Consumer medicine information

DBL Glyceryl Trinitrate Concentrate Injection

Glyceryl trinitrate

BRAND INFORMATION

Brand name

DBL Glyceryl Trinitrate Concentrate Injection

Active ingredient

Glyceryl trinitrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Glyceryl Trinitrate Concentrate Injection.

SUMMARY CMI

DBL™ Glyceryl Trinitrate Concentrate Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being treated with DBL Glyceryl Trinitrate Concentrate Injection?

DBL Glyceryl Trinitrate Concentrate Injection contains the active ingredient glyceryl trinitrate. DBL Glyceryl Trinitrate Concentrate Injection is used to relax the muscles surrounding blood vessels (arteries and veins) and so helps more blood and oxygen reach the heart. It is also used to control or lower the blood pressure during some surgical procedures.

For more information, see Section 1. Why am I being treated with DBL Glyceryl Trinitrate Concentrate Injection? in the full CMI.

2. What should I know before treatment with DBL Glyceryl Trinitrate Concentrate Injection?

Do not start treatment if you have ever had an allergic reaction to glyceryl trinitrate, any medicine or food containing nitrates, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before treatment with DBL Glyceryl Trinitrate Concentrate Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DBL Glyceryl Trinitrate Concentrate Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is DBL Glyceryl Trinitrate Concentrate Injection given?

Your doctor will decide how much DBL Glyceryl Trinitrate Concentrate Injection you will receive. This depends on your condition and other factors, such as your age and weight.

More instructions can be found in Section 4. How is DBL Glyceryl Trinitrate Concentrate Injection given? in the full CMI.

5. What should I know during treatment with DBL Glyceryl Trinitrate Concentrate Injection?

Things you should do
  • Remind any doctor, nurse, dentist or pharmacist who is treating you that you are being treated with DBL Glyceryl Trinitrate Concentrate Injection.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how DBL Glyceryl Trinitrate Concentrate Injection affects you.
  • This medicine may cause dizziness, light-headedness, fainting and headache in some people. If this occurs do not drive or do anything else that could be dangerous.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • If you drink alcohol, dizziness or light-headedness may be worse.

For more information, see Section 5. What should I know during treatment with DBL Glyceryl Trinitrate Concentrate Injection? in the full CMI.

6. Are there any side effects?

Common side effects include headache and dizziness. Less common side effects include: rapid or irregular heart beat, bleeding easily, swelling, nausea, vomiting or abdominal pain, pins and needles, tiredness, sleepiness, state of confusion, seizure, muscle twitching or restlessness, muscle weakness, shoulder, neck and upper body pain, abdominal tenderness of the right upper quadrant, dry mouth, frequent urination, shortness of breath, vision problems.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

DBL™ Glyceryl Trinitrate Concentrate Injection

Active ingredient(s): glyceryl trinitrate (GLIS-er-ile tri-NITE-rate)


Consumer Medicine Information (CMI)

This leaflet provides important information about using DBL Glyceryl Trinitrate Concentrate Injection. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about being treated with DBL Glyceryl Trinitrate Concentrate Injection.

Where to find information in this leaflet:

1. Why am I being treated with DBL Glyceryl Trinitrate Concentrate Injection?
2. What should I know before treatment with DBL Glyceryl Trinitrate Concentrate Injection?
3. What if I am taking other medicines?
4. How is DBL Glyceryl Trinitrate Concentrate Injection given?
5. What should I know during treatment with DBL Glyceryl Trinitrate Concentrate Injection?
6. Are there any side effects?
7. Product details

1. Why am I being treated with DBL Glyceryl Trinitrate Concentrate Injection?

DBL Glyceryl Trinitrate Concentrate Injection contains the active ingredient glyceryl trinitrate. Glyceryl trinitrate belongs to a group of medicines called nitrates or vasodilators.

DBL Glyceryl Trinitrate Concentrate Injection is used to relax the muscles surrounding blood vessels (arteries and veins) and so helps more blood and oxygen reach the heart.

It is also used to control or lower the blood pressure during some surgical procedures.

Your doctor may have prescribed glyceryl trinitrate for another reason. Ask your doctor if you have any questions about why glyceryl trinitrate has been prescribed for you.

Glyceryl trinitrate is not addictive.

2. What should I know before treatment with DBL Glyceryl Trinitrate Concentrate Injection?

Warnings

You must not be given DBL Glyceryl Trinitrate Concentrate Injection if:

  • you are allergic to:
    - glyceryl trinitrate, or any of the ingredients listed at the end of this leaflet.
    - any medicine or food containing nitrates
    Symptoms of an allergic reaction to glyceryl trinitrate 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.
    Always check the ingredients to make sure you can use this medicine.
  • you have any of the following conditions:
    - low blood pressure
    - increased pressure in the head (such as a recent head injury or stroke)
    - disease of the heart muscle or swelling around the heart
    - reduced red blood cells and iron stores (anaemia) or a lack of oxygen in the blood
    - an abnormality of haemoglobin, part of your red blood cells, responsible for carrying oxygen.
  • you are taking the following medicines:
    - phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil used to treat impotence in men and/or for treating high blood pressure in the lungs in men and women.
    - riociguat used to treat high blood pressure in your lungs.

If you use these medicines together with DBL Glyceryl Trinitrate Concentrate Injection, your blood pressure may fall to a dangerously low level.

If you are not sure whether you should be given DBL Glyceryl Trinitrate Concentrate Injection, talk to your doctor or pharmacist.

Check with your doctor if you:

  • have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  • have or have had any other medical conditions especially the following:
    - liver disease
    - kidney disease
    - a recent heart attack or any heart condition for which you already use a nitrate vasodilator drug such as patches or sprays containing a nitrate
    - heart disease caused by poor blood flow in the arteries of the heart
    - any other heart condition
    - any lung condition
    - closed angle glaucoma
  • take any medicines for any other condition

If you have not told your doctor or pharmacist about any of the above, tell them before you are given DBL Glyceryl Trinitrate Concentrate Injection.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Glyceryl trinitrate is not recommended for use during pregnancy. If there is a need to consider glyceryl trinitrate during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Glyceryl trinitrate is not recommended while you are breastfeeding. It is not known if glyceryl trinitrate is excreted into breast-milk.

Use in Children

Glyceryl trinitrate is not recommended for use in children, as there is not enough information on its effects in children.

3. What if I am taking other medicines?

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

Some medicines and DBL Glyceryl Trinitrate Concentrate Injection may interfere with each other and affect how they work. These include:

  • aspirin and other non-steroidal anti-inflammatory medicines
  • morphine, a medicine used for pain
  • some medicines for depression such as tricyclic antidepressants
  • some medicines that block nerve conduction to muscles such as anticholinergics
  • heparin, a medicine used to prevent blood clots
  • some medicines used to treat high blood pressure or heart problems
  • ergotamine, methysergide and dihydroergotamine; medicines used to prevent or treat migraine headaches
  • tranquillisers, medicines used to treat some mental illnesses
  • some medicines for impotence such as sildenafil
  • riociguat used to treat high blood pressure in your lungs.

These medicines may be affected by glyceryl trinitrate or may affect how well it works. You may need different amounts of your medicines, or you may need to take or use different medicines. Your doctor or pharmacist will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DBL Glyceryl Trinitrate Concentrate Injection.

4. How is DBL Glyceryl Trinitrate Concentrate Injection given?

How much is given

Due to variations in the response of individual patients to the drug, the dose of glyceryl trinitrate varies. Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your age or weight.

How it is given

DBL Glyceryl Trinitrate Concentrate Injection must be diluted and given as a slow infusion or ‘drip’ injection into your veins (intravenously). It should not be mixed with other drugs.

If you are given too much DBL Glyceryl Trinitrate Concentrate Injection

As DBL Glyceryl Trinitrate Concentrate Injection is given to you in hospital under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience severe side effects tell your doctor immediately.

Symptoms of a glyceryl trinitrate overdose include the side effects listed below in Section 6. Are there any side effects? but are usually of a more severe nature.

Ask your doctor or pharmacist if you have any concerns.

If you think that you have been given too much DBL Glyceryl Trinitrate Concentrate Injection, you may need urgent medical attention.

You should immediately:

  • contact your doctor, or
  • phone the Poisons Information Centre
  • (by calling 13 11 26), or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with DBL Glyceryl Trinitrate Concentrate Injection?

Things you should do

Remind any doctor, nurse, dentist or pharmacist who is treating you that you are being treated with DBL Glyceryl Trinitrate Concentrate Injection.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DBL Glyceryl Trinitrate Concentrate Injection affects you.

DBL Glyceryl Trinitrate Concentrate Injection may cause dizziness, light-headedness, fainting and headache in some people.

Make sure you know how glyceryl trinitrate affects you before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, dizziness or light-headedness may be worse.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
General
  • headache
  • dizziness
Speak to your doctor if you have any of these common side effects and they worry you.
Mostly these are short-lived.

Less common side effects

Less common side effectsWhat to do
Heart and blood related
  • rapid or slow or irregular heart beat
  • bleeding easily
  • swelling
Stomach related
  • nausea, vomiting or abdominal pain
Nervous system related
  • pins and needles
  • tiredness
  • sleepiness, state of confusion
  • seizure
Muscle related
  • muscle twitching or restlessness
  • muscle weakness
Pain or discomfort in your body
  • shoulder, neck and upper body pain
  • abdominal tenderness of the right upper quadrant
Mouth related
  • dry mouth
Urinary related
  • frequent urination
Respiratory related
  • shortness of breath
Eye related
  • vision problems
Call your doctor straight away if you notice any of these side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop treatment with any of your medicines.

7. Product details

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

What DBL Glyceryl Trinitrate Concentrate Injection contains

Active ingredient
(main ingredient)
glyceryl trinitrate
Other ingredients
(inactive ingredients)
ethanol absolute
propylene glycol
water for injections

DBL Glyceryl Trinitrate Concentrate Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Do not use this medicine if you are allergic to any of these ingredients.

What DBL Glyceryl Trinitrate Concentrate Injection looks like

DBL Glyceryl Trinitrate Concentrate Injection is a clear, practically colourless solution (Aust R 16341).

DBL Glyceryl Trinitrate Concentrate Injection is available in the following strength and pack:

  • 50mg in 10mL, 5 x 10mL ampoules

How is DBL Glyceryl Trinitrate Concentrate Injection stored

DBL Glyceryl Trinitrate Concentrate Injection will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Who distributes DBL Glyceryl Trinitrate Concentrate Injection

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in June 2022.

™ Trademark

© Pfizer Australia Pty Ltd 2022

Published by MIMS August 2022

BRAND INFORMATION

Brand name

DBL Glyceryl Trinitrate Concentrate Injection

Active ingredient

Glyceryl trinitrate

Schedule

S4

 

1 Name of Medicine

Glyceryl trinitrate.

2 Qualitative and Quantitative Composition

Each millilitre of DBL Glyceryl Trinitrate Concentrate Injection contains 5 milligrams of glyceryl trinitrate, absolute ethanol and propylene glycol in Water for Injections.

Excipient with known effect.

Ethanol absolute.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Glyceryl trinitrate is a white to pale yellow, thick, flammable, explosive liquid. It is slightly soluble in water, and soluble in acetone, alcohol, carbon disulphide, chloroform, dichloromethane, ether, ethyl acetate, glacial acetic acid and methanol.
DBL Glyceryl Trinitrate Concentrate Injection is a sterile, clear, practically colourless solution for intravenous infusion after dilution.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Glyceryl Trinitrate Concentrate Injection is indicated for:
Control of blood pressure in perioperative hypertension, i.e. hypertension associated with surgical procedures, especially cardiovascular procedures, such as the hypertension seen during intratracheal intubation, anaesthesia, skin incision, sternotomy, cardiac bypass and in the immediate post-surgical period.
Congestive heart failure associated with acute myocardial infarction.
Treatment of angina pectoris in patients who have not responded to recommended doses of organic nitrates and/or a beta-blocker.
Production of controlled hypotension during neurosurgical and orthopaedic surgical procedures.

4.2 Dose and Method of Administration

Dosage.

The initial dosage of glyceryl trinitrate when nonabsorbing tubing is used should be 5 microgram/min delivered through an infusion pump capable of exact and constant delivery of the drug. Subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen. Initial titration should be in 5 microgram/min increments, with increases every 3 to 5 minutes until some response is noted. If no response is seen at 20 microgram/min, increments of 10 and later 20 microgram/min can be used. Once a partial blood pressure response is observed, the dose increase should be reduced and the interval between dosage increments should be lengthened.
There is no fixed optimum dose of glyceryl trinitrate. Due to variations in the responsiveness of individual patients to the drug, each patient must be titrated to the desired level of haemodynamic function. Therefore, continuous monitoring of physiologic parameters (e.g. blood pressure, heart rate and pulmonary capillary wedge pressure) must be performed to achieve the correct dose. Adequate systemic blood pressure and coronary perfusion pressure must be maintained.

Method of administration.

Not for direct intravenous injection.
DBL Glyceryl Trinitrate Concentrate Injection is a concentrated potent drug which must be diluted in 5% glucose or 0.9% sodium chloride prior to its infusion.
DBL Glyceryl Trinitrate Concentrate Injection should not be admixed with other drugs.

Glyceryl trinitrate for injection must be mixed under aseptic conditions immediately after opening.
Due to the problem of glyceryl trinitrate absorption by polyvinyl chloride (PVC) tubing, glyceryl trinitrate concentrate infusion should be used with the least absorptive infusion tubing (i.e. non-PVC tubing) available. Administration sets which incorporate polyethylene are recommended.

Initial dilution.

To obtain a final concentration of 100 microgram/mL glyceryl trinitrate, aseptically transfer the contents of one DBL Glyceryl Trinitrate Concentrate Injection 50 mg/10 mL ampoule into a glass infusion bottle containing 490 mL of either 5% glucose or 0.9% sodium chloride. Invert the glass parenteral bottle several times following admixture to ensure uniform dilution of glyceryl trinitrate.

Maintenance dilution.

It is important to consider the fluid requirements of the patient as well as the expected duration of infusion in selecting the appropriate dilution of DBL Glyceryl Trinitrate Concentrate Injection.
After the initial dosage titration, the concentration of the admixture solution may be increased, if necessary, to limit fluids given to the patient. The glyceryl trinitrate concentration should not exceed 400 microgram/mL.
If the glyceryl trinitrate concentration is adjusted, it is imperative to flush or replace the infusion set before a new concentration is utilised. Depending on the infusion set used and the flow rate, it could take from 1 to 2 minutes to 3 hours for the new concentration to reach the patients if the infusion set is not flushed or replaced.
When stored in glass containers, the diluted solution is physically and chemically stable for up to 40 hours when stored below 25°C and up to seven days under refrigeration.
However, to avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation of the solution. Infusion should be completed within 24 hours and any residue discarded.
Dosage is affected by the type of containers and administration sets used (see Section 4.4 Special Warnings and Precautions for Use).
Although the usual starting adult dose range reported in clinical studies was 25 microgram/min or more, these studies used PVC administration sets. Doses need to be reduced if nonabsorbing tubing is used.

Dosage adjustments.

Some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure (e.g. angina patients without other complications) may be hypersensitive to the effects of glyceryl trinitrate and may respond fully to doses as small as 5 microgram/min. These patients require especially careful titration and monitoring.
The posology of intravenous glyceryl trinitrate should be adjusted to achieve the desired clinical response. Additional dose adjustments in patients with severe hepatic insufficiency or severe renal failure may be necessary and require additional monitoring.

Paediatric population.

Not recommended for use in children.

Elderly population.

See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

DBL Glyceryl Trinitrate Concentrate Injection is contraindicated in the following cases:
Hypersensitivity to glyceryl trinitrate or a known idiosyncratic reaction to organic nitrates.
Hypersensitivity to any other component of this product.
Hypotension or uncorrected hypovolaemia, as the use of DBL Glyceryl Trinitrate Concentrate Injection, in such states, could produce severe hypotension or shock.
Increased intracranial pressure (e.g. head trauma or cerebral haemorrhage).
Constrictive pericarditis and pericardial tamponade.
Severe anaemia, angina caused hypertrophic obstructive cardiomyopathy or arterial hypoxaemia.
Acute circulatory failure (shock, circulatory collapse).
Pronounced hypotension (systolic blood pressure < 90 mmHg).
Cardiogenic shock, in so far as sufficiently high left ventricular end-diastolic pressure is not ensured by intra-aortal counterpulsation or positive inotropic medicines.
Concomitant administration of glyceryl trinitrate with phosphodiesterase inhibitors used for the treatment of erectile dysfunction or pulmonary arterial hypertension, such as sildenafil which has been shown to potentiate the vasodilatory effects of glyceryl trinitrate, resulting in severe hypotension.
As a supplementary medication for obstructive cardiomyopathy, especially if it is associated with aortic or mitral stenosis or constrictive pericarditis; as it has been shown that nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Concomitant administration of a soluble guanylate cyclase (GC) stimulator, such as riociguat due to potentiation of hypotensive effects.

4.4 Special Warnings and Precautions for Use

Not for direct intravenous injection.
DBL Glyceryl Trinitrate Concentrate Injection must be diluted in 5% glucose or 0.9% sodium chloride prior to infusion (see Section 4.2 Dose and Method of Administration). The administration set used will affect the amount of glyceryl trinitrate delivered to the patient (see below; see Section 4.2 Dose and Method of Administration).
Glyceryl trinitrate readily migrates into many plastics. To avoid absorption of glyceryl trinitrate into plastic parenteral solution containers, DBL Glyceryl Trinitrate Concentrate Injection should only be diluted and stored in glass parenteral solution bottles.
Filters should be avoided as some absorb glyceryl trinitrate.

Forty to eighty percent of the total amount of glyceryl trinitrate in the final diluted solution for infusion is absorbed by the polyvinyl chloride (PVC) tubing of the intravenous administration sets currently in general use. The higher rates of absorption occur when flow rates are low, glyceryl trinitrate concentrations are high, and the administration set is long.
Although the rate of loss is highest during the early phase of infusion (when flow rates are lowest), the loss is neither constant nor self-limiting; consequently no simple calculation or correction can be performed to convert the theoretical infusion rate (based on the concentration of the infusion solution) to the actual delivery rate.
Due to the problem of glyceryl trinitrate absorption by polyvinyl chloride (PVC) tubing, glyceryl trinitrate concentrate infusion should be used with the least absorptive infusion tubing (i.e. non-PVC tubing) available. Administration sets which incorporate polyethylene are recommended.

Use with caution in the following circumstances.

Severe hypotension may occur with even small doses of glyceryl trinitrate.
Glyceryl trinitrate should only be used in acute myocardial infarction for treating definite left ventricular failure. Careful haemodynamic monitoring must be observed during infusion of glyceryl trinitrate in patients with acute myocardial infarction to avoid a sudden fall in arterial blood pressure and reflex tachycardia, which might reduce coronary perfusion and increase myocardial oxygen demand, thereby extending the area of ischaemic tissue injury.
Dosage must be carefully titrated to avoid the significant risk of a precipitous fall in blood pressure, particularly in patients with severe coronary or cerebral arteriosclerosis. Profound hypotension and bradycardia have been reported with sublingual, topical and intravenous glyceryl trinitrate.
Excessive hypotension, especially for prolonged periods of time, must be avoided because of the possible deleterious effects on the brain, heart, liver and kidney from impaired perfusion and the attendant risk of ischaemia, thrombosis and altered functions of these organs. Paradoxical bradycardia and increased angina pectoris may accompany glyceryl trinitrate induced hypotension. Patients with low pulmonary wedge pressure are especially sensitive to the hypotensive effects of glyceryl trinitrate. As a fall in pulmonary capillary wedge pressure precedes the onset of arterial hypotension, the pulmonary capillary wedge pressure is a useful guide to safe titration of glyceryl trinitrate dosage.
Glyceryl trinitrate should be used with caution in patients predisposed to closed angle glaucoma.
Administration of vasodilators to hypertensive patients has been suspected of causing acute blindness.
Long-term or repeated administration of organic nitrates may induce tolerance or cross tolerance to glyceryl trinitrate or other organic nitrates. Larger doses of glyceryl trinitrate may be required with chronic sublingual administration or when a patient is receiving oral nitrate vasodilators. Although clinical tolerance has not been observed during intravenous infusion of glyceryl trinitrate, the possibility of this occurring should be kept in mind.
Nitrate dependence is a potentially serious problem. Death, myocardial infarction, coronary spasm and chest pain syndromes have been documented in industrial workers who leave the work environment for several days after exposure to glyceryl trinitrate and nitroglycol. There is some clinical evidence of nitrate dependence in patients with both angina and congestive heart failure.
Although withdrawal syndromes have not been reported to occur following intravenous infusion of glyceryl trinitrate for up to 9 days, it may be necessary to carefully taper therapy in patients with proven coronary arteriosclerosis who have received prolonged high dose infusions of the drug.
Arterial oxygen tension decreases after administration of glyceryl trinitrate in normal subjects and in patients with coronary artery disease. Hypoxaemia occurs as a result of increased pulmonary ventilation perfusion mismatch but the clinical significance of this effect is dependent on the severity of the underlying pulmonary disease and pre-existing hypoxaemia. Caution should be observed in patients with severe ischaemic heart disease as a decrease in available oxygen may oppose the antianginal effect of glyceryl trinitrate. Glyceryl trinitrate may worsen hypoxaemia in patients with pulmonary disease or cor pulmonale.
Methaemoglobinaemia has been reported in association with glyceryl trinitrate therapy. Methaemoglobinaemia may be clinically significant, especially in the presence of methaemoglobin reductase deficiencies or in congenital M haemoglobulin variants.
Glyceryl trinitrate should be used with caution in patients with malnutrition, hypothermia, hypothyroidism or hyperthyroidism.
Glyceryl trinitrate concentrate contains propylene glycol which can lead to hyperosmolality, haemolysis and lactic acidosis.

Use in hepatic/renal impairment.

Glyceryl trinitrate should be used with caution in patients with severe liver or renal disease.

Use in the elderly.

Elderly patients may be particularly sensitive to the side effects of glyceryl trinitrate. If side effects occur, the dose should be reduced.

Paediatric use.

The use of glyceryl trinitrate in children is not recommended, as its safety and effectiveness in children have not been established.

Effects on laboratory tests.

Nitrates may interfere with the Zlatkis-Zak colour reaction, causing a false report of decreased serum cholesterol.
Serum triglyceride assays that rely on glycerol oxidase may give falsely elevated serum triglyceride concentrations as a result of the propylene glycol content of this product.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant use with alcohol and levodopa may cause hypotension due to an enhanced vasodilatory effect of glyceryl trinitrate. The risk of syncope may also be enhanced.
Information on potential interaction with other medicines is poorly documented. Caution should be observed if other medicines are given concomitantly during infusion of glyceryl trinitrate as an interaction may adversely affect the haemodynamic response to the drug. Careful haemodynamic monitoring is essential.
Infusion of glyceryl trinitrate increases the duration of pancuronium induced neuromuscular blockade. This clinical observation has been supported by studies in the cat, however, glyceryl trinitrate did not prolong neuromuscular blockade induced by succinylcholine and d-tubocurarine. The mechanism of the interaction between glyceryl trinitrate and pancuronium is unknown.
Caution should be observed when morphine and glyceryl trinitrate are administered concurrently. One patient who received four 3 mg doses of intravenous morphine sulphate during a 24 hour period with intravenous glyceryl trinitrate became unarousable, eventually responding to nalorphine. The possibility that intravenous glyceryl trinitrate slows morphine metabolism in this patient has been suggested.
As ergot alkaloids may precipitate angina, patients being treated with glyceryl trinitrate for angina should avoid ergot alkaloids if at all possible.
Tricyclic antidepressants, anticholinergic agents, vasodilators such as hydralazine, minoxidil, prazosin and antihypertensive agents (including calcium antagonists, beta-blockers, diuretics and ACE inhibitors), major tranquillisers and opioid analgesics may potentiate the hypotensive effect of glyceryl trinitrate. Caution should, therefore, be observed when any of these medicines are given concomitantly with glyceryl trinitrate. Dosage adjustment may be required in these circumstances.
Glyceryl trinitrate may potentiate the action of other hypotensive drugs, and the hypotensive and anticholinergic effects of tricyclic anti-depressants.
Concomitant use of phosphodiesterase inhibitors used for the treatment of erectile dysfunction or pulmonary arterial hypertension, such as sildenafil with glyceryl trinitrate is contraindicated. A severe and possibly dangerous fall in blood pressure may occur. This can result in collapse, unconsciousness and may be fatal. If a patient treated with these drugs for erectile dysfunction or pulmonary arterial hypertension needs a rapidly effective nitrate, he/she should be closely monitored (see Section 4.3 Contraindications).
Concomitant use of a soluble guanylate cyclase (GC) stimulator, such as riociguat with glyceryl trinitrate is contraindicated due to potentiation of hypotensive effect (see Section 4.3 Contraindications).
Aspirin and other non-steroidal anti-inflammatory drugs may diminish the therapeutic response to glyceryl trinitrate.
The effects of noradrenaline may be decreased when it is used concurrently with glyceryl trinitrate.
Concurrent use of sympathomimetics may reduce the antianginal effects of nitrates. Nitrates may counteract the pressor effects of sympathomimetics, possibly resulting in hypotension.
The anticoagulant effect of heparin may be decreased in patients receiving intravenous glyceryl trinitrate. The solvent propylene glycol may be responsible for this effect. Patients should, therefore, be monitored to avoid inadequate anticoagulation. If intravenous glyceryl trinitrate therapy is discontinued in patients receiving heparin, a reduction in heparin dosage may be necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Lower doses of glyceryl trinitrate did not affect fertility in rats, but doses up to 230 milligrams/kg/day caused moderate to severe testicular degeneration and/or atrophy, with severe to complete aspermatogenesis.
(Category B2)
Category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
Animal reproduction studies have not been conducted with glyceryl trinitrate. It is also not known whether glyceryl trinitrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Glyceryl trinitrate should be given to a pregnant woman only if clearly needed.
It is not known whether glyceryl trinitrate or its metabolites are excreted into breast milk. Caution should be exercised if there is a need to administer glyceryl trinitrate to a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. Patients should refrain from driving or using machines until they know that the medicinal product does not negatively affect these abilities.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions to glyceryl trinitrate are generally dose related; almost all the reported reactions are the result of its vasodilatory activity.
The most frequent adverse reaction in patients treated with glyceryl trinitrate is headache, which occurs in approximately 2% of patients and is dose dependent. Other adverse reactions occurring in less than 1% of patients are the following: tachycardia, nausea, vomiting, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness and abdominal pain. Hypotension and bradycardia (see Section 4.4 Special Warnings and Precautions for Use) have been reported with intravenous glyceryl trinitrate. Decreased arterial oxygen tension has also been reported.
Severe arterial hypotension with bradycardia has been reported in patients who received intravenous glyceryl trinitrate within the first 24 hours after myocardial infarction; these effects were reversed by discontinuing the drug and elevating the lower extremities.
Adverse reactions to the solvents in DBL Glyceryl Trinitrate Concentrate Injection may occur. Alcohol intoxication has been reported in patients receiving high dose intravenous infusions. The propylene glycol content may lead to hyperosmolarity.
The following additional adverse reactions have been reported with the oral and/or topical use of glyceryl trinitrate: cutaneous flushing, weakness and occasionally drug rash or exfoliative dermatitis, hypertension, methaemoglobinaemia, postural hypotension and syncope on assuming upright posture, withdrawal syndrome, e.g. increased frequency of angina attack, blurred vision, cyanosis (rarely), fainting/ lightheadedness and anaphylaxis.

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.

Overdosage of glyceryl trinitrate may result in severe hypotension, transient headache and reflex tachycardia.
Methaemoglobinaemia has been reported in accidental overdosage (see Section 4.4 Special Warnings and Precautions for Use).

Treatment.

Patients should be treated by elevating the legs and decreasing or temporarily terminating the infusion until the patient's condition stabilises. Since the duration of the haemodynamic effects following glyceryl trinitrate administration is quite short, additional corrective measures are usually not required. However, if further therapy is indicated, administration of an intravenous alpha-adrenergic agonist (e.g. dopamine, methoxamine or phenylephrine) should be considered.
Methaemoglobinaemia may be treated with intravenous methylene blue at a dose of 1 to 2 milligrams/kg. Oxygen and assisted respiration may be required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia). In New Zealand call 0800 764 766.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Glyceryl trinitrate, an organic nitrate, is a vasodilator. Its principal pharmacological action is the relaxation of vascular smooth muscle. Glyceryl trinitrate produces a dose related dilation of both arterial and venous beds. Venous dilation predominates over dilation of the arterioles. Dilation of the postcapillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (pre-load). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). Glyceryl trinitrate also dilates the coronary arteries, although this effect is short lived.
Myocardial oxygen consumption or demand (as measured by the pressure rate product, tension time index and stroke work index) is decreased by both the arterial and venous effects of glyceryl trinitrate, and a more favourable supply demand ratio can be achieved.
Therapeutic doses of intravenous glyceryl trinitrate reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or an increased heart rate decreases diastolic filling time.
Glyceryl trinitrate reduces elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and systemic vascular resistance. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure.
Cardiac index may be increased, decreased or unchanged. Patients with elevated left ventricular filling pressure and systemic vascular resistance values in conjunction with a depressed cardiac index are likely to experience an improvement in cardiac index. Alternatively, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced by intravenous glyceryl trinitrate.

5.2 Pharmacokinetic Properties

Distribution.

Glyceryl trinitrate is widely distributed in the body with an apparent volume of distribution of 200 litres in adult male subjects. In smooth muscle cells the nitrate group is cleaved to inorganic nitrite and then to nitric oxide (thought to be responsible for glyceryl trinitrate's vasodilator effect).

Metabolism.

Glyceryl trinitrate also undergoes hydrolysis in plasma and is rapidly hydrolysed in the liver by glutathione organic nitrate reductase to dinitrates and mononitrates. It is also metabolised by enzymes in the blood.
Glyceryl trinitrate has a short half-life estimated at 1 to 4 minutes. This results in a low plasma concentration after intravenous infusion. A therapeutic effect is apparent within 1 to 2 minutes of intravenous administration, while the duration of action following a single intravenous dose of glyceryl trinitrate is about 3 to 5 minutes.
At plasma concentrations of between 50 and 500 nanogram/mL, glyceryl trinitrate is approximately 60% bound to plasma proteins, while its metabolites 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate are approximately 60% and 30% bound, respectively. The activity and half-life of the dinitrate metabolites are not well characterised. However, in animal studies, the vasodilator effects of glyceryl trinitrate were 10 to 14 times greater than those of its dinitrate metabolites. Glyceryl mononitrate, the principal metabolite, is inactive. The dinitrates are metabolised further to inactive mononitrates, and are metabolised ultimately to glycerol and carbon dioxide.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies were undertaken with glyceryl trinitrate.

Carcinogenicity.

Glyceryl trinitrate, given in the diet to rats at doses up to 1% caused an increase in the incidence of hepatic cholangiofibrosis, hepatocellular carcinomas and/or neoplastic nodules and Leydig cell tumours in the testis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol absolute, propylene glycol, water for injections.

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

DBL Glyceryl Trinitrate Concentrate Injection is available in glass ampoules in the following strength:
50 mg glyceryl trinitrate/10 mL (cartons contain 5 ampoules).

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

Chemical structure.

The chemical structure of glyceryl trinitrate is:
Its chemical formula is C3H5N3O9, molecular weight is 227.1. The chemical name of glyceryl trinitrate is propane-1,2,3-triol trinitrate.

CAS number.

CAS registry number is 55-63-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes