25 mg/5 ml, 50 mg/10 ml
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
NITROSOL (Nitroglycerin) is an organic nitrate vasodilator, active on both arteries and veins. Chemically, Nitroglycerin is 1,2,3-propanetriol trinitrate. The molecular formula is C3H5N3O9 and the molecular weight is 227.09.
STRUCTURAL FORMULA :
Its structural formula is :
NITROSOL is a sterile, clear, practically colourless solution for intravenous infusion after dilution. The solution is sterile, nonpyrogenic and nonexplosive.
Each ml contains :
Diluted Nitroglycerin USP
equivalent to Nitroglycerin 5 mg
Absolute Alcohol USP 30 % v/v
Propylene Glycol USP 30 % v/v
Water for Injection USP q.s.
Contains no preservatives.
Nitroglycerin, an organic nitrate, is a vasodilator. Its principal pharmacological action is the relaxation of vascular smooth muscle. Nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation 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 the arterial and venous effect of Nitroglycerin and a more favourable supply demand ratio can be achieved. Therapeutic doses of intravenous Nitroglycerin 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. Nitroglycerin 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 fillings 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 Nitroglycerin.
Nitroglycerin is widely distributed in the body with an apparent volume of distribution of 200 L in adult male subjects. It is rapidly metabolised in the liver to dinitrates and mononitrates, with a short half life estimated at 1-4 minutes. This results in a low plasma concentration after intravenous infusion. At plasma concentrations of between 50 - 500 mg/ml, the binding of Nitroglycerin to plasma proteins is approximately 60 % while those of its metabolites, 1,3-glyceryldinitrate and 1,2-glyceryldinitrate are approximately 60 % and 30 % respectively. The activity and half-life of dinitroglycerin metabolities are not well characterized. Glyceryl mononitrate, the principal metabolite, is inactive.
NITROSOL permits rapid attainment of high concentration of drug in the systemic circulation and prompt initiation of therapy. Because of its rapid degradation, the concentration can be titrated quickly and safely.
NITROSOL is indicated for :
1. Control of blood pressure in pre-operative hypertension i.e. hypertension associated with surgical procedures, especially cardiovascular procedures such as hypertension during intra-tracheal intubation, anaesthesia, skin incisions, sternotomy, cardiac bypass and in immediate post- surgical period.
2. The treatment of congestive heart failure associated with acute myocardial infarction.
3. The treatment of angina pectoris in the patients who have not responded to the recommended doses of organic nitrates and/or a beta blocker, unstable angina pectoris and coronary vasospasm.
4.The production of controlled hypotension during surgical procedures.
INSTRUCTIONS FOR USE OF AMPOULE :
The ampoule used in this product is equipped with O.P.C (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.
Initial Dilution :
Aseptically transfer the desired volume of NITROSOL (see the Dilution Table) into the glass bottle containing stated volume of either 5 % w/v Dextrose Injection or 0.9 % w/v Sodium Chloride Injection (Diluent Volume). This yields a final concentration of 100 to 400 microgram/ml (see the Dilution Table). Invert the glass parenteral bottle several times following admixture to assure uniform dilution of NITROSOL.
Maintenance Dilution :
It is important to consider the fluid requirements of the patients as well as the expected duration of the infusion in selecting the appropriate dilution of NITROSOL. After initial dosage titration, the concentration of the admixture solution may be increased, if necessary, to limit fluids given to the patient. The concentration of the infusion solution should not exceed 400 mcg/ml of Nitroglycerin. Invert the glass parenteral bottle several times following admixture to assure uniform dilution of Nitroglycerin. When stored in glass containers, the diluted solution is physically and chemically stable for upto 40 hours when stored below 25°C and upto seven days under refrigeration. However, to avoid microbial contamination hazards infusion should be commenced as soon as practicable after preparation of the solution. Infusion should be completed within 24 hours and any residue discarded. Dosage is affected by the type of containers and administration sets used. If the concentration is adjusted, it is imperative to flush or replace the infusion set, before a new concentration is utilised. If the set were not flushed or replaced, it could take minutes to hours, depending upon the flow rates and dead space of the set, for the new concentration to reach the patient.
NITROSOL should not be administered to individuals with :
1.A known hypersensitivity to Nitroglycerin or a known idiosyncratic reaction to organic nitrates.
2.Hypotension or uncorrected hypovolemia, as the use of NITROSOL such states could produce severe hypotension or shock.
3.Increased intracranial pressure (e.g. head trauma or cerebral hemorrhage).
4. Inadequate cerebral circulation.
5.Constrictive pericarditis and pericardial tamponade.
6.Severe anaemia and arterial hypoxaemia.
7.Concomitant administration of Nitroglycerin with Viagra (sildenafil), as sildenafil has been shown to potentiate the vasodilatory effects of glyceryl trinitrate, resulting in severe hypotension.
1.Nitroglycerin readily migrates into many plastics. To avoid absorption of Nitroglycerin into plastic parenteral solution containers, the dilution of NITROSOL should be made in glass parenteral solution bottles.
2.Some filters absorb Nitroglycerin; they should be avoided.
3.40% to 80% of the total amount of Nitroglycerin in the final diluted solution for infusion is absorbed by the Polyvinyl Chloride (PVC) tubing of the intravenous administration sets currently in general use. The higher rates of absorption occur when flow-rates are low, Nitroglycerin concentrations are high and tubing is long. Although the rate of loss is highest during the early phase of administration (when flow rates are lowest) the loss is either constant nor self-limiting, consequently, no simple calculation or correction can be performed to convert the theoretical infusion rate (based on the concentration of the infusion solution) to the actual delivery rate. Because of this problem, we recommend the use of the least absorptive infusion tubing available (i.e. non-PVC tubing) for infusion of NITROSOL.
4.A potential safety problem exists with the combined use of some infusion pumps and some non-PVC infusion sets. Because special tubing required to prevent the absorption of Nitroglycerin (Non-PVC tubing) tends to be less pliable than the conventional PVC tubing normally used with such infusion pumps, the pumps may fail to occlude the infusion sets completely. The results may be excessive flow at low infusion rate settings, causing alarms or unregulated gravity flow when the infusion pump is stopped; this could lead to over-infusion of Nitroglycerin. All infusion pumps should be tested with the infusion sets to ensure their ability to deliver Nitroglycerin accurately at low flow rates and to occlude the infusion sets properly when the infusion is stopped.5.Acute Myocardial Infarction : NITROSOL should only be used in acute myocardial infarction for treating definite left ventricular failure. Careful haemodynamic monitoring must be observed during infusion of Nitroglycerin in patients with acute myocardial infraction to avoid a sudden fall in arterial blood pressure and reflex tachycardia, which might by reducing coronary perfusion and increasing myocardial oxygen demand, extend the area of ischaemic tissue injury.
6.Hypotension : Dosage must be carefully titrated to avoid the significant risk of precipitous fall in blood pressure, particularly in patients with severe coronary or cerebral atherosclerosis. Profound hypotension and bradycardia have been reported with sublingual, topical and intravenous Nitroglycerin.
Use in Pregnancy :
Pregnancy category B2
No studies have been conducted. NITROSOL should be given to pregnant woman only if clearly needed.
Use in Lactation :
It is not known whether Nitroglycerin is excreted into breast milk. Caution should be exercised if there is a need to administer NITROSOL to a nursing woman.
Paediatric Use :
The use of NITROSOL in children is not recommended, as its safety and effectiveness in children have not been established.
INTERACTIONS AND INCOMPATIBILITY :
1.Alcohol : Concomitant use with Alcohol may cause hypotension due to enhanced vasodilatory effects of Nitroglycerin.
2.Other drugs : Information on potential interaction with other drugs is poorly documented. Caution should be observed if other drugs are given concomitantly during infusion of NITROSOL as an interaction may adversely affect the haemodynamic response to the drug. Careful haemodynamic monitoring is essential.
3.Pancuronium : Infusion of Nitroglycerin Injection increases the duration of Pancuronium induced neuromuscular blockade. This clinical observation has been reported by studies in the cat, however neuromuscular blockade induced by Succinylcholine and d-tubocurarine were not prolonged by Nitroglycerin. The mechanism of interaction is unknown.
4.Morphine : One patient who received four 3 mg doses of I.V. Morphine sulphate during 24 hour period with I.V. Nitroglycerin became unarousable, eventually responding to Nalorphin. The possibility that I.V. Nitroglycerin slows the Morphine metabolism in this patient has been suggested. Caution should be observed when administering these two drugs simultaneously.
SIDE EFFECTS :
The most frequent possible side effect (natural, expected and unavoidable drug actions) in patients treated with NITROSOL is headache which occurs in approximately 2 % of patients. Other side effects (unusual, unexpected and infrequent reactions) occurring in less than 1 % patients are the following tachycardia, nausea, vomiting, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness and abdominal plain.
OVERDOSAGE AND TREATMENT OF OVERDOSAGE :
Accidental overdosage of NITROSOL may result in severe hypotension and reflex tachycardia which can be treated by elevating the legs and decreasing or temporarily terminating the infusion until patients condition stabilises. Since the duration of haemodynamic effects following administration is quite short, additional corrective measures are usually not required. However, if further therapy is indicated, administration of an intravenous alphaadrenergic agonist (e.g. Methoxamine or Phenylephrine) should be considered. Infusions of plasma or suitable electrolyte solutions should also be considered.
PHARMACEUTICAL PRECAUTIONS :
NITROSOL ampoules are intended for single use only. Properly discard any unused portion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is sterile, nonpyrogenic and nonexplosive.
Store below 30°C (86°F), protected from light.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
NITROSOL is supplied as Diluted Nitroglycerin USP equivalent to Nitroglycerin 5 mg/ml in 5 ml and 10 ml sterile solution.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.