Glyceryl Trinitrate 1 mg/ml solution for infusion

1 ml solution contains 1 mg glyceryl trinitrate.

Amount of active substance per pack size:

For excipients, see 6.1.

Solution for infusion

The product is a clear and colourless solution.

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.

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.

For instructions on dilution of the product before administration, see section 6.6.

Adults and the elderly - the dose should be titrated against the individual clinical response.

Unresponsive congestive heart failure, acute myocardial infarction and left-sided 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.

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.

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 – Glyceryl Trinitrate 1 mg/ml solution for infusion is not recommended for use in children.

Glyceryl Trinitrate should not be used in the following cases: Known hypersensitivity to nitrates, 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. Sildenafil potentiates the hypotensive effects of nitrates and its co-administration with Glyceryl Trinitrate is contraindicated.

Glyceryl Trinitrate should be administered with caution and under continuous monitoring to patients with acute left-sided heart failure or acute myocardial infarction and only when the systolic blood pressure exceeds 90 mm Hg.

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 may potentiate the action of other hypotensive drugs, and the hypotensive and anticholinergic effects of tricyclic antidepressants; it may also slow the metabolism of morphine-like analgesics.

The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil. 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 contraindicated (section 4.3).

This product should not be used in pregnancy or in women who are breast feeding infants unless considered essential by the physician.

Not applicable, because the product is used in hospitalised patients.

Frequencies of the adverse reactions are listed according to the following convention:

Very common ( 1/10),

Common ( 1/100, < 1/10),

Uncommon ( 1/1000, < 1/100)

Rare ( 1/10000, < 1/1000),

Very rare (< 1/10000),

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

*particularly if the infusion is administered too rapidly.

These symptoms should be readily reversible on reducing the rate of infusion or, if necessary, discontinuing treatment.

Signs and symptoms: Vomiting, restlessness, hypotension, syncope, cyanosis, coldness of the skin, impairment of respiration, bradycardia, psychosis and methaemoglobinaemia may occur.

Treatment: The symptoms may be readily reversed by discontinuing treatment; if hypotension persists, raising the foot of the bed 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.

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.

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.

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.

Water for injections

Glucose monohydrate

Hydrochloric acid

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.

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.

Keep the container in the outer carton.

Do not store above 25°C.

5 ml, 10 ml or 25 ml ampoules, made of colourless glass, type I.

50 ml vial, made of colourless glass, type I, 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.

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.

hameln pharma plus gmbh

Langes Feld 13

31789 Hameln

Germany

PL 25215/0011

04/09/2008

04/06/2009

Prescription-only medicine