1. Name Of The Medicinal Product
Nitrocine 1mg/ml, solution for infusion
2. Qualitative And Quantitative Composition
Ampoules containing 10 mg glyceryl trinitrate in 10 ml, or as glass bottles containing 50 mg glyceryl trinitrate in 50 ml.
For excipients see 6.1.
3. Pharmaceutical Form
Isotonic sterile solution for infusion
4. Clinical Particulars
4.1 Therapeutic Indications
Surgery:
Nitrocine is indicated for:
1. the rapid control of hypertension during cardiac surgery.
2. reducing blood pressure and maintaining controlled hypotension during surgical procedures.
3. controlling myocardial ischaemia during and after cardiovascular surgery.
Unresponsive congestive heart failure:
Nitrocine may be used to treat unresponsive congestive heart failure secondary to acute myocardial infarction.
Unstable angina:
Nitrocine may be used to treat unstable angina, which is refractory to treatment with beta blockers and sublingual nitrates.
4.2 Posology And Method Of Administration
Adults and Elderly
The dose of Nitrocine 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.
Children:
The safety and efficacy of Nitrocine has not yet been established in children.
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 stabilized. 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.
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 10mcg/min being made at approximately 30 minute intervals according to the needs of the patient.
Administration
Nitrocine can be administered undiluted by slow intravenous infusion using a syringe pump incorporating a glass or rigid plastic syringe.
Alternatively, Nitrocine may be administered intravenously as an admixture using a suitable vehicle such as Sodium Chloride Injection B.P. or Dextrose Injection B.P.
Prepared admixtures should be given by intravenous infusion or with the aid of a syringe pump to ensure a constant rate of infusion.
During Nitrocine administration there should be close haemodynamic monitoring of the patient.
Example of admixture preparation
To obtain an admixture of GTN at a concentration of 100 mcg/ml, add 50 ml Nitrocine 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. This is equivalent to a drip rate of 60 paediatric microdrops per minute or 20 standard drops per minute. At this drip rate the admixture provides enough solution for an infusion time of 8 hours 20 minutes.
For full details it is advisable to consult the dosage chart on the package insert.
Bottles of Nitrocine are for single use only and should not be regarded as multi-dose containers.
4.3 Contraindications
Nitrocine should not be used in the following cases:
Known hypersensitivity to nitrates, marked anaemia, severe cerebral haemorrhage, head trauma, uncorrected hypovolaemia or severe hypotension.
As the safety of Nitrocine during pregnancy and lactation has not yet been established, it should not be used unless considered absolutely essential.
Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contraindicated.
4.4 Special Warnings And Precautions For Use
Close attention to pulse and blood pressure is necessary during the administration of Nitrocine infusions.
Nitrocine should be used with caution in patients suffering from hypothyroidism, severe liver or renal disease, hypothermia and malnutrition.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concurrent intake of drugs with blood pressure lowering properties e.g. beta blockers, calcium antagonists, vasodilators etc. and/or alcohol may potentiate the hypotensive effect of Nitrocine. The hypotensive effect of nitrates are potentiated by concurrent administration of sildenafil (Viagra®). This might also occur with neuroleptics and tricyclic antidepressants.
4.6 Pregnancy And Lactation
There is no, or inadequate, evidence of safety of the drug in human pregnancy or lactation, but it has been in widespread use for many years without apparent ill consequence, animal studies having shown no hazard. If drug therapy is needed in pregnancy, this product can be used if there is no safer alternative.
4.7 Effects On Ability To Drive And Use Machines
None stated.
4.8 Undesirable Effects
In common with other nitrates, headaches and nausea may occur during administration. Other possible adverse reactions include hypotension, tachycardia, retching, diaphoresis, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness and abdominal pain. Paradoxical bradycardia has also been observed.
4.9 Overdose
Mild overdose usually results in hypotension and tachycardia. If arterial systolic blood pressure drops below 90 mmHg and if heart rate increases 10% above its initial value, the infusion should be discontinued to allow a return to pre-treatment levels. If hypotension persists, or in more severe cases, this may be reversed by elevating the legs and/or treatment with hypertensive agents.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: C01DA 02 – Organic Nitrates
Glyceryl trinitrate reduces the tone of vascular smooth muscle. This action is more marked on the venous capacitance vessels than the arterial vessels. There is a reduction in venous return to the heart and a lowering of elevated filling pressure. This lowering of filling pressure reduces the left ventricular end diastolic volume and preload. The net effect is a lowering of myocardial oxygen consumption.
Systemic vascular resistance, pulmonary vascular pressure and arterial pressure are also reduced by glyceryl trinitrate and there is a net reduction in the afterload.
By reducing the preload and afterload, glyceryl trinitrate reduces the workload on the heart.
Glyceryl trinitrate affects oxygen supply by redistributing blood flow along collateral channels from the epicardial to endocardial regions.
5.2 Pharmacokinetic Properties
As with all commonly used organic nitrates the metabolic degradation of glyceryl trinitrate occurs via denitration and glucuronidation. The less active metabolites resulting from this biotransformation can be recovered from the urine within 24 hours.
Glyceryl trinitrate is eliminated from plasma with a short half-life of about 2-3 minutes. This rapid disappearance from plasma is consistent with the high systemic clearance values for this drug (up to 3270 L/hour)
5.3 Preclinical Safety Data
None stated
6. Pharmaceutical Particulars
6.1 List Of Excipients
Glucose
Propylene glycol
Water for injection.
Hydrochloric acid (for pH adjustment)
6.2 Incompatibilities
Nitrocine contains glyceryl trinitrate in isotonic sterile solution and is compatible with commonly employed infusion solutions. No incompatibilities have so far been demonstrated.
Nitrocine is compatible with glass infusion bottles and with rigid infusion packs made of polyethylene. Nitrocine may also be infused slowly using a syringe pump with a glass or plastic syringe.
Nitrocine 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.
6.3 Shelf Life
Glass ampoules 5 years
Glass vials 5 years
For admixture shelf life, refer to section 6.4.
6.4 Special Precautions For Storage
Chemical and physical in-use stability of the admixture has been demonstrated for 24 hours at 25˚C in suitable containers.
From a microbiological point of view, 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 to 8˚C, unless dilution has taken place in controlled and validated aseptic conditions.
6.5 Nature And Contents Of Container
Glass ampoules 10 ml (Type I glass)
Glass, rubber stoppered vials 50 ml (Type II glass)
6.6 Special Precautions For Disposal And Other Handling
Bottles of Nitrocine are for single use only and should not be regarded as multi-dose containers.
Admixtures are prepared by replacing a given volume of infusion vehicle with an equal volume of the product to produce the final infusion solution. For admixture storage, refer to section 6.4.
7. Marketing Authorisation Holder
UCB Pharma Limited
208 Bath Road
Slough
Berkshire
SL1 3WE
United Kingdom
8. Marketing Authorisation Number(S)
PL 00039/0747
9. Date Of First Authorisation/Renewal Of The Authorisation
21 January 2009
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