Consumer medicine information

Alphapress

Hydralazine hydrochloride

BRAND INFORMATION

Brand name

Alphapress

Active ingredient

Hydralazine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alphapress.

What is in this leaflet

This leaflet answers some common questions about ALPHAPRESS. 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 you taking ALPHAPRESS against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What ALPHAPRESS is used for;[0ol

ALPHAPRESS is used to lower high blood pressure, also known as hypertension. It is normally used together with other medicines for high blood pressure.

This medicine works by widening the blood vessels so that blood passes through them more easily. This helps to lower blood pressure.

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 reason.

There is not enough information to recommend the use of this medicine in children.

This medicine is available only with a doctor's prescription.

There is no evidence that this medicine is addictive.

Before you take ALPHAPRESS

When you must not take it

Do not take ALPHAPRESS if you have an allergy to:

  • any medicine containing hydralazine hydrochloride
  • 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

Do not take ALPHAPRESS if you have:

  • systemic lupus erythematosus (SLE)
  • certain heart conditions such as heart failure, narrowing of the valves in the heart or swelling around the heart
  • a very fast, irregular or pounding heart beat
  • a condition called dissecting aortic aneurysm where there is swelling and weakening of a large blood vessel
  • thyrotoxicosis (an overactive thyroid gland)

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Do not give this medicine to children. Safety and effectiveness in children have not been established.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take 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 medical conditions, especially the following:

  • heart failure, coronary heart disease such as angina or a recent heart attack, or any other heart problem
  • stroke or any other problems with poor blood flow to the brain
  • kidney problems
  • liver problems

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

Tell your doctor if you are pregnant or plan to become pregnant. ALPHAPRESS may affect your developing baby if you take it during pregnancy.

Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding or wish to breastfeed. The active ingredient in ALPHAPRESS passes into breast milk and there is a possibility that your baby may be affected.

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you start taking ALPHAPRESS.

Taking other medicines

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

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

  • medicines used to treat high blood pressure or heart conditions such as beta-blockers (e.g. propranolol, metoprolol); ACE inhibitors and calcium channel blockers
  • diuretics, also called fluid or water tablets
  • monoamine oxidase inhibitors and tricyclic antidepressants, which are medicines used to treat depression
  • medicines used to treat certain mental and emotional conditions such as schizophrenia
  • adrenaline, a medicine used in emergency situations or to treat a severe allergic reaction

These medicines may be affected by ALPHAPRESS or may affect how well it works. You may need 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 taking this medicine.

How to take ALPHAPRESS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

The usual starting dose is 25 mg twice a day.

Your doctor may increase your dose depending on how you respond to this medicine.

How to take it

Swallow the tablets with a glass of water.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ALPHAPRESS.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include having a very fast or irregular heart beat, chest pain, sweating, feeling sick, dizzy or faint.

While you are using ALPHAPRESS

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ALPHAPRESS.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, including dental surgery, tell your surgeon, anaesthetist or dentist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your pgoress can be checked. You may need to have tests to check your blood and kidneys.

Things you must not do

Do not take ALPHAPRESS to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how ALPHAPRESS affects you. This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness or light-headedness may be worse.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ALPHAPRESS.

This medicine helps most people with high blood pressure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • dizziness
  • headache
  • flushing
  • nausea (feeling sick), vomiting
  • diarrhoea
  • blocked nose
  • fast, irregular or pounding heart beat

The above list includes the more common side effects of your medicine. These side effects generally go away with continued treatment.

Tell your doctor as soon as possible if you notice any of the following:

  • severe pain in the stomach with bloating, gut cramps and vomiting
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • frequent signs of infection such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • tingling or numbness of the hands or feet
  • agitation, anxiety, depression, hallucinations

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • chest pain
  • wheezing or shortness of breath
  • skin rash, itching or hives
  • muscle aches, painful swollen joints
  • systemic lupus erythematosus (SLE)-like syndrome with symptoms such as joint pain, fever and skin rash
  • shortness of breath and swelling of the feet or legs due to fluid build-up
  • passing little urine or no urine

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell. Other side effects not listed above may also occur in some people.

After using ALPHAPRESS

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C. Protect from light.

Do not store ALPHAPRESS or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

ALPHAPRESS is available in 2 strengths:

  • 25 mg - scored, cream coloured tablet
  • 50 mg - pink tablet marked HE over 50 on one side and G on the other

Each bottle contains 100 tablets.

Ingredients

ALPHAPRESS contains either 25 mg or 50 mg of hydralazine hydrochloride as the active ingredient.

The tablets also contain the following inactive ingredients:

  • microcrystalline cellulose
  • pregelatinised maize starch
  • disodium edetate
  • sodium starch glycollate
  • colloidal anhydrous silica
  • purified talc
  • magnesium stearate
  • Opadry Pink OY-LS-34902 [50 mg strength only]

The 50 mg tablets also contain lactose and traces of sulfites.

The tablets are gluten free.

Manufacturer

ALPHAPRESS is made in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

ALPHAPRESS 25 - AUST R 17575

ALPHAPRESS 50 - AUST R 60380

This leaflet was prepared in
September 2019.

alphapress_cmi\sep19/01


Published by MIMS November 2019

BRAND INFORMATION

Brand name

Alphapress

Active ingredient

Hydralazine hydrochloride

Schedule

S4

 

1 Name of Medicine

Hydralazine hydrochloride.

2 Qualitative and Quantitative Composition

Each Alphapress tablet contains either 25 mg and 50 mg of hydralazine hydrochloride as the active ingredient.

Excipients of known effect.

Lactose monohydrate (50 mg only) and traces of sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alphapress 25: flat bevelled edged cream tablet with score mark on one side.
Alphapress 50: pink film coated normal convex tablet marked HE 50 on one side, G on reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension (drug resistant, moderate to severe).

As supplementary medication for use together with other antihypertensives such as beta-blockers and diuretics; the complementary mechanisms of action of such combined therapy enable the drugs to exert their antihypertensive effects at low doses. In addition, unwanted accompanying effects of the individual substances are either partially offset or even cancelled out.

4.2 Dose and Method of Administration

The dosage must always be adjusted to the individual requirements of the patient and the following recommendations adhered to.

Adults.

Treatment should begin with low doses of Alphapress which, depending on the patient's response, should be increased stepwise in order to achieve an optimal therapeutic effect and to avoid unwanted effects as far as possible.
Give Alphapress in a twice daily regimen; the usual starting dosage of 25 mg twice daily is generally sufficient. This dosage can be increased as required within the effective maintenance dosage range of 50 to 200 mg daily. However, the dose should not be increased above 100 mg daily without determining the acetylator phenotype (see Section 4.4 Special Warnings and Precautions for Use).

Children.

Safety and efficacy of hydralazine have not been established in children.

4.3 Contraindications

Known 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

Cardiac dysfunction.

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, it must be used with caution in patients with suspected coronary artery disease. Patients with suspected or confirmed coronary artery disease should therefore be given Alphapress 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 Alphapress.
Patients who have survived a myocardial infarction should not receive Alphapress until a postinfarction stabilisation phase has been achieved. Hydralazine should not be used in heart failure.

SLE-like syndrome with long-term use of oral hydralazine.

Prolonged treatment with hydralazine (i.e. usually treatment for more than 6 months) may provoke a systemic lupus erythematosus (SLE)-like syndrome, especially when dosages exceeding 100 mg daily are prescribed. In its mild form this syndrome is reminiscent of rheumatoid arthritis (arthralgia, sometimes associated with fever, anaemia, leucopoenia, thrombocytopenia and skin rash) and proves 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; 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 Alphapress 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 hydralazine. If overt clinical signs and symptoms develop, the drug should be withdrawn at once. 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 are also applicable if the patient develops arthralgia, fever, chest pain, persistent malaise, or other unexplained signs or symptoms.
Treatment with hydralazine may induce systemic vasculitis, including ANCA (anti-neutrophil 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.

Cerebrovascular disease.

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

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.

When undergoing surgery, patients treated with Alphapress 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.

Use in hepatic or renal impairment.

In patients with renal impairment (creatinine clearance less than 30 mL/minute or serum creatinine concentration greater than 2.5 mg/100 mL or 221 micromol/L) and in patients with hepatic dysfunction, the dose or the dosing interval must be adapted according to the clinical response, in order to avoid accumulation of the 'apparent' active substance.

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, Use in hepatic or renal impairment).

Paediatric use.

Safety and efficacy of hydralazine have not been established in children. Alphapress 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 hydralazine are potentiated by other antihypertensives medicines (including vasodilators, calcium antagonists, ACE inhibitors, diuretics), tricyclic antidepressants, anaesthetics and major tranquillisers, as well as the consumption of alcohol, or any medicine exerting a central depressant action.
Administration of Alphapress shortly before or after diazoxide may give rise to marked hypotension.
Monoamine oxidase inhibitors (MAOIs) should be used with caution in patients receiving Alphapress.
Concurrent administration of Alphapress 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 drugs may be required when they are given concomitantly with Alphapress.
Adrenaline (epinephrine) enhances the cardiac accelerating effects of hydralazine. Patients taking Alphapress who develop hypotension should not be treated with sympathomimetics, e.g. adrenaline (epinephrine), as Alphapress can cause tachycardia, and sympathomimetics could enhance this (see Section 4.4 Special Warnings and Precautions for Use, Use during surgery).
There is a potential for the hypotensive effect of hydralazine to be antagonised when used concomitantly with oestrogens or non-steroidal 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)
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 crosses the placenta and following intravenous administration has been associated with foetal distress and foetal cardiac arrhythmia in the last trimester of pregnancy. In view of the possible teratogenic potential in humans, use of Alphapress in pregnancy before the third trimester should be avoided. The drug should only be given in the third trimester after weighing the needs of the mother against the risk to the foetus.
 Hydralazine passes into human breast milk. Alternatives to hydralazine should be considered in breastfeeding women unless the benefits are considered to outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Alphapress, especially at the start of treatment, may impair the patient's reactions. 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 machines.

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 listed below, 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: ≥ 10%; common: ≥ 1 to < 10%; uncommon: ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare: < 0.01%; not known: cannot be estimated from the available data.

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: flushing, hypotension, anginal pectoris, anginal symptoms. Uncommon: oedema, congestive heart failure. Very rare: paradoxical pressor responses.

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 hepatic 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, SLE-like syndrome with long-term use of oral hydralazine), hypersensitivity reactions. Uncommon: SLE-like syndrome (see Section 4.4 Special Warnings and Precautions for Use, SLE-like syndrome with long-term use of oral hydralazine), 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.

Central and peripheral nervous system.

Very common: headache. Uncommon: dizziness. Very rare: Peripheral neuropathy, polyneuropathy, paraesthesiae (these unwanted effects may be reversed by administration of 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.

Miscellaneous.

Uncommon: fever.

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

Symptoms.

The chief manifestations are cardiovascular disorders such as pronounced tachycardia and hypotension, which are accompanied by nausea, dizziness and sweating, 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 and coma.

Treatment.

Activated charcoal may be administered. Treatment is supportive and symptomatic care. 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

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 β-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 increase unless the fall in blood pressure is very marked. Vascular resistance in the cutaneous and muscle beds is not consistently affected.
The use of hydralazine 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.

Hydralazine is rapidly and completely absorbed after oral administration. 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. Peak plasma concentrations are reached within 1 hour in most cases.
Orally administered hydralazine undergoes a dose dependent first-pass effect (systemic availability 26 to 55%), this first-pass effect being dependent on the individual's acetylator status. In response to the same dose, slow acetylators show higher ‘apparent’ plasma hydralazine levels than rapid acetylators.
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 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. Hydralazine persists for longer periods at its site of action, arteriolar smooth muscle, which enables twice daily dosing. In patients with impaired renal function, the plasma half-life is prolonged to up to 16 hours at creatinine clearance of less than 20 mL/minute. Renal elimination may be impaired in patients of advanced age.

Excretion.

Hydralazine and its metabolites are rapidly excreted by the kidney. Within 24 hours after an oral dose, approximately 80% of it can be recovered in the urine. 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.

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 to 1250 ppm (approximately 50 to 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 incidence of hepatic neoplasms in both sexes and 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

The tablets contain the following inactive ingredients: colloidal anhydrous silica, disodium edetate, magnesium stearate, microcrystalline cellulose, pregelatinized maize starch, purified talc, sodium starch glycollate and Opadry Pink OY-LS-34902 (proprietary ingredient number: 2948) (50 mg strength only).

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

Container type: bottle (HDPE).
Pack sizes: 60 (25 mg only), 90 and 100 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

A white or almost white, crystalline powder, soluble in water, slightly soluble in alcohol, very slightly soluble in methylene chloride. It melts at about 275°C with decomposition.
Chemical name: 1-hydrazinophthalazine hydrochloride.
Molecular formula: C8H8N4,HCl.
Molecular weight: 196.6.

Chemical structure.


CAS number.

304-20-1.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes