SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution for infusion contains 1 mg of glyceryl trinitrate (trinitrine), 1 ampoule of 5 ml contains 5 mg trinitrine, 1 ampoule of 10 ml contains 10 mg trinitrine, 1 ampoule of 25 ml contains 25 mg trinitrine, 1 vial of 50 ml contains 50 mg trinitrine.

Excipient: glucose monohydrate (0.05 g/ml) For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for infusion, clear and colourless solution

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Surgery/anaesthesia: Prevention of myocardial ischemia during coronary interventions. Cardiology: 1. Left ventricular failure, in particular during the acute phase of the myocardial infarction. 2. Unstable angina pectoris

4.2 Posology and method of administration

General: It is recommended to start with a low dose of 5 µg/min and increase it gradually every 5 minutes. The dosage must be determined by the patient’s individual requirement and depending on the required response and possible adverse effects, including increased heart rate and hypotension. The dosages determined for individual patients may differ by a factor of 10. In most cases the dosage ranges from 5 - 200 µg/min. Careful clinical monitoring and measurement of blood pressure are necessary for correct adjustment of the infusion rate.

1 4.3 Contraindications

Glyceryl trinitrate must not be used in patients with: - hypersensitivity to glyceryl trinitrate and/or nitro compounds in general or for one of the other (inactive) ingredients; - increased intracranial pressure (head injury or cerebral haemorrhage); - insufficient cerebral perfusion; - constrictive pericarditis or pericardial tamponade; - hypotension, with or without cardiogenic shock (systolic blood pressure below 90 mmHg); - uncorrected hypovolemia; - toxic pulmonary oedema.

Concurrent use of phosphodiesterase-5-inhibitors (e.g. sildenafil, vardenafil and tadalafil).

4.4 Special warnings and precautions for use

During continuous infusion of glyceryl trinitrate, reduction in its activity (tachyphylaxis) must be considered. Tolerance development and occurrence of cross intolerance to other nitro compounds have been reported. Increase of dosage may be necessary. Administration must not be discontinued abruptly. In order to avoid attenuation or loss of effect, high continuous dosage should be avoided.

In individual patients the necessary dose to reach the required reduction in blood pressure may differ significantly. Therefore continuous monitoring of the blood pressure is necessary. The hypotensive effect of glyceryl trinitrate occurs almost immediately after administration. The effect also quickly disappears if the infusion is discontinued or the dose is reduced. In case of left ventricular failure use of the product is not safe unless the effect on cardiac filling pressure can be measured by means of a balloon catheter in the pulmonary artery.

A severe drop in the arterial blood pressure of more than 20 mmHg, an increase in the heart rate of more than 20 beats/min or a reduction in filling pressure below normal values is an imperative indication to reduce or discontinue infusion of glyceryl trinitrate because it reduces coronary perfusion. Infusion of glyceryl trinitrate should not be given if systolic pressure is below 13,3 kPa (= 100 mm Hg) and/or diastolic pressure is below 8,0 kPa (= 60 mm Hg), since severe hypotension may occur. Intravenous infusion of glyceryl trinitrate in patients with myocardial infarction without cardial decompensation may cause undesirable reduction in left ventricular filling pressure and reduction in cardiac output. In addition to direct measuring of left ventricular filling pressure, careful monitoring of heart rate and arterial blood pressure is imperative.

In treating diabetic patients one should avoid using glucose as dilution solution and bear in mind that Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie contains 5 % glucose.

To be used exclusively in perfusor pump systems: the use of PVC tubings for infusion should be avoided (See 6.2 Incompatibilities).

Caution is recommended in patients with restricted cardiac outflow, e.g. hypertrophic obstructive cardiomyopathy, aorta stenosis and mitral valve stenosis.

2 4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie and other vasodilating antihypertensives, ß-blockers, calcium antagonists, ACE- inhibitors, , tricyclic antidepressants, sapropterin and alcohol may cause increased hypotensive effect.

In patients who are treated simultaneously with organic nitrates (e.g. and isosorbide- 5-mononitrate) it may be necessary to increase the dosage of glyceryl trinitrate in order to achieve the desired effect.

The vasodilating effect of organic nitrates is potentiated by phosphodiesterase-5-inhibitors (e.g. sildenafil, vardenafil and tadalafil). This might cause life threatening cardiovascular complications in susceptible patients. Concomitant use of organic nitrates and phosphodiesterase-5-inhibitors should be avoided.

4.6 Pregnancy and lactation

Pregnancy

There are no adequate data from the use of Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy or embryofoetal development or parturition or postnatal development (see section 5.3). The potential for human is unknown. Intravenous administration may show reversible pharmacological effects, including isolated case reports of a reduction in fetal heart rate.

Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie is not recommended during pregnancy except for acute situations.

Lactation It is not known whether glyceryl trinitrate is excreted in human milk. Lactation is not recommended during use of Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie, because of possible pharmacological effects in the infant.

4.7 Effects on ability to drive and use machines

Even when used according to the instructions, the drug may effect the ability to drive and to operate machinery. This may occur particularly at the start of the treatment, when the dosage is increased, when changing to another medicinal product or when used in combination with alcohol. Because of the fact that Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie is used exclusively in a clinical setting and closely monitored circumstances, the above effects will not occur in practice.

3 4.8 Undesirable effects

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).

Nervous system disorders: Common: headache1

Vascular disorders: Uncommon: drop in blood pressure with subsequent heart rate increase2, orthostatic hypotension, facial flushing, collapse cardiovascular with bradycardia and syncope Not known: ischaemia3

Gastrointestinal disorders: Uncommon: nausea, vomiting

Skin and subcutaneous tissue disorders: Uncommon: allergic skin reaction Very rare: exfoliative dermatitis

1 May occur at the start of treatment, usually subsides with continuous use.

2 A dose-dependent reduction in blood pressure and heart rate increase may occur. In case of severe reduction in blood pressure, the infusion must be discontinued. If this does not result in spontaneous recovery, it may become necessary to take cardiovascular measures, e.g. raising the patient’s legs or volume replacement. A large drop in blood pressure may lead to a paradoxical exacerbation of angina pectoris symptoms.

3 Transient hypoxaemia may occur as a result of relative redistribution of the blood flow due to hypoventilation of alveolar tissues. In patients with coronary heart disease this may lead to ischaemia.

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 national reporting system listed in Appendix V*.

4.9 Overdose a) Symptoms of overdose

Reduction in blood pressure with orthostatic regulatory disturbances, reflex tachycardia and headache, weakness, dizziness, drowsiness, diminution of consciousness, flushes, nausea, vomiting and diarrhoea may occur.

At high doses (more than 20 mg/kg body weight) occurrence of methaemoglobinemia, cyanosis, dyspnoea and tachypnoea, due to the formation of nitrite ions during metabolism of glyceryl trinitrate.

At very high doses an increase in intracranial pressure with cerebral symptoms (convulsions) may occur. b) Treatment in case of overdose

Place the patient in recumbent position with the legs raised; the vital parameters should be monitored in intensive-care setting and corrected if necessary.

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Volume replacement should be performed in case of severe hypotension and/or shock; in exceptional cases, intravenous infusion of and/or should be given as a cardiovascular treatment. Administration of and related substances is contra-indicated.

Methaemoglobinemia may be treated with intravenous methylthionine (methylene blue) and /or toluidine blue.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: organic nitrates, ATC-Code: C01 DA 02

Mechanism of action:

Glyceryl trinitrate has a direct relaxing effect on the smooth muscular tissue of the vascular wall, resulting in vasodilatation.

Vasodilatation in the venous vascular system enhances venous capacity (pooling), while venous return to the heart is reduced. Ventricular filling pressures and volume will decrease (preload reduction). Diminished ventricular radius and reduced systolic wall tension result in reduced need for myocardial energy and oxygen, respectively.

Reduction of cardiac filling pressure enhances perfusion of the ischaemic regions of the subendocardial wall. Eventually, these effects will cause a reduction in oxygen requirement and an increase in oxygen supply, resulting in improvement of the anginal symptoms.

Dilatation of the large pericardial arteries causes a reduction in systemic (afterload reduction) as well as in pulmonary ejection resistance.

At molecular level, the action of nitrates is probably based on the formation of nitric oxide (NO) and cyclic guanosyl monophosphate (cGMP), substances that are thought to be relaxants.

5.2 Pharmacokinetic properties

Glyceryl trinitrate is completely absorbed in the intestines and metabolised in the liver. During metabolism one or more nitrate groups are isolated. Elimination of the metabolites occurs by way of the kidneys. In adult males the nominal distribution volume is approx. 200 l. Erythrocyte binding is high and accumulation in the vascular wall occurs. The bioavailability shows large interindividual differences with a mean value of approx. 39%.

In plasma concentrations of 50 to 500 ng/ml, the plasma-protein binding of glyceryl trinitrate is approx. 60% and those for glyceryl-1,2-dinitrate and glyceryl-1,3-dinitrate respectively 60% and 30%. The elimination half-life of glyceryl trinitrate is rather short and amounts to approx. 2,5 - 4,4 minutes. The activity and half-life time of glyceryl trinitrate metabolites has not been defined properly. The mononitrate is inactive.

5.3 Preclinical safety data

Preclinical safety studies show no particular risks for humans, based on studies concerning genotoxicity, carcinogenicity, fertility and embryotoxicity. In gravid rats, fetotoxicity (reduced birth

5 weight) occurred after administration of doses of more than 1 mg/kg/day (i.p.) and 28 mg/kg (dermal) during the fetal period.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glucose monohydrate, diluted hydrochloric acid (for pH adjustment), water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Do not use alkaline infusion solutions.

There is evidence that the use of polyethylene or polytetrafluorethylene tubings is to be recommended for the infusion of Nitro "Pohl" Infus voor perfusorpompsystemen 1 mg/ml, oplossing voor infusie. Polyvinylchloride tubings cause considerable loss of the active ingredient due to adsorption.

6.3 Shelf life

Ampoule: 3 years Injection vial: 2 years After the container has been opened, the diluted product has a physicochemical stability of 48 hours at 22°C. From a microbiological point of view, the product should be administered immediately after opening and diluting. If the product is not used immediately after opening and diluting, the user / administrator is responsible for the time limit and conditions of administration. Normally, in that case, the administration time limit is not more than 24 hours at 2-8°C, unless opening/diluting took place under controlled and validated aseptic circumstances.

6.4 Special precautions for storage

Store below 25°C. Do not freeze.

6.5 Nature and contents of container

10 ampoules (glass class I, brown) containing 5 ml 10 ampoules (glass class I, brown) containing 10 ml 10 ampoules (glass class I, brown) containing 25 ml 1 vial (glass class I, colourless) containing 50 ml

The vial is closed with a stopper (bromobutyl rubber) and an aluminium cap.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

This medicinal product can be administered either undiluted or diluted in sodium chloride 0.9 % or glucose 5 % (see section 4.2).

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7. MARKETING AUTHORISATION HOLDER

G. Pohl-Boskamp GmbH & Co. KG Kieler Strasse 11 D-25551 Hohenlockstedt Germany Tel: +49 4826 59 0 Fax: +49 4826 59 109 E-Mail: [email protected]

8. MARKETING AUTHORISATION NUMBER

RVG 10393

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19 September 1984/5 July 2010

10. DATE OF REVISION OF THE TEXT

January 2018

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