SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Glyceryl Trinitrate 5 mg/ml Sterile Concentrate.

2.    Qualitative and Quantitative Composition

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

For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Concentrate for solution for infusion

Ampoules containing a clear, practically colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Surgery: Glyceryl trinitrate is indicated for:

1.    the rapid control of hypertension during cardiac surgery.

2.    reducing blood pressure and maintaining controlled hypotension during surgical procedures.

3.    controlling myocardial ischaemia during and after cardiovascular surgery.

Unresponsive Congestive Heart Failure: Glyceryl trinitrate may be used to treat unresponsive congestive heart failure secondary to acute myocardial infarction.

Unstable Angina: Glyceryl trinitrate may be used to treat unstable angina that is refractory to treatment with beta-blockers and sublingual nitrates.

4.2    Posology and method of administration

Posology

Adults: The dose of glyceryl trinitrate should be adjusted to meet the individual needs of the patient. The recommended dose range is 10-200 microgram/min, although up to 400 microgram/min may be necessary during some surgical procedures.

Paediatric Population: The safety and efficacy of glyceryl trinitrate has not yet been established in children.

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

Surgery: A starting dose of 25 microgram/min is recommended for the control of hypertension, or to produce hypotension during surgery. This may be increased by increments of 25 microgram/min at 5 minute intervals until the blood pressure is stabilised. Doses between 10-200 microgram/min are usually sufficient during surgery, although doses of up to 400 microgram/min have been required in some cases. The treatment of perioperative myocardial ischaemia may be started with a dose of 15-20 microgram/min, with subsequent increments of 10-15 microgram/min until the required effect is obtained.

Unresponsive Congestive Heart Failure: The recommended starting dose is 20-25 microgram/min. This may be decreased to 10 microgram/min, or increased in steps of 20-25 microgram/min every 15-30 minutes until the desired effect is achieved.

Unstable Angina: An initial dose of 10 microgram/min is recommended with increments of 10 microgram/min being made at approximately 30 minute intervals according to the needs of the patient.

Administration

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.

Glyceryl Trinitrate Sterile Concentrate must be mixed under aseptic conditions immediately after opening.

Prepared admixtures should be given by intravenous infusion or with the aid of a syringe pump to ensure a constant rate of infusion.

During administration of glyceryl trinitrate there should be close haemodynamic monitoring of the patient.

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.

For an example of an admixture preparation, see Section 6.6.

For full details it is advisable to consult the following dosage chart.

(ml/hour or	100 micrograms/ml	200 micrograms/ml	300 micrograms/ml	400 micrograms/ml
microdrops/min)	(1 x 10 ml ampoule in 500 ml)	(2 x 10 ml ampoules in 500 ml)	(3 x 10 ml ampoules in 500 ml)	(4 x 10 ml ampoules in 500 ml)
	(2 x 5 ml ampoules in 500ml)	(4 x 5 ml ampoules in 500ml)	(6 x 5 ml ampoules in 500ml)	(8 x 5 ml ampoules in 500ml)
6	10	20	30	40
12	20	40	60	80
18	30	60	90	120
24	40	80	120	160
30	50	100	150	200
36	60	120	180	240
42	70	140	210	280
48	80	160	240	320
54	90	180	270	360
60	100	200	300	400
66	110	220	330	440
72	120	240	360	480
78	130	260	390	520
84	140	280	420	560
90	150	300	450	600

1 ml = 60 paediatric microdrops = 20 standard drops

4.3 Contraindications

To those who have or are:

1.    Hypersensitive to glyceryl trinitrate and nitrates

2.    Hypotensive or hypovolaemic

3.    Increased intracranial pressure

4.    Constrictive periocarditis and pericardial tamponade

5.    Severe anaemia and arterial hypoxaemia.

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

7.    Cerebral haemorrhage

8.    Angina caused by hypertrophic obstructive cardiomyopathy.

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.

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

Not to be given by bolus injection.

4.5 Interaction with other medicinal products and other forms of interaction

Sildenafil (Viagra):    sildenafil and other phosphodiesterase inhibitors has known

effects on the nitric oxide/cGMP pathway, and has been shown to potentiate the hypotensive effects of nitrates such as Glyceryl TrinitrateSterile Concentrate. A severe and possibly dangerous fall in blood pressure may occur. This can result in collapse, unconsciousness and may be fatal. Such use, therefore, is contraindicated. 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.

Glyceryl trinitrate may potentiate the action of other hypotensive drugs, and the

hypotensive and anticholinergic effects of tricyclic anti-depressants.

Glyceryl trinitrate may slow the metabolism of morphine-like analgesics.

4.6. Pregnancy and Lactation

The safety of Glyceryl Trinitrate during pregnancy and lactation has not been demonstrated and therefore it should not be used in these situations unless considered essential by the physician.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Undesirable effects frequencies are defined as: very common (>1/10), common (>1/100 <1/10), uncommon (>1/1,000 <1/100), rare (>1/10,000 <1/1,000) or very rare (<1/10,000), not known (cannot be estimated from the available data).

During administration of Glyceryl Trinitrate Sterile Concentrate, the following undesirable effects may be observed:

Nervous system disorders very common: headache

common: dizziness (including dizziness postural), somnolence

Cardiac disorders common: tachycardia,

uncommon: enhanced angina pectoris symptoms.

Not known: Palpitations

Vascular disorders

common: orthostatic hypotension ,

uncommon: circulatory collapse (sometimes accompanied by bradyarrhythmia and syncope).

Not known: Flushing, Hypotension

Gastrointestinal disorders uncommon: nausea, vomiting, very rare: heartburn.

Skin and subcutaneous tissue disorders:

uncommon: allergic skin reactions (e.g. rash,) allergic contact dermatitis. not known: dermatitis exfoliative, Rash Generalised.

General disorders and administration site conditions common: asthenia

uncommon: pruritus, burning, erythema and irritation.

Investigations

Not known: Heart rate increase

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor, and excessive perspiration.

During treatment with Glyceryl Trinitrate Sterile Concentrate, a temporary hypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease this may lead to a myocardial hypoxia

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:

Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

4.9 Overdose

Overdosage usually results in hypotension and tachycardia and can be reversed by elevating the legs or decreasing or terminating the infusion. In severe cases of overdosage, intravenous administration of methoxamine or phenylephrine is recommended.

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC-Code: C0IDA02

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 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

Glyceryl Trinitrate is widely distributed in the body with an apparent volume of distribution of 200 L in adult male subjects, 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 500ng/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.

5.3. Preclinical Safety Data

Not applicable.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Ethanol

Propylene Glycol Water for Injections

6.2. Incompatibilities

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.

6.3. Shelf Life

As packaged for sale 36 months.

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 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.

6.5. Nature and Contents of Container

Clear, Type I Glass Ampoules - 5ml and 10ml in packs of 5 ampoules.

6.6 Special precautions for disposal

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.

Glyceryl Trinitrate Sterile Concentrate must be mixed under aseptic conditions immediately after opening.

Admixtures are prepared by replacing a given volume of infusion vehicle with an equal volume of the product to produce the final infusion solution. For admixture storage, refer to Section 6.4.

Example of admixture preparation

To obtain an admixture of glyceryl trinitrate at a concentration of 100 micrograms/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 micrograms/min can be obtained by giving 60 ml of this admixture per hour. This is equivalent to a drip rate of 20 standard drops per minute or 60 paediatric microdrops per minute. At this drip 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. For single use only.

7. MARKETING AUTHORISATION HOLDER

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04515/0006

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/12/1985 / 14/09/2001

10 DATE OF REVISION OF THE TEXT

08/08/2016