SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nitronal®

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Glyceryl trinitrate 1 mg/ml.

3 PHARMACEUTICAL FORM

Solution for infusion.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

1.    Unresponsive congestive heart failure, including that secondary to acute myocardial infarction.

2.    Refractory unstable angina pectoris and coronary insufficiency, including Prinzmetal’s angina.

3.    Control of hypertensive episodes and / or myocardial ischaemia during and after cardiac surgery. For the induction of controlled hypotension for surgery.

4.2 Posology and method of administration

For intravenous use. Nitronal® should be administered by means of a microdrip set infusion pump or similar device which permits maintenance of constant infusion rate.

Adults and the elderly - the dose should be titrated against the individual

clinical response.

1.    Unresponsive congestive heart failure. The normal dose range is 10-100 micrograms / minute administered as a continuous intravenous infusion with frequent monitoring of blood pressure and heart rate. The infusion should be started at the lower rate and increased cautiously until the desired clinical response is achieved. Other haemodynamic measurements are extremely important in monitoring response to the drug: These may include pulmonary capillary wedge pressure, cardiac output and precordial electrocardiogram depending on the clinical picture.

2.    Refractory unstable angina pectoris. An initial infusion rate of 10-15 micrograms / minute is recommended; this may be increased cautiously in increments of 5-10 micrograms until either relief of angina is achieved, headache prevents further increase in dose, or the mean arterial pressure falls by more than 20 mm Hg.

3.    Use in surgery. An initial infusion rate of 25 micrograms / minute is recommended; this should be increased gradually until the desired systolic arterial pressure is attained. The usual dose is 25-200 micrograms / minute.

Children - Not recommended for use in children.

4.3 Contraindications

Hypersensitivity to nitrates or any of the excipients.

Acute circulatory failure (shock, circulatory collapse)

Hypotensive shock,

Severe hypotension (systolic blood pressure below 90 mm Hg)

Arterial hypoxaemia,

Uncorrected hypovolaemia and angina caused by hypertrophic obstructive cardiomyopathy.

Cardiogenic shock, unless intra-aortic counterpulsation or positively inotropic drugs ensure an adequately high left-ventricular end-diastolic pressure

Severe anaemia

Toxic pulmonary oedemaConcomitant administration of phosphodiesterase inhibitors used for the treatment of erectile dysfunction or pulmonary arterial hypertension (section 4.5), can cause a considerable increase in the hypotensive effect and the resulting severe side effects (e.g. syncopes, paradoxical myocardial ischaemia). Therefore these drugs should not be used at the same time as Nitronal.

Cerebral haemorrhage and conditions associated with increased intracranial pressure (further elevation of the blood pressure has so far been observed only in association with high-dose IV administration of glyceryl trinitrate)

4.4 Special warnings and precautions for use

Caution should be exercised in patients with severe liver or renal disease, hypothermia, hypothyroidism.

Nitronal® should not be given by bolus injection.

Nitronal contains glucose monohydrate (49mg/ml). This should be considered if Nitronal is to be administered to patients with diabetes mellitus.

Glyceryl Trinitrate 1 mg/ml solution for infusion should be administered using polyethylene or polytetrafluorethylene tubings. Use of polyvinylchloride tubings may lead to a considerable loss of active substance due to adsorption.

Caution should be exercised when glyceryl trinitrate is administered to patients with:

-    hypertrophic obstructive cardiomyopathy, constrictive pericarditis and pericardial tamponade

-    Low filling pressures arising from conditions including acute myocardial infarction, and left ventricular failure. A reduction of the systolic blood pressure below 90 mm Hg must be avoided in such situations.

-    aortic and/or mitral stenosis

-    a tendency to orthostatic disturbances of circulatory regulation

-    In volume depleted patients, adequate volume replacement is required at the start of treatment.

4.5 Interaction with other medicinal products and other forms of interaction

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

It may also slow the metabolism of morphine-like analgesics.

The hypotensive effects of glyceryl trinitrate solution for infusion are potentiated by concurrent administration of

-    phosphodiesterase inhibitors used for the treatment of erectile dysfunction or pulmonary arterial hypertension. A severe and possibly dangerous fall in blood pressure may occur. This can result in collapse, unconsciousness and may be fatal. Such use is therefore contra-indicated (section 4.3) 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.

-    other vasodilators, B-blockers, calcium antagonists, neuroleptics, alcohol and sapropterin

If used concomitantly with dihydroergotamine, glyceryl trinitrate solution for infusion may lead to an increase in the DHE level and thus potentiate its hypertensive action.

When heparin and glyceryl trinitrate are used simultaneously, the effects of heparin are reduced. The heparin dosage must be adjusted accordingly while closely monitoring blood coagulation parameters. After discontinuation of glyceryl trinitrate, blood coagulation may be considerably reduced (sharp increase in the PTT), which may necessitate a reduction of the heparin dose.

In patients previously treated with organic nitrates, e.g. isosorbide dinitrate, isosorbide-5-mononitrate, a higher dose of glyceryl trinitrate may be necessary to achieve the desired haemodynamic effect.

4.6 Fertility, pregnancy and lactation

Fertility

Animal studies did not indicate harmful effects with respect to fertility. However, the relevance of these animal findings to man is unknown.

Pregnancy

For glyceryl trinitrate no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Lactation

It is unknown if glyceryl trinitrate or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue/abstain from breast-feeding or to discontinue/abstain from glyceryl trinitrate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Even when used as directed, this drug may affect the ability to drive or operate machinery.

This can occur in particular at the beginning of the treatment, with an increase of the dosage, when changing the medicinal product or when used in combination with alcohol.

4.8 Undesirable effects

Adverse reactions are listed below in descending order by frequency of occurrence.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common	(> 1/10)
Common	(> 1/100 to < 1/10)
Uncommon	(> 1/1,000 to < 1/100)
Rare	(> 1/10,000 to < 1/1,000)
Very rare	(< 1/10,000)
Not known	(cannot be estimated from the available data)
Blood and lymphatic system disorders Very rare: Methaemoglobinaemia Psychiatric disorder Very rare: Restlessness Nervous system disorders Very common: Headache*, Common: Dizziness, Drowsiness Uncommon: Syncope Very rare: Cerebral ischaemia** Cardiac disorders

Common: Tachycardia

Uncommon:_Enhanced angina pectoris symptoms, Bradycardia, Cyanosis, Cardiac disorders

Vascular disorders

Common: Orthostatic hypotension*

Uncommon: Facial flushing, Circulatory collapse

Gastrointestinal disorders Uncommon: nausea, vomiting

Respiratory, thoracic and mediastinal disorders Very rare: Impairment of respiration***

Skin and subcutaneous tissue disorders Very rare: Exfoliative dermatitis, Drug rash

General disorders and administration site conditions

Common: Asthenia

Not known: drug tolerance****

Not known: Diaphoresis

Investigations

Common: Blood pressure decreased*

*Particularly upon initiation of therapy and following an increase in dose.

**Glyceryl trinitrate-induced hypotension may cause cerebral ischaemia.

***During the administration of Nitronal®, a transient hypoxaemia may occur due to relative redistribution of the blood flow in hypoventilated alveolar regions, which, in patients with coronary heart disease, may lead to ischaemia.

****The development of tolerance and the occurrence of cross tolerance to other nitro compounds have been described. In order to avoid attenuation or loss of effect, high continuous dosage should be avoided.

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

Symptoms of overdose

Signs and symptoms of overdose are generally similar to the described adverse reactions: e.g. drop in blood pressure with orthostatic regulatory disturbances, reflex tachycardia and headaches, weakness, dizziness, somnolence, flush, nausea, vomiting and diarrhoea may occur.

At high doses (more than 20 mg/kg body-weight) methaemoglobinemia, cyanosis, dyspnoea and tachypnoea must be anticipated owing to nitrite ions formed during the metabolism of glyceryl trinitrate.

At very high doses an increase in intracranial pressure with cerebral symptoms may occur.

At chronic overdosage increased methaemoglobin levels were measured of which the clinical relevance is controversial.

Treatment in the event of overdose

In the case of overdose, the patient’s clinical status including vital signs and mental status should be assessed and supportive treatment of the cardiovascular and respiratory systems provided as clinically indicated or as recommended by the national poisons centre, where available.

In the event of mild hypotension, passive elevation of the patient’s legs and/or lowering of the head may be effective.

If there is pronounced hypotension and/or shock a volume replacement should be performed; in exceptional cases, norepinephrine (noradrenaline) and/or dopamine can be infused as a cardiovascular therapy. Administration of epinephrine and related substances is contraindicated.

Arterial blood gas estimation should be performed and if there is acidosis or the patient is clinically cyanosed, then severe methaemoglobinaemia must be assumed. Oxygen therapy should be given with 1 - 2 mg/kg bodyweight of IV Methylene Blue over five min unless the patient is known to have Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Glyceryl trinitrate exerts a spasmolytic action on smooth muscle, particularly in the vascular system. The predominant effect is an increase in venous capacitance resulting in marked diminution of both the left ventricular filling pressure and volume (preload). There is also a reduction in afterload due to moderate dilation of the arteriolar resistance vessels. These haemodynamic changes lower the myocardial oxygen demand. By direct action and through the reduction of myocardial wall tension glyceryl trinitrate also lowers the resistance to flow in the coronary collateral channels and allows re-distribution of blood flow to ischaemic areas of the myocardium.

Administration of Nitronal® by intravenous infusion to patients with congestive heart failure results in a marked improvement in haemodynamics, reduction of elevated left ventricular filling pressure and systolic wall tension, and an increase in the depressed cardiac output. It reduces the imbalance that exists between myocardial oxygen demand and delivery, thereby diminishing myocardial ischaemia and controlling ischaemia-induced ventricular arrhythmias.

5.2 Pharmacokinetic properties

It is important that the dose of Nitronal® be titrated against the individual clinical response.

After intravenous administration, glyceryl trinitrate is widely distributed in the body with an estimated apparent volume of distribution of approximately 200 litres, and is rapidly metabolised to dinitrate and mononitrate with an estimated half life of 1 to 4 minutes, resulting in plasma levels of less than 1 microgram / ml.

5.3 Preclinical safety data

None, of relevance to the prescriber, which are not given elsewhere in this document.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Glucose, water for injections, hydrochloric acid.

6.2 Incompatibilities

Glyceryl trinitrate is adsorbed onto administration systems composed of polyvinyl chloride, - see 6.6.

6.3    Shelf life

Ampoules: 4 years Vial: 2 years

The diluted solution should be administered as soon as possible; it is stable for up to 24 hours in the    recommended infusion    system.

6.4    Special precautions    for    storage

Do not store above 25°C. Store in the original container.

6.5    Nature and contents of container

Cartons of 10 ampoules or single vials.

Amber glass ampoule (containing 5ml or 25ml).

Clear glass vial (containing 50ml).

6.6    Special precautions    for    disposal and    other handling

Nitronal® need not be diluted before use but can be diluted with Dextrose Injection BP, Sodium Chloride and Dextrose Injection BP, 0.9% Sodium Chloride Injection BP or other protein-free infusion solution, if required.

The solution, whether or not diluted, should be infused slowly (see dosage section) and not given by bolus injection.

To ensure a constant infusion rate of glyceryl trinitrate it is recommended that Nitronal® be administered by means of a syringe pump or polyethylene infusion bag with a counter, or with a glass or rigid polyethylene syringe and polyethylene tubing. Systems made of polyvinyl chloride may absorb up to 50% of the glyceryl trinitrate from the solution, thus reducing the efficacy of the infusion. If the recommended type of system is unavailable, a 1:10 dilution of Nitronal® should be used and the infusion rate modified according