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

The posology of intravenous glyceryl trinitrate should be adjusted to achieve the desired clinical response.

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 use of glyceryl trinitrate in children is not recommended, as the safety and efficacy of glyceryl trinitrate has not yet been established in this population.

Elderly population

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

Hepatic/renal impairment

Additional dose adjustments in patients with severe hepatic insufficiency or severe renal failure may be necessary and require additional monitoring.

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.

Method of administration

Not to be given by bolus injection.

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

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

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

Infusion Rate

(ml/hour or microdrops/min)

Dosage (micrograms/min) by concentration of admixture

100 micrograms/ml

200 micrograms/ml

300 micrograms/ml

400 micrograms/ml

(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 ampoule in 500ml)

(4 x 5 ml ampoule in 500ml)

(6 x 5 ml ampoule in 500ml)

(8 x 5 ml ampoule in 500ml)

6

12

18

24

30

36

42

48

54

60

66

72

78

84

90

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

30

60

90

120

150

180

210

240

270

300

330

360

390

420

450

40

80

120

160

200

240

280

320

360

400

440

480

520

560

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 or to any of the excipients listed in section 6.1

2. Hypotensive shock or uncorrected hypovolaemia

3. Increased intracranial pressure

4. Constrictive pericarditis 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 (see section 4.5)

7. Cerebral haemorrhage

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 (see section 4.5).

4.4. Special warnings and precautions for use

Not to be given by bolus injection.

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

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.

Severe hypotension may occur with even small doses of Glyceryl trinitrate.

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.

Excipient Information

Glyceryl Trinitrate Sterile Concentrate contains propylene glycol and ethanol (see section 2).

Each 5 ml ampoule of Glyceryl Trinitrate Sterile Concentrate contains 2639.2 mg of anhydrous ethanol, which is equivalent to less than 66 ml of beer or 27 ml of wine. Each 10 ml ampoule of Glyceryl Trinitrate Concentrate contains 5278.4 mg of anhydrous ethanol which is equivalent to less than 132 ml of beer or 53 ml of wine. Administration of a 10 ml ampoule of Glyceryl Trinitrate Sterile Concentrate over 125 min (i.e. at an infusion rate of 400 microgram/min that is higher than normally recommended but may be necessary during some surgical procedures, see section 4.2) to an adult weighing 70 kg would result in exposure to 75.4 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 12.6 mg/100 ml. For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml. Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, particularly in young children with low or immature metabolic capacity. The ethanol content in this preparation is likely to affect children and neonates. These effects may include somnolence and changes in behaviour. The ethanol may also affect their ability to concentrate and take part in physical activities.

The ethanol content in this medicinal product should be carefully considered in the following patient groups who may be at higher risk of ethanol-related adverse effects:

• Pregnant or breast-feeding women (see section 4.6)

• Patients with liver disease

• Patients with epilepsy.

• Patients suffering from alcoholism.

The amount of ethanol in this medicinal product may impair the ability to drive or use machines (see section 4.7). The amount of ethanol in this medicinal product may alter the effects of other medicines. The effects of ethanol may be reduced when the dose is administered more slowly using an infusion rate of 10-200 microgram/min (see section 4.2).

A 24 hour infusion of Glyceryl Trinitrate Sterile Concentrate at the maximum recommended infusion rate of 200 microgram/min administered to an adult weighing 70 kg would result in a propylene glycol exposure of 36.8 mg/kg/day. A propylene glycol exposure of ≥50 mg/kg/day might result in case of a 24 hour infusion at an infusion rate that is higher than the maximum recommended infusion rate (e.g. 300 microgram/min) or administration to a lower weight patient (e.g. 50 kg adult). Medical monitoring, including measurement of the osmolar and/or anion gap, is required in patients with impaired renal and/or hepatic function who receive ≥50 mg/kg/day of propylene glycol. Various adverse effects attributed to propylene glycol have been reported, such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction. Prolonged administration of propylene glycol-containing products, as well as co-administration with other substrates of alcohol dehydrogenase (e.g. ethanol), increase the risk of propylene glycol accumulation and toxicity, especially in patients with liver or kidney impairment. Propylene glycol doses of ≥1 mg/kg/day may induce serious adverse effects in neonates, while doses of ≥50 mg/kg/day may induce adverse effects in children less than 5 years old. Administration of ≥50 mg/kg/day of propylene glycol to pregnant or lactating women should only be considered on a case by case basis (see section 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

Phosphodiesterase inhibitors

Sildenafil (Viagra) 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 Trinitrate Sterile 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 (see section 4.3).

Hypotensive Agents and Tricyclic Anti-depressants

Glyceryl trinitrate may potentiate the action of other hypotensive drugs, and the hypotensive and anticholinergic effects of tricyclic anti-depressants.

Soluble guanylate cyclase (GC) stimulators

Concurrent use of Glyceryl trinitrate and a soluble guanylate cyclase stimulator such as riociguat is contraindicated due to potentiation of hypotensive effects (see section 4.3).

Heparin

Glyceryl trinitrate may interfere with the anticoagulant effect of heparin and can induce heparin resistance.

Analgesics

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

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of glyceryl trinitrate during pregnancy has not been demonstrated and therefore it should not be used unless considered essential by the physician.

The ethanol and propylene glycol content of Glyceryl Trinitrate Sterile Concentrate should be taken into account for pregnant women (see section 4.4). Propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, however, it may reach the foetus. Administration of ≥50 mg/kg/day propylene glycol to pregnant women should only be considered on a case by case basis.

Breast-feeding

The safety of glyceryl trinitrate during lactation has not been demonstrated and therefore it should not be used unless considered essential by the physician.

The ethanol and propylene glycol content of Glyceryl Trinitrate Sterile Concentrate should be taken into account in women who are breast-feeding (see section 4.4). Propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, however, it has been found in milk and may be orally absorbed by a nursing infant. Administration of ≥50 mg/kg/day propylene glycol to lactating women should only be considered on a case by case basis.

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. Patients should refrain from driving or using machines until they know that the medicinal product does not negatively affect these abilities.

The amount of ethanol in Glyceryl Trinitrate may impair the ability to drive or use machines (see section 4.4).

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

Bradycardia, palpitations

Vascular disorders:

Common

Orthostatic hypotension

Uncommon

Circulatory collapse (sometimes accompanied by bradyarrhythmia and syncope).

Not known

Hypotension, flushing

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and Symptoms

Overdosage usually results in hypotension and tachycardia.

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

Treatment

The symptoms may be readily reversed by discontinuing treatment; if hypotension persists, raising the foot of the bed or compression bandaging of the patient's legs and the use of vasoconstrictors such as intravenous methoxamine or phenylephrine are recommended.

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