1. Name Of The Medicinal Product
Glyceryl Trinitrate 5 mg/ml Sterile Concentrate.
2. Qualitative And Quantitative Composition
1 ml of solution contains 5 mg of glyceryl trinitrate. Each 5 ml and 10 ml ampoules contains 25 mg and 50 mg glyceryl trinitrate respectively.
For excipients, see 6.1
3. Pharmaceutical Form
Concentrate for solution for infusion
Ampoules containing a clear, practically colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Surgery: Glyceryl trinitrate is indicated for the prompt control of hypertension during cardiac surgery.
It may also be used for the production and maintenance of controlled hypotension during surgical procedures.
Glyceryl trinitrate may be given for the control of myocardial ischaemia both during and following cardiovascular surgery.
Unresponsive Congestive Cardiac Failure Secondary to Acute Myocardial Infarction: Glyceryl trinitrate may be used in patients presenting with unresponsive congestive heart failure secondary to acute myocardial infarction.
Unstable Angina: Glyceryl trinitrate infusion may be used to reduce myocardial oxygen demand in proportion to the reduction in pre- and after-load. It may be indicated for the control of anginal episodes in patients with unstable angina who do not respond to standard treatment and/or beta-blockers.
It is recommended that blood pressure and pulse rate are regularly monitored during infusion of glyceryl trinitrate.
4.2 Posology And Method Of Administration
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.
The dosage range for most patients is 10-200 microgram/min. However, doses up to 400 microgram/min may be required during surgical procedures.
Dosage: The recommended dose range is 10-200 microgram/min, although larger doses than this have been used. During some surgical procedures, doses of up to 400 microgram/min may be required. In order to maintain the appropriate infusion rate, clinical assessment and regular blood pressure monitoring are necessary. Measurement of pulmonary capillary wedge pressure and cardiac out-put may also be used to titrate dosage to response.
Surgery: For the control of hypertensive episodes the recommended starting dose is 25 microgram/min increasing in steps of 25 microgram/min at 5 minute intervals until the desired drop in blood pressure is achieved. Although most patients respond to doses between 10-200 microgram/min, doses up to 400 microgram/min have been required during some surgical procedures. In the treatment of perioperative myocardial ischaemia, the recommended starting dose is 15-20 microgram/min increasing in steps of 10-15 microgram/min until the desired effect is achieved.
Unresponsive Congestive Cardiac Failure Secondary to Acute Myocardial Infarction: The recommended starting dose is 20-25 microgram/min which can be decreased to 10 microgram/min or increased in steps of 20-25 microgram/min at 15-30 minute intervals until the desired effect is achieved.
Unstable angina: The recommended starting dose is 10 microgram/min increasing in steps of 5-10 microgram/min at approximately 30 minute intervals.
Children and the Elderly: The use of glyceryl trinitrate in children and elderly patients is not recommended, as the safety and effectiveness of glyceryl trinitrate in children and elderly patients have not been established.
4.3 Contraindications
To those who have or are:
1. Hypersensitive to glyceryl trinitrate
2. Hypotensive or hypovolaemic
3. Increased intracranial pressure
4. Constrictive periocarditis and pericardial tamponade
5. Severe anaemia and arterial hypoxaemia.
6. Taking sildenafil (Viagra)
4.4 Special Warnings And Precautions For Use
Warnings
Glyceryl Trinitrate Sterile Concentrate contains propylene glycol which can lead to lactic acidosis. It is recommended that the use of this preparation be restricted to not more than three successive days.
Precautions
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.
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Sildenafil (Viagra): sildenafil has known effects on the nitric oxide/cGMP pathway, and has been shown to potentiate the hypotensive effects of nitrates such as Glyceryl TrinitrateSterile Concentrate.
4.6 Pregnancy And Lactation
The safety of glyceryl trinitrate during pregnancy and lactation has not been demonstrated and therefore it should not be used in these situations unless considered essential by the physician.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Adverse reactions to organic nitrates which have been reported include hypotension, tachycardia, nausea, retching, diaphoresis, apprehension, headache, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness, and abdominal pain, paradoxical bradycardia has rarely been observed.
4.9 Overdose
Overdosage usually results in hypotension and tachycardia and can be reversed by elevating the legs or decreasing or terminating the infusion. In severe cases of overdosage, intravenous administration of methoxamine or phenylephrine is recommended.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Glyceryl trinitrate, an organic nitrate, is a vasodilator. The principal pharmacological action of glyceryl trinitrate is the relaxation of vascular smooth muscle. Glyceryl trinitrate produces, in a dose-related manner, dilation of both arterial and venous beds. Dilatation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (pre-load).
Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension time index and stroke work index) is decreased by both arterial and venous effects of glyceryl trinitrate, and a more favourable supply demand ratio can be achieved.
Therapeutic doses of intravenous glyceryl trinitrate reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or increased heart rate decreases diastolic filling time.
Glyceryl trinitrate reduces elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and systemic vascular resistance. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, decreased or unchanged.
Patients with elevated left ventricular filling pressure and systemic vascular resistance values in conjunction with a depressed cardiac index are likely to experience an improvement in cardiac index. Alternatively, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced by intravenous glyceryl trinitrate.
5.2 Pharmacokinetic Properties
Glyceryl trinitrate is widely distributed in the body with an apparent volume of distribution of 200 litres in adult male subjects, and is rapidly metabolised to dinitrates and mononitrates, with a short half-life estimated at 1-4 minutes. This results in a low plasma concentration after intravenous infusion. Glyceryl trinitrate is also well absorbed from the gastro-intestinal tract, but it is not known if it is distributed into milk.
At plasma concentrations of between 50 and 500 ng/ml, the binding of glyceryl trinitrate to plasma proteins is approximately 60% and 30% respectively. The plasma half-life of glyceryl trinitrate is about 1-4 minutes. Glyceryl mononitrate which is inactive, is the principal metabolite.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Ethanol
Propylene glycol
Water for Injections
6.2 Incompatibilities
Glyceryl Trinitrate Sterile Concentrate is incompatible with polyvinylchloride (PVC) and severe losses of glyceryl trinitrate (over 40%) may occur if this material is used. Contact with polyvinylchloride bags should be avoided. Polyurethane also induces a loss of the active ingredient. No other drug should be admixed with this medicinal product.
6.3 Shelf Life
As packaged for sale: 36 months.
6.4 Special Precautions For Storage
Prior to first use: Do not store above 25°C. Keep container in the outer carton.
Open ampoules of glyceryl trinitrate should be used immediately and any unused portion discarded.
In use:
Following dilution in either 0.9% sodium chloride or 5% dextrose injection solutions in glass containers, chemical and physical in-use stability has been demonstrated for 7 days at both 18°C and 4°C.
Following dilution in 5% dextrose solution in polycarbonate or polypropylene syringes at concentrations of 1 mg or 4 mg per ml protected from light, chemical and physical in-use stability has been demonstrated for 72 hours at room temperature.
However, 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 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Do not use if the solution is discoloured.
6.5 Nature And Contents Of Container
Clear, Type I glass ampoules – 5 ml and 10 ml in packs of 5 ampoules.
6.6 Special Precautions For Disposal And Other Handling
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.
Compatible with commonly employed infusion solutions, Sodium Chloride (0.9%) Injection and Dextrose (5%) Injection.
Compatible with glass infusion bottles and rigid infusion packs made of polyethylene.
7. Marketing Authorisation Holder
Hopsira UK Limited
Queensway
Royal Leamington Spa
Warwickshire, CV31 3RW
8. Marketing Authorisation Number(S)
PL 04515/0006
9. Date Of First Authorisation/Renewal Of The Authorisation
21 December 1995
10. Date Of Revision Of The Text
31st December 2007
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