Hospira UK Ltd

Glyceryl Trinitrate 5 mg/ml Sterile Concentrate.

1 ml of solution contains 5 mg glyceryl trinitrate. Each 5 ml and 10 ml ampoules contains 25 mg and 50 mg glyceryl trinitrate respectively.

1 ml of solution also contains 0.699 ml of ethanol and 0.043 ml propylene glycol

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (Sterile Concentrate).

Ampoules containing a clear, practically colourless solution.

Surgery: Glyceryl trinitrate is indicated for the prompt control of hypertension during cardiac surgery.

It may also be used for the production and maintenance of controlled hypotension during surgical procedures.

Glyceryl trinitrate may be given for the control of myocardial ischaemia both during and following cardiovascular surgery.

Unresponsive Congestive Cardiac Failure Secondary to Acute Myocardial Infarction: Glyceryl trinitrate may be used in patients presenting with unresponsive congestive heart failure secondary to acute myocardial infarction.

Unstable Angina: Glyceryl trinitrate infusion may be used to reduce myocardial oxygen demand in proportion to the reduction in pre- and after-load. It may be indicated for the control of anginal episodes in patients with unstable angina who do not respond to standard treatment and/or beta-blockers.

Posology

Elderly Population

There is no evidence that a posology adjustment is required in the elderly.

Paediactric Population

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

Surgery

For the control of hypertensive episodes or to produce hypotension during surgery the recommended starting dose is 25 microgram/min increasing in steps of 25 microgram/min at 5 minute intervals until the desired drop in blood pressure is achieved. Although most patients respond to doses between 10-200 microgram/min, doses up to 400 microgram/min have been required during some surgical procedures. In the treatment of perioperative myocardial ischaemia, the recommended starting dose is 15-20 microgram/min increasing in steps of 10-15 microgram/min until the desired effect is achieved.

Unresponsive Congestive Cardiac Failure Secondary to Acute Myocardial Infarction

The recommended starting dose is 20-25 microgram/min which can be decreased to 10 microgram/min or increased in steps of 20-25 microgram/min at 15-30 minute intervals until the desired effect is achieved.

Unstable Angina

The recommended starting dose is 10 microgram/min increasing in steps of 5-10 microgram/min at approximately 30 minute intervals.

Method of Administration

Intravenous Infusion: Glyceryl Trinitrate Sterile Concentrate is a concentrated, potent drug which must be diluted prior to its infusion. (see Section 6.6 Instructions for use and handling).

Dosage: The recommended dose range is 10-200 microgram/min, although larger doses than this have been used. During some surgical procedures, doses of up to 400 microgram/min may be required. During administration of glyceryl trinitrate there should be close haemodynamic monitoring of the patient.

The posology of glyceryl trinitrate i.v. 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.

To those who have or are:

1. Hypersensitive to glyceryl trinitrate and nitrates

2. Hypotension or hypovolaemic shock

3. Increased intracranial pressure

4. Constrictive pericarditis and pericardial tamponade

5. Severe anaemia and arterial hypoxaemia.

6. Taking sildenafil or other phosphodiesterase inhibitors used for the treatment of erectile dysfunction or pulmonary arterial hypertension.

7. Cerebral hemorrhage

8. Angina caused by hypertrophic obstructive cardiomyopathy.

9 Concomitant administration of a soluble guanylate cyclase (GC) stimulator, such as riociguat due to potentiation of hypotensive effects.

Warnings

Glyceryl Trinitrate Sterile Concentrate contains propylene glycol which can lead to lactic acidosis. It is recommended that the use of this preparation be restricted to not more than three successive days.

Precautions

Glyceryl Trinitrate Sterile Concentrate should not be administered to patients known to be hypersensitive to organic nitrates, nor should it be given to patients with uncorrected hypovolaemia, severe anaemia or cerebral haemorrhage or hypotension.

Glyceryl trinitrate should be used with caution in patients presenting with malnutrition, hypothyroidism, severe hypothermia, or severe impairment of hepatic and/or renal function.

Evidence is not available to demonstrate the safety of glyceryl trinitrate for intracoronary injection.

Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms). Similarly, caution in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.

Glyceryl Trinitrate Sterile Concentrate should be used with caution in patients predisposed to closed angle glaucoma.

Not to be given by bolus injection.

There is no information available regarding the effects of glyceryl trinitrate on the ability to drive and operate machinery.

If dizziness, weakness or cardiac symptoms are experienced, the patient should be advised not to drive or use machinery.

In terms of frequency of classification of adverse effects the following convention was used: Very common ≥ 1/10, common ≥ 1/100 and <1/10, uncommon ≥ 1/1000 and <1/100, rare ≥ 1/10,000 and <1/1000, very rare <1/10,000. Not known: cannot be estimated from the data available.

Adverse reactions to organic nitrates which have been reported include:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Overdosage usually results in hypotension and tachycardia and can be reversed by elevating the legs, decreasing or terminating the infusion or if necessary, compression bandaging of the patient's legs. In severe cases of overdosage, intravenous administration of methoxamine or phenylephrine may be necessary.

Vomiting, restlessness, syncope, cyanosis, coldness of the skin, impairment of respiration, bradycardia, psychosis and methemoglobinaemia may also occur.

Methemoglobinemia should be treated by intravenous methylene blue. Oxygen and assisted respiration may be required.

Glyceryl trinitrate, an organic nitrate, is a vasodilator. The principal pharmacological action of glyceryl trinitrate is the relaxation of vascular smooth muscle. Glyceryl trinitrate produces, in a dose-related manner, dilation of both arterial and venous beds. Dilatation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (pre-load).

Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension time index and stroke work index) is decreased by both 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 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 slightly 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.

Glyceryl trinitrate is widely distributed in the body and is rapidly metabolised to dinitrates and mononitrates, with a short half-life estimated at 1-4 minutes. This results in a low plasma concentration after intravenous infusion. Glyceryl trinitrate is also well absorbed from the gastro-intestinal tract, but it is not known if it is distributed into milk.

At plasma concentrations of between 50 and 500 ng/ml, the binding of glyceryl trinitrate to plasma proteins is approximately 60% and 30% respectively. The plasma half-life of glyceryl trinitrate is about 1-4 minutes. Glyceryl mononitrate which is inactive, is the principal metabolite.

There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Ethanol

Propylene glycol

Water for Injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6, Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.

Glyceryl Trinitrate Sterile Concentrate is incompatible with polyvinylchloride (PVC) and severe losses of glyceryl trinitrate (over 40%) may occur if this material is used. Contact with polyvinylchloride bags should be avoided. Polyurethane also induces a loss of the active ingredient. No other drug should be admixed with this medicinal product.

As packaged for sale: 3 years.

Once opened: see section 6.4, Special precautions for storage.

Prior to first use: Do not store above 25°C. Keep container in the outer carton.

Open ampoules of glyceryl trinitrate should be used immediately and any unused portion discarded.

In use:

Following dilution in either 0.9% sodium chloride or 5% dextrose injection solutions in glass containers, chemical and physical in-use stability has been demonstrated for 7 days at both 18°C and 4°C.

Following dilution in 5% dextrose solution in polycarbonate or polypropylene syringes at concentrations of 1 mg or 4 mg per ml protected from light, chemical and physical in-use stability has been demonstrated for 72 hours at room temperature.

However, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not use if the solution is discoloured.

Clear, Type I glass ampoules – 5 ml and 10 ml in packs of 5 ampoules.

Not all pack sizes may be marketed.

Glyceryl Trinitrate Sterile Concentrate is a concentrated, potent drug which must be diluted in Dextrose (5%) Injection BP or Sodium Chloride (0.9%) Injection BP prior to its infusion.

Example of admixture preparation.

To obtain an admixture of GTN at a concentration of 100 microgram/ml add 10 ml (containing 50 mg glyceryl trinitrate) to 490 ml of infusion vehicle to give a final volume of 500 ml.

A dosage of 100 microgram/min can be obtained by giving 60 ml of the admixture per hour. This is equivalent to a drip rate of 20 standard drops per minute or 60 microdrops per minute. At this drop rate the mixture provides enough solution for an infusion time of 8 hours 20 minutes.

Compatible with commonly employed infusion solutions, Sodium Chloride (0.9%) Injection and Dextrose (5%) Injection.

Compatible with glass infusion bottles and rigid infusion packs made of polyethylene.

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

UK

PA 437/12/1

Date of first authorisation: 1^st October 1987

Date of last renewal: 1^st October 2007

04/2017