein or by infusion (drip) over a longer period.

How long your treatment will last

Apresoline is only used over a short period to bring down very high blood pressure quickly. After that, you may have to take blood pressure tablets to help keep your blood pressure down.

If you have too much (overdose)

If you think that you may have been given too much Apresoline, immediately alert your doctor or the nursing staff in the hospital.

Symptoms such as a fast or irregular heartbeat, dizziness or faintness, nausea (feeling sick), vomiting, headache, chest pain, tremors, fits or sweating, may mean your blood pressure has fallen too far.

While you are being given Apresoline

Things you must do

Before having any surgery or emergency treatment, tell the doctor or anaesthetist in charge that you are being treated with Apresoline. This medicine may interfere with some of the medicines used during surgery.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being treated with Apresoline.

Tell any other doctor, dentist or pharmacist who treats you that you are being treated with Apresoline.

Things to be careful of

If you are driving, operating machinery or doing jobs that require you to be alert shortly after having Apresoline, be careful until you know how this medicine has affected you.

This medicine may cause dizziness or light headedness in some people.

Be careful drinking alcohol after being treated with Apresoline. The combination could make your blood pressure fall further than usual, causing you to feel dizzy or light headed.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being treated with Apresoline.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them.

Tell your doctor if you notice any of the following side effects and they worry you:

dizziness or light headedness
fast or irregular heart beat (pounding, racing, skipping beats)
feeling anxious or agitated
headache
nausea (feeling sick) or vomiting
feeling generally unwell, loss of appetite or weight loss
diarrhoea
flushing of the skin
congested (blocked) nose
red, swollen or teary eyes
shaking or tremors
numbness or tingling in hands or feet

Tell your doctor immediately if you notice any of the following:

signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath or wheezing
painful or swollen joints, particularly if accompanied by skin rash, fever, persistent tiredness or chest pain
difficult or painful breathing
constant "flu-like" symptoms such as fever, sore throat, swollen glands, tiredness, lack of energy
unusual bruising or bleeding under the skin
yellow colour to skin or eyes
sudden decrease in the amount of urine or pain when passing urine; blood in the urine
swelling of feet or legs due to extra fluid
pain in the stomach or abdomen
depression or hallucinations (seeing things that aren't there)

The above side effects could be serious. You may need urgent medical attention.

Some side effects can only be found if your doctor does tests on your blood or urine.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

After being given Apresoline

Storage

The pharmacy is responsible for the appropriate storage of Apresoline.

The ampoules should be stored protected from light, where the temperature stays below 25°C.

Disposal

If you have any unused Apresoline, return it to the pharmacy. The pharmacy will dispose of any unused Apresoline.

Product description

What it looks like

Apresoline comes in a clear glass ampoule containing the active ingredient, hydralazine hydrochloride, in a dry powder form. Each pack contains 5 ampoules in a cardboard carton.

Ingredients

Each ampoule of Apresoline contains 20 mg of hydralazine hydrochloride. The ampoule contains no other ingredients.

Sponsor

Amdipharm Mercury (Australia) Pty Ltd
Level 9, 76 Berry Street
North Sydney, NSW 2060

Australian Registration Number:
AUST R 43190

Date of preparation:
This leaflet was revised on 3 April 2017.

Amdipharm Mercury (Australia) Pty Ltd is licensed to use the trademark Apresoline.

Published by MIMS July 2017

BRAND INFORMATION

Brand name

Apresoline

Active ingredient

Hydralazine hydrochloride

Schedule

1 Name of Medicine

Hydralazine hydrochloride.

2 Qualitative and Quantitative Composition

Each ampoule contains 20 mg hydralazine hydrochloride.

3 Pharmaceutical Form

Hydralazine hydrochloride is a white to yellowish odourless crystalline powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertensive crises, especially during late pregnancy (pre-eclampsia and eclampsia).

4.2 Dose and Method of Administration

Treatment with Apresoline for injection should always be carried out with caution and under strict medical surveillance (if possible in hospital).

Adult dosage.

The initial dose is 5 to 10 mg, administered by slow intravenous injection in order to avoid precipitous decreases in mean arterial pressure with a critical reduction in cerebral or uteroplacental perfusion. If it is necessary to repeat the injection, this should be done after an interval of 20 to 30 minutes, throughout which the blood pressure and heart rate should be monitored. A satisfactory response can be defined as a decrease in diastolic blood pressure to 90 to 100 mmHg.
Apresoline may also be given by continuous intravenous infusion, beginning with a flow rate of 200 to 300 micrograms/min. Maintenance flow rates must be determined individually and are usually within the range of 50 to 150 micrograms/min.

Instructions for use.

Prior to each injection, the contents of the ampoule should be completely dissolved in 1 mL water for injections. The freshly prepared solution should be used immediately. For the preparation of infusion solutions, this fresh solution should be diluted with sodium chloride intravenous infusion 9 mg/mL. Glucose infusion solutions are not compatible because contact between hydralazine and glucose causes the active substance to be rapidly broken down.
The product contains no antimicrobial preservative. Infusion of the reconstituted injection and of admixtures of the injection should be commenced as soon as possible after preparation in order to reduce microbiological hazards. Both the reconstituted injection and admixtures of the injection should be stored at 2°C to 8°C. Preparations not used within 24 hours of reconstitution should be discarded. Each vial is intended for single use in one patient only. Discard any unused portion.

Use in children.

Safety and efficacy of hydralazine have not been established in children. Apresoline is not recommended for paediatric use.

Renal and hepatic impairment.

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

4.3 Contraindications

Hypersensitivity to hydralazine or 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 constrictive pericarditis).
Isolated right ventricular heart failure due to pulmonary hypertension (cor pulmonale).
Dissecting aortic aneurysm.
Porphyria.

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 or provoke myocardial infarction. Hydralazine can cause anginal attacks and ECG changes indicative of myocardial ischaemia. Therefore, Apresoline must be used with caution in patients with suspected coronary artery disease. Patients with suspected or confirmed coronary artery disease should, be given Apresoline only under cover of a 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 postinfarction stabilisation phase has been achieved. Apresoline should not be used in heart failure.

Cerebrovascular disease.

Like all potent antihypertensives, Apresoline should be used with caution in patients suffering from cerebrovascular disease, since it can increase ischaemia.

Immune system.

Prolonged treatment with Apresoline (i.e. usually treatment for more than 6 months) may provoke an SLE-like syndrome, especially where dosages exceeding 100 mg daily are prescribed. In its mild form, this syndrome is reminiscent of rheumatoid arthritis (arthralgia, sometimes associated with fever, anaemia, leucopenia, thrombocytopenia and skin rash) and proves reversible after withdrawal of the medicine. In its more severe form it resembles acute SLE (similar manifestations as the milder form, plus pleurisy, pleural effusions and pericarditis; nervous system and renal involvement are rarer than in idiopathic lupus). Early detection and a timely diagnosis with appropriate therapy (treatment discontinuation and possibly long-term treatment with corticosteroids may be required to reverse the effects) 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 dosage and the longer the duration of the medication, and since they are also more common in slow acetylators, it is recommended that for maintenance therapy the lowest dosage that still proves effective 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 a greater risk of developing an SLE-like syndrome. In such patients every effort should therefore be made not to exceed a dosage of 100 mg daily; a careful watch should also be kept for clinical signs and symptoms suggestive of an SLE-like syndrome.
Rapid acetylators, by contrast, often respond inadequately even to dosages of 100 mg daily. In these patients, the dosage can be raised with only a slightly increased risk of an SLE-like syndrome.
During long-term treatment with Apresoline it is advisable to determine the antinuclear factors (ANF) and to carry out full blood count and urine analyses 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. A positive ANF titre requires that the physician carefully weighs the implications of the test results against the benefits of continued therapy with Apresoline. If overt clinical signs and symptoms develop, the medicine should be withdrawn at once. A complete blood count and ANF titre determination is indicated before and periodically during prolonged therapy with Apresoline 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.
Treatment with Apresoline may induce systemic vasculitis, including ANCA (antineutrophil cytoplasm antibody) positive vasculitis, 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 treatment in an intensive care unit. The syndrome is characterised by a fulminant course if left untreated, and may sometimes be fatal.

Nervous system.

Isolated cases of peripheral neuritis in the form of paraesthesia have been reported, which may respond to pyridoxine administration or medicine withdrawal.

Renal or hepatic impairment.

In patients with renal impairment (creatinine clearance < 30 mL/min or serum creatinine concentration > 2.5 mg/100 mL or 221 micromol/L) and in patients with hepatic dysfunction, the dose or the dosing interval has to be adapted according to the clinical response, in order to avoid accumulation of the "apparent" active substance (see Section 4.2 Dose and Method of Administration).

Haematological effects.

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

Skin.

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

Use during surgery.

Patients treated with Apresoline may show a fall in blood pressure when undergoing surgery. In such cases, one should not use adrenaline (epinephrine) to correct the hypotension, since it enhances the cardiac accelerating effects of hydralazine.

Use in the elderly.

No studies in the elderly have been performed. Concurrent hepatic and renal insufficiency should be taken into account (see Section 4.4 Special Warnings and Precautions for Use, Renal or hepatic impairment).

Paediatric use.

Safety and efficacy of hydralazine have not been established in children. Apresoline is not recommended for paediatric use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The effects of Apresoline are potentiated by other antihypertensive medicines (including vasodilators, calcium antagonists, ACE inhibitors, diuretics), tricyclic antidepressants, alcohol, anaesthetics, major tranquillisers, or any medicine exerting a central depressant action. In particular, 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, such as propranolol, metoprolol and other beta-blockers subject to a strong first pass effect, may increase their bioavailability. Downward dosage adjustment of these medicines may be required when they are given concomitantly with Apresoline.
Glucose infusion solutions are not compatible with Apresoline because contact between hydralazine and glucose causes the active substance to be rapidly broken down.
Adrenaline (epinephrine) enhances the cardiac accelerating effects of hydralazine. Patients taking Apresoline who develop hypotension should not be treated with sympathomimetics, e.g. adrenaline (epinephrine), as Apresoline can cause tachycardia, and sympathomimetics could enhance this (see Section 4.4 Special Warnings and Precautions for Use, Use during surgery).
There is potential for the hypotensive effect of Apresoline to be antagonised when used concomitantly with oestrogens or nonsteroidal anti-inflammatory drugs (NSAIDs).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of hydralazine on fertility in humans are not known.
(Category C)
Category C: drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Animal experiments have shown hydralazine, causing cleft palate and malformations of facial and cranial bones, is teratogenic in mice at oral doses equal to or greater than 20 mg/kg/day; a "no effect" dose has not been clearly established. Hydralazine was teratogenic in rabbits where oral doses equal to and greater than 75 mg/kg/day caused phalangeal defects. Hydralazine was not teratogenic in rats at oral doses up to 180 mg/kg/day. Embryolethality was observed in mice at doses equal to or greater than 20 mg/kg/day. Hydralazine was, however, not embryolethal in rats and rabbits at oral doses up to 180 and 60 mg/kg/day, respectively. Delayed ossification was observed in mice and rats at maternotoxic doses greater than 20 and 60 mg/kg/day, respectively, and reduced fetal weight was seen in mice at doses greater than 20 mg/kg/day.
Hydralazine is known to cross the placenta following intravenous administration and has been associated with fetal distress and fetal cardiac arrhythmia in the last trimester of pregnancy. In view of the possible teratogenic potential in humans, use of Apresoline in pregnancy before the third trimester should be avoided. The medicine should only be given in the third trimester after weighing the needs of the mother against the risk to the fetus.
Hydralazine passes into the breast milk. Alternatives to Apresoline should be considered in nursing mothers unless the benefits are considered to outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Apresoline may impair the patient's reactions especially at the start of treatment. Dizziness or hypotension may occur due to the established mechanism of action (see Section 4.8 Adverse Effects (Undesirable Effects)). It is therefore advisable to exercise caution when driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The unwanted effects listed below are derived from the use of both oral and parenteral hydralazine. Some of the unwanted effects such as tachycardia, palpitation, anginal symptoms, flushing, headache, dizziness, nasal congestion and gastrointestinal disturbances, are commonly seen at the start of treatment, especially if the dosage is raised rapidly. However, such reactions generally subside in the further course of treatment.
Frequency estimates: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000; not known: cannot be estimated from the available data.

Adverse drug reactions from multiple sources including clinical trials and spontaneous reports.

Blood and lymphatic system disorders.

Uncommon: anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura. Very rare: haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis.

Cardiac disorders.

Very common: tachycardia, palpitation. Common: angina pectoris, anginal symptoms. Uncommon: congestive heart failure.

Eye disorders.

Uncommon: increased lacrimation, conjunctivitis. Very rare: exophthalmos.

Gastrointestinal disorders.

Common: gastrointestinal disorder, diarrhoea, nausea, vomiting. Very rare: paralytic ileus, retroperitoneal fibrosis.

General disorders and administration site conditions.

Uncommon: pyrexia, malaise, oedema.

Hepatobiliary disorders.

Uncommon: jaundice, hepatomegaly, abnormal liver function sometimes in association with hepatitis. Not known: hepatosplenomegaly (usually associated with SLE-like symptoms).

Immune system disorders.

Common: positive test for ANF (see Section 4.4 Special Warnings and Precautions for Use, Immune system). Uncommon: SLE-like syndrome (see Section 4.4 Special Warnings and Precautions for Use, Immune system), hypersensitivity reactions such as pruritus, urticaria, vasculitis including pulmonary renal syndrome, eosinophilia, hepatitis.

Investigations.

Uncommon: weight decrease.

Musculoskeletal and connective tissue disorders.

Common: arthralgia, joint swelling, myalgia.

Nervous system disorders.

Very common: headache. Uncommon: dizziness. Very rare: peripheral neuropathy, polyneuropathy, paraesthesia (these unwanted effects may be reversed by administering pyridoxine), tremor.

Psychiatric disorders.

Uncommon: agitation, anorexia nervosa, anxiety. Very rare: depression, hallucinations.

Renal and urinary disorders.

Uncommon: proteinuria, increased plasma creatinine, haematuria sometimes in association with glomerulonephritis.
Very rare: acute renal failure, urinary retention.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, pleural pain, nasal congestion.

Skin and subcutaneous tissue disorders.

Uncommon: rash.

Vascular disorders.

Common: flushing, hypotension. Very rare: paradoxical pressor responses.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

The chief manifestations of overdosage 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, hypothermia and coma.

Management.

Severe hypotension may respond to placing the patient in the supine position with the feet raised. The effects of gross overdosage may be treated by the infusion of plasma expanders.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Hydralazine exerts its peripheral vasodilating effect through a direct relaxation of smooth muscle tissue in vascular resistance vessels, predominantly in the arterioles. The cellular mechanism of action responsible for this effect is not fully understood.
In hypertension, this effect results in decreased arterial blood pressure (diastolic more than systolic). A reflex action by the sympathetic nervous system compensates for this fall in blood pressure by increasing heart rate, stroke volume and cardiac output. Up to 75% of the therapeutic effect of hydralazine can be lost by this reflex action. To counteract the reflex action, hydralazine is often given in conjunction with a beta-blocker.
The preferential dilatation of arterioles, as compared with veins, minimises postural hypotension and promotes the increase in cardiac output. The peripheral vasodilatation is widespread but not uniform.
Splanchnic, coronary, cerebral, and renal blood flow increases unless the fall in blood pressure is very marked. Vascular resistance in the cutaneous and muscle beds is not consistently affected.
The use of Apresoline can result in sodium and fluid retention, producing oedema and reduced urinary volume. These unwanted effects are best prevented by concomitant administration of a diuretic.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

After intravenous administration of Apresoline no first pass effect occurs; acetylator status therefore has no influence on the plasma levels. In the plasma only small amounts of the free drug can be traced, the bulk circulating in conjugated form, i.e. mainly as pyruvic acid hydrazone. Only the so called "apparent" hydralazine, i.e. the sum of the free and conjugated hydralazine, can be measured reliably.
Hydralazine becomes bound to plasma proteins (chiefly albumin) to the extent of 88 to 90%. It is rapidly distributed in the body and displays a specific affinity for muscle tissue in the arterial walls. It crosses the placental barrier and also passes into the human milk.

Metabolism.

The pattern of the metabolites depends on the subject's acetylator and presumably hydroxylator status. Urinary excretion of NAc-HPZ (N-acetyl-hydrazine-phthalazinone), the main metabolite from the acetylation pathway, may be used to determine acetylator phenotype.
The plasma half-life generally ranges from 2 to 3 hours, but in rapid acetylators it is shorter, averaging 45 minutes. In patients with impaired renal function, the plasma half-life is prolonged to up to 16 hours at a creatinine clearance of < 20 mL/min.

Excretion.

Hydralazine and its metabolites are rapidly excreted by the kidney. The bulk of the hydralazine excreted is in the form of acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid; 2 to 14% is excreted as "apparent" hydralazine. Renal elimination may be impaired in patients of advanced age.

5.3 Preclinical Safety Data

Genotoxicity.

Hydralazine induces gene mutations, chromosomal aberrations and DNA damage in mammalian cells in vitro, as well as gene mutations in bacteria, yeast and Drosophila. The potential for similar effects in vivo has not been adequately reported.

Carcinogenicity.

Carcinogenicity studies in Swiss mice showed an increased incidence of pulmonary adenomas and adenocarcinomas when hydralazine was administered in the drinking water at concentrations of 312-1250 ppm (approximately 50-200 mg/kg/day); a "no effect" dose has not been established. A carcinogenicity study in rats dosed by gavage at 15, 30 and 60 mg/kg/day showed increases in the incidences of hepatic neoplasms in both sexes and of Leydig cell tumours in males.
In the absence of adequate information on the genotoxic activity of hydralazine in in vivo studies, the possibility that the carcinogenic effects of hydralazine may be related to its genotoxic activity cannot be ruled out. The extent to which these findings indicate a risk to humans is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiological studies have so far been insufficient to arrive at any conclusions.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Powder for Injection 20 mg in glass ampoules; 5 ampoules per pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Molecular formula: 1-hydrazinophthalazine hydrochloride (C₈H₈N₄.HCl).
Molecular weight: 196.64.
Hydralazine hydrochloride has a bitter saline taste. It is soluble 1 in 25 parts of water and 1 in 500 parts of alcohol; very slightly soluble in ether. A 2% solution in water has a pH of 3 to 4.

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