#

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT    w hameln

Glyceryl Trinitrate 1 mg/ml solution for infusion

Read all of this leaflet carefully before you receive this medicine because it contains important information for you.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor or pharmacist.

•    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

See section 4_

The name of your medicine is Glyceryl Trinitrate 1 mg/ml solution for infusion, which will be referred to as Glyceryl Trinitrate throughout this leaflet.

WHAT IS IN THIS LEAFLET:

1.    What Glyceryl Trinitrate is and what it is used for

2.    What you need to know before you receive Glyceryl Trinitrate

3.    How to use Glyceryl Trinitrate

4.    Possible side effects

5.    How to store Glyceryl Trinitrate

6.    Contents of the pack and other information

1.    WHAT GLYCERYL TRINITRATE IS AND WHAT IT IS USED FOR

Glyceryl Trinitrate belongs to a group of drugs called nitrates. This medicine is used to prevent and relieve the pain or discomfort of an angina attack (chest pain). It relaxes the muscle around blood vessels and makes the heart’s work easier.

This solution is only used in hospitals and is given to you by a doctor or nurse. It is used in the following conditions:

•    heart failure and acute myocardial infarction (heart attack)

•    angina attack

•    to lower blood pressure during surgery

•    to control blood pressure during and after cardiac surgery

2.    WHAT YOU NEED TO KNOW BEFORE YOU RECEIVE GLYCERYL TRINITRATE

Do not use Glyceryl Trinitrate:

•    if you are allergic (hypersensitive) to nitrate medicines or to any of the other ingredients in Glyceryl Trinitrate (See section 6).

•    if you are taking a medicine for the treatment of erectile dysfunction (e.g. sildenafil vardenafil, tadalafil). If you take Glyceryl Trinitrate concomitantly with such medicines a severe and possibly dangerous fall in blood pressure can occur. This would result in collapse, unconsciousness and could be fatal. You should not take such medicines whilst on Glyceryl Trinitrate treatment.

•    if you are in shock (a life-threatening medical condition where insufficient blood flow reaches the body tissues)

•    if you have severe anaemia (lack of red blood cells)

•    if you have low blood pressure

•    if you have low blood volume

•    if you have low blood oxygen (this can make you feel fatigued and short of breath) and angina caused by a heart disease where the muscle mass of the left heart ventricle is enlarged

•    if you have severe blood loss

•    if you have fluid accumulation in the lung

•    if you have ever had a serious head injury, cerebral haemorrhage (bleeding in the brain) or a disease which is

—x

accompanied by increased pressure on the brain

•    If you have or had heart conditions Warnings and precautions

Talk to your doctor or pharmacist before using Glyceryl Trinitrate if:

•    you have acute left-sided heart failure - providing that systolic blood pressure (the blood pressure when the heart is contracting) is over 90 mmHg

•    you have had an acute myocardial infarction (heart attack) -providing that systolic blood pressure is over 90 mmHg

•    you have severe liver or kidney problems

•    you have an under active thyroid

•    your body temperature is lower than normal (hypothermia)

•    you are pregnant or breastfeeding.

Children

This medicine is not recommended in children.

Other medicines and Glyceryl Trinitrate

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is especially important with the following medicines as they may interact with your Glyceryl Trinitrate:

•    Medicines which lower blood pressure (e.g. other vasodilators, beta-blockers, calcium channel blockers)

•    Medicines for the treatment of erectile dysfunction (e.g. sildenafil, vardenafil, tadalafil)

•    Certain antidepressants (tricyclics e.g. amitriptyline, nortiptyline, clomipramine, imipramine)

•    Certain very strong pain killers which are similar to morphine (opioids e.g. alfentanil)

•    Medicines used to treat anxiety (neuroleptics)

•    Sapropterine containing medicines

•    Non-steroidal anti-inflammatory drugs (NSAIDs) except acetyl salicylic acid.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine

Driving and using machines

This medicine is used in hospitalised patients. Therefore if you have any concerns ask your doctor or pharmacist.

3. HOW TO USE GLYCERYL TRINITRATE

Usually Glyceryl Trinitrate will be given to you by your doctor or a nurse and you will be monitored very carefully.

•    This solution is always given slowly into the blood stream as a diluted solution for (intravenous) infusion.

SUMMARY OF PRODUCT CHARACTERISTICS    _w ha_mel_n

Glyceryl Trinitrate 1 mg/ml solution for infusion

1.    NAME OF THE MEDICINAL PRODUCT

Glyceryl Trinitrate 1 mg/ml solution for infusion

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 1 mg glyceryl trinitrate.

Amount of active substance per pack size:

3.    PHARMACEUTICAL FORM

Solution for infusion

The product is a clear and colourless solution.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

The following indications exist for Glyceryl Trinitrate:

•    Unresponsive congestive heart failure, including that secondary to acute myocardial infarction; acute left-sided heart failure and acute myocardial infarction,

•    Refractory unstable angina pectoris and coronary insufficiency, including Prinzmetal‘s angina,

•    Control of hypertensive episodes and/or myocardial ischaemia during and after cardiac surgery,

•    Induction of controlled hypotension for surgery.

4.2    Posology and method of administration

For intravenous use. Glyceryl Trinitrate should be administered by means of a micro-drip set infusion pump or similar device which permits maintenance of constant infusion rate.

Recommendations on the dilution of the product are presented in this section. For further instructions on dilution of the product before administration, see section 6.6.

Adults

The dose of Glyceryl Trinitrate should be adjusted to meet the individual needs of the patient.

The recommended dosage range is 10-200 mcg/min but up to 400 mcg/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 Use in surgery

A starting dose of 25 mcg/min is recommended for the control of hypertension, or to produce hypotension during surgery. This may be increased by increments of 25 mcg/min at 5 minute intervals until the blood pressure is stabilised. Doses between 10-200 mcg/ min are usually sufficient during surgery, although doses of up to 400 mcg/min have been required in some cases.

Myocardial ischaemia

The treatment of perioperative myocardial ischaemia may be started with a dose of 15-20 mcg/min, with subsequent increments of 10-15 mcg/min until the required effect is obtained. Unresponsive congestive heart failure:

The recommended starting dose is 20-25 mcg/min. This may be decreased to 10 mcg/min, or increased in steps of 20-25 mcg/min every 15-30 minutes until the desired effect is obtained.

Unstable angina:

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

Method of administration

Glyceryl Trinitrate can be administered undiluted by slow intravenous infusion using a syringe pump incorporating a glass or rigid plastic syringe.

Alternatively, Glyceryl Trinitrate may be administered intravenously as an admixture using a suitable vehicle such as Sodium Chloride Injection B.P or Dextrose Injection B.P In case of dilution, Glyceryl Trinitrate 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 Glyceryl Trinitrate administration 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.

Example of admixture preparation

To obtain an admixture of Glyceryl Trinitrate at a concentration of 100 mcg/ml, add 50 ml Glyceryl Trinitrate solution (containing 50 mg glyceryl trinitrate) to 450 ml of infusion vehicle to give a final volume of 500 ml.

A dosage of 100 mcg/min. can be obtained by giving 60 ml of the admixture per hour.

Vials of Glyceryl Trinitrate are for single use only and should not be regarded as multi-dose containers.

4.3    Contraindications

Glyceryl Trinitrate should not be used in the following cases:

•    Hypersensitivity to the active substance, other nitrates or any of the excipients listed in Section 6.1

•    Acute circulatory failure (shock, collapse)

•    Cardiogenic shock (unless a sufficient end-diastolic pressure is maintained by appropriate measures)

•    Severe anaemia,

•    Severe cerebral haemorrhage

•    Head trauma

•    Uncorrected hypovolaemia and hypotensive shock

•    Arterial hypoxaemia and angina caused by hypertrophic obstructive cardiomyopathy

•    Constrictive pericarditis

•    Pericardial tamponade

•    Toxic pulmonary oedema.

•    During nitrate therapy, phosphodiesterase inhibitors type 5 (PDE5) (e. g. sildenafil, vardenafil, tadalafil) must not be used because PDE5 inhibitors may amplify the vasodilatory effects of Glyceryl Trinitrate resulting in severe hypotension (see sections 4.4 and 4.5).

•    Conditions associated with an increased intracranial pressure.

•    Myocardial insufficiency due to obstruction, aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy or constrictive pericarditis.

4.4    Special warnings and precautions for use

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

Glyceryl Trinitrate should not be given by bolus injection.

Glyceryl Trinitrate must be used only with particular caution and under medical supervision in:

•    Low filling pressures e.g. in acute myocardial infarction, impaired left ventricular function (left ventricular failure). Reducing systolic blood-pressure below 90 mmHg must be avoided

•    Orthostatic dysfunction

The development of tolerance and cross tolerance to other nitro compounds has been described.

Glyceryl Trinitrate must not be used in patients known to be taking phosphodiesterase inhibitor-containing products (e. g. sildenafil, vardenafil, tadalafil). Patients who receive Glyceryl Trinitrate solution therapy must be warned not to take phosphodiesterase inhibitor-containing products (e.g. sildenafil, vardenafil, tadalafil) (see sections 4.3 and 4.5).

Materials made of polyethylene (PE), polypropylene (PP) or polytetrafluorethylene (PTFE) have proven to be suitable for infusing Glyceryl Trinitrate solution. However, infusion material made of polyvinyl chloride (PVC) or polyurethane (PU) has been shown to induce a loss of the active substance due to adsorption. If these materials are used the dose must be adjusted to suit patient‘s needs (see also section 6.2).

The solution contains glucose; this should be taken into account in patients with diabetes mellitus.

Hvpoxaemia:

Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is reduced.

Similarly, caution is called for in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.

Patients with angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia).

Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (see also section 4.8). As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen. Methaemoglobinaemia

Following treatment with Glyceryl Trinitrate, methaemoglobinaemia has been reported. Treatment of methaemoglobinaemia with methylene blue is contraindicated in patients with glucose-6-phosphate deficiency or methaemoglobin-reductase deficiency (see also section 4.9).

4.5    Interaction with other medicinal products and other forms of interaction

Concomitant treatment with other vasodilators, calcium antagonists,    ACE inhibitors, beta-blockers,    diuretics,

antihypertensives, tricyclic antidepressants and neuroleptics, as well as the consumption of alcohol, may potentiate the hypotensive effect of the preparation.

The blood pressure lowering effect of Glyceryl Trinitrate will be increased if used together with phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) which are used for erectile dysfunction (see Section 4.3). This might lead to life threatening cardiovascular complications. Patients who are on nitrate therapy must not use phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil).

Simultaneous intravenous infusions of tissue plasminogen activator (tPA) and glyceryl trinitrate may accelerate plasma clearance of tPA by increasing hepatic blood flow.

Reports suggest that, when administered concomitantly, Glyceryl Trinitrate may increase the blood level of dihydroergotamine and its effect. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises the effect of Glyceryl Trinitrate and may lead to coronary vasoconstriction. The use of heparin and Glyceryl Trinitrate solution can lead to a partial loss of action of heparin when both drugs are given simultaneously by intravenous route.

Concurrent administration of Glyceryl Trinitrate with acetyl salicylic acid may potentiate the blood pressure lowering effects of Glyceryl Trinitrate.

The non-steroidal anti-inflammatory drugs except acetyl salicylic acid may diminish the therapeutic response of Glyceryl Trinitrate. Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).

4.6    Fertility, pregnancy and lactation

Fertility

Reproduction toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on mating, fertility and general reproductive parameters. There is no data available on the effect of Glyceryl Trinitrate on fertility in humans.

Pregnancy

Developmental toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on the embryos, fetuses or the young animals even at toxic doses for the dam.

Lactation

Available evidence is inconclusive or inadequate for determining infant risk when used during breastfeeding. There is data that nitrates are excreted in breast milk and may cause methaemoglobinaemia in infants. The extent of excretion of nitroglycerin in human breast milk has not been determined. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue 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

Glyceryl Trinitrate may affect the patient‘s reactivity to an extent that her/his ability to drive or to operate machinery is impaired. This effect is increased in combination with alcohol

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 the following undesirable effects may be observed

•    The dose depends on the condition. Your doctor will decide the correct dose and duration of therapy for you, while carefully monitoring the effects of the drug.

Dosage in adults and the elderly:

•    unresponsive congestive heart failure (a condition in which the heart is not able to pump enough blood to meet the oxygen demands of the body), acute myocardial infarction (heart attack) and left-sided heart failure

-    The usual doses are: 10-100 micrograms per minute administered as a continuous intravenous infusion with frequent monitoring of blood pressure and heart rate.

•    refractory unstable angina pectoris (angina attack with chest pain)

-    An initial infusion rate of 10-15 micrograms per minute is recommended.

•    use in surgery

-    An initial infusion rate of 25 micrograms per minute is recommended; this may be increased by 25 micrograms per minute at 5 minute intervals until your blood pressure is stabilised. Doses up to 400 micrograms per minute may occasionally be needed.

If you receive more Glyceryl Trinitrate than you should

Since Glyceryl Trinitrate will be administered to you by a doctor or nurse, it is unlikely that you will be given too much. In the event of overdose following signs or symptoms can occur vomiting, restlessness, fall in blood pressure, coldness of the skin, breathing difficulties, mental illness, blue discolouration of the skin, slow heart rate of less than 60 beats per minute, a temporary loss of consciousness and posture and a very rare blood disorder where the blood is unable to carry oxygen to cells in the body.

These symptoms may be readily reversed by discontinuing your treatment, therefore please tell your doctor or nurse immediately if one or more of these symptoms occur.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Glyceryl Trinitrate can cause side effects, although not everybody gets them. These side effects require special management to minimise the risk of complications. Your doctor will discuss these side effects with you and explain the risks and benefits of your treatment.

Tell your doctor immediately if you experience the following:

•    An allergic skin reaction - this occurs uncommonly. Symptoms may include skin rash, redness, itch, burning sensation, irritation.

The following side effects have been reported:

Very common (may affect more than 1 in 10 people):

•    headache

Common (may affect up to 1 in 10 people):

•    dizziness, light-headedness

•    sleepiness

•    fast or irregular heart beat

•    dizziness when standing up suddenly

•    weakness

Uncommon (may affect up to 1 in 100 people):

•    chest pain

•    heart failure

•    nausea

•    vomiting

Very rare (may affect up to 1 in 10,000 people):

•    Heartburn

Not known (frequency cannot be estimated from the available data)

•    irregular heart beat (palpitations)

•    flushing

•    low blood pressure

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects you can help provide more information on the safety of this medicine.

5.    HOW TO STORE GLYCERYL TRINITRATE Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after “Exp”. The expiry date refers to the last day of that month.

Glyceryl Trinitrate ampoules and vials will be stored below 25°C in the outer carton to protect the medicine from light.

This medicine should not be given to you if the solution for infusion shows any discolouration, precipitation or any other visible particles.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6.    CONTENTS OF THE PACK AND OTHER INFORMATION What Glyceryl Trinitrate contains:

•    The active substance is glyceryl trinitrate.

1 ml solution for infusion contains 1 mg glyceryl trinitrate.

•    The other ingredients are water for injections, glucose monohydrate and hydrochloric acid.

What Glyceryl Trinitrate looks like and the contents of the pack

The product is a clear and colourless solution for infusion. This solution is packed in boxes containing:

Vials are closed with bromobutyl rubber stoppers. Not all pack sizes may be marketed.

Marketing Authorisation Holder:

hameln pharma plus gmbh,

Langes Feld 13, 31789 Hameln, Germany Manufacturer:

hameln pharmaceuticals gmbh,

Langes Feld 13, 31789 Hameln, Germany Distributor:

hameln pharmaceuticals ltd,

Gloucester, United Kingdom

This package leaflet was last revised in June 2016.

44480/44774/32/16

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

During treatment with Glyceryl Trinitrate, 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.

4.9 Overdose

Symptoms of overdose

Symptoms could include the following:

•    Fall in blood pressure s 90 mmHg

•    Pallor

•    Sweating

•    Weak pulse

•    Reflex tachycardia

•    Collapse

•    Syncope

•    Dizziness postural

•    Headache

•    Asthenia

•    Dizziness

•    Nausea

•    Vomiting

•    Diarrhoea

•    Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During glyceryl trinitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It can not be excluded that an overdose of glyceryl trinitrate may cause this adverse reaction

•    In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms

T reatment of overdose General procedure:

•    Stop delivery of the drug.

•    General procedures in the event of nitrate-related hypotension:

-    Patient should be kept horizontal with the head lowered and legs raised or, if necessary, compression bandaging of the patient‘s legs

-    Supply oxygen

-    Expand plasma volume

-    For specific shock treatment admit patient to intensive care unit

Special procedure:

•    Raising the blood pressure if the blood pressure is very low

•    Treatment of methaemoglobinaemia:

Treatment with intravenous methylene blue

-    Initially 1 to 2 mg/kg, not exceeding 4 mg/kg of a 1% solution over 5 minutes.

-    Repeat dose in 60 minutes if there is no response.

-    Administer oxygen (if necessary)

-    Initiate artificial ventilation

Treatment of methaemoglobinaemia with methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or methaemaglobin reductase deficiency (see also section 4.4).

Where treatment with methylene blue is contraindicated or is not effective, exchange transfusion and/or transfusion of packed red blood cells is recommended.

Resuscitation measures:

In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vasodilators used in cardiac diseases ATC-Code: C01DA02 Organic nitrates

Glyceryl trinitrate exerts a spasmolytic action on smooth muscle, particularly in the vascular system. This action is more marked on the venous capacitance vessels than the arterial vessels; the predominant increase in venous capacitance results in marked diminution of both the left ventricular filling pressure and volume (preload). The moderate dilation of the arteriolar resistance vessels results in a reduction in afterload. These haemodynamic changes (reductions) in preload and afterload lower the myocardial oxygen demand. In addition, 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 glyceryl trinitrate 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.

Glyceryl trinitrate relaxes smooth muscles cells in other organs to some extent. The cellular molecular mechanism of action is a synthesis of nitric oxide and cyclic guanosyl monophosphate which acts as a mediator for muscle relaxation.

5.2    Pharmacokinetic properties

After intravenous administration, glyceryl trinitrate is widely distributed in the body with an estimated apparent volume of distribution of approximately 200 litres. It is strongly bound to erythrocytes and vessel walls; the plasma protein binding is approx. 60%. The therapeutic plasma concentration range is 0.1 to 3 ng/ml (up to 5 ng/ml).

Glyceryl trinitrate is rapidly metabolised to dinitrate and mononitrate and further metabolised by glucuronidation in the liver, showing a marked first-pass effect.

Spontaneous hydrolysis occurs in plasma. The estimated plasma half-life of glyceryl trinitrate is 1 to 4 minutes. The rapid disappearance from plasma is consistent with the high systemic clearance values (up to 3270 litres per hour). The less active metabolites resulting from biotransformation can be recovered from the urine within 24 hours.

5.3    Preclinical safety data

The acute toxicity has been reported for rats after intravenous (LD₅₀ 17-41 mg/kg body weight), as well as in dogs after intravenous administration (LD₅₀ 19-24 mg/kg body weight). Autopsy did not reveal any pathological findings.

Subacute studies in rats at doses of 2.5, 5.0 and 10.0 mg/kg per day, and in dogs at doses of 1.0 and 3.0 mg/kg per day elicited only minimal reactions. In rats, suppression of body weight gain and food consumption occurred among treated and vehicle-control animals. Mild tissue irritation at injection sites was noted in treated and vehicle-control groups. There were no clearly drug-related clinical or pathological findings in dogs. Further results of studies on repeated-dose toxicity in different species revealed no indication of drug-specific clinically relevant toxicity.

Glyceryl trinitrate is insufficiently tested for a potential mutagenic action. There are no adequate state-of-the-art long-term studies on a possible tumourigenic action of glyceryl trinitrate.

There is inadequate experience with glyceryl trinitrate during human pregnancy, particularly during the first trimester. Sufficient evidence is available from animal studies with intravenous, intraperitoneal and topical administration. Studies on fertility and embryotoxicity did not result in any toxic effect on the embryo or on reproductive performance. Any indication of a teratogenic potential of glyceryl trinitrate was not found. Doses in excess of 1 mg/kg/ day (i.p.) or 28 mg/kg/day (topical) reduced the birth weight in rats. There are no investigations on the passage of glyceryl trinitrate into breast milk.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for injections Glucose monohydrate Hydrochloric acid

6.2    Incompatibilities

Glyceryl Trinitrate is not compatible with polyvinylchloride (PVC) and severe losses of glyceryl trinitrate (up to 50%) may occur if polyvinylchloride is used, resulting in a reduction of delivered dose and efficacy. Contact of the solution with polyvinylchloride bags should be avoided.

The product is compatible with glass infusion sets and with rigid infusion packs made of polyethylene; it may also be infused slowly using a syringe pump with a glass or plastic syringe.

6.3    Shelf life

Unopened ampoules: 3 years Unopened vials: 2 years Opened ampoules or vials:

The product should be used immediately after opening the container.

Any unused solution from opened containers should be discarded. Prepared infusion solutions:

Chemical and physical in-use stability has been demonstrated in glucose solution 5% and sodium chloride solution 0.9% for 24 hours at room temperature.

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°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Keep the container in the outer carton.

Do not store above 25°C.

6.5    Nature and contents of container

5 ml, 10 ml or 25 ml ampoules, made of colourless glass, type I (Ph. Eur.).

50 ml vial, made of colourless glass, type I (Ph. Eur.), bromobutyl rubber stopper.

Box of 10 ampoules with 5 ml

Box of 10 ampoules with 10 ml

Box of 10 ampoules with 25 ml

Box of 1 vial with 50 ml

Box of 10 vials with 50 ml

Box of 25 vials with 50 ml

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

Glyceryl Trinitrate need not be diluted before use but can be diluted by 1:10 up to 1:40 with 5% glucose solution, 5% glucose solution and 0.9% sodium chloride solution, or with 0.9% sodium chloride solution.

The solution, whether or not diluted, should be infused slowly and not given by bolus injection. To ensure a constant infusion rate of glyceryl trinitrate it is recommended that Glyceryl Trinitrate 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 (PVC) may absorb up to 50% of the glyceryl trinitrate from the solution.

Vials of 50 ml Glyceryl Trinitrate are for single use only and should not be regarded as multi-dose containers.

7.    MARKETING AUTHORISATION HOLDER hameln pharma plus gmbh

Langes Feld 13 31789 Hameln Germany

8.    MARKETING AUTHORISATION NUMBER

PL 25215/0011

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/09/2008

10.    DATE OF REVISION OF THE TEXT

June 2016

Prescription-only medicine

44480/44774/32/16