Nitorol

1. Intravenous

Nitorol is indicated in the treatment of unresponsive left ventricular failure secondary to acute myocardial infarction, unresponsive left ventricular failure of various aetiology and severe to unstable angina pectoris.

2. Intra-coronary

Nitorol is indicated during percutaneous transluminal coronary angioplasty to facilitate prolongation of balloon inflation and to prevent or relieve coronary spasm.

- Treatment of unresponsive left ventricular failure, secondary to acute myocardial infarction.

- Unresponsive left ventricular failure of various aetiologies.

- Severe or unstable angina pectoris.

- To facilitate or prolong balloon inflation and to prevent or relieve coronary spasm during percutaneous transluminal coronary angioplasty.

Adults, including the elderly

Intravenous route

Nitorol 0.5 mg/ml (undiluted) is intended for intravenous administration by slow infusion via a syringe pump. Alternatively it can be administered as an admixture with a suitable vehicle such as Sodium Chloride Injection B.P. or Dextrose Injection B.P.

A dose of between 2mg and 12mg per hour is usually satisfactory. However, dosages up to 20mg per hour may be required. In all cases the dose administered should be adjusted to the patient response.

Intra-coronary Route

Nitorol 0.5 mg/ml 10ml prefilled syringes may be used for direct administration (through a catheter by means of an adaptor, if necessary) during percutaneous transluminal coronary angioplasty.

The usual dose is 1mg given as a bolus injection prior to balloon inflation. Further doses may be given not exceeding 5mg within a 30 minute period.

Children

The safety and efficacy of Nitorol has not yet been established in children.

Avoid administration through PVC tubing and giving sets, because of adsorption of ISDN into plastic.

Intravenous administration: Dosage should be adjusted according to patient response. Typically, a dose of between 2mg and 12 mg per hour is suitable, although doses of up to 20mg per hour may be necessary.

Nitorol 0.05% can be administrated undiluted by slow intravenous infusion using a syringe pump.

Intracoronary administration: Nitorol 0.05% can be injected directly by this route according to the proposed dosage schedule. The usual dose is 1mg given as a bolus injection prior to balloon inflation. Additional doses may be given, not exceeding 5mg over 30 minutes.

The safety and efficacy of Nitorol 0.05% has not been established in children.

No modifications to the dosage are necessary for elderly patients.

Nitorol 0.05% is presented in 50mL vials intended for single use only.

These are common to all nitrates: hypersensitivity to isosorbide dinitrate, other nitrates or any of the excipients, marked anaemia, cerebral haemorrhage, head trauma, diseases associated with an increased intracranial pressure, hypovolaemia, severe hypotension (systolic blood pressure less than 90 mmHg), aortic and/or mitral valve stenosis, closed angle glaucoma.

Use in circulatory collapse or low filling pressure is also contraindicated.

Nitorol should not be used in the treatment of cardiogenic shock (unless some means of maintaining an adequate diastolic pressure is undertaken), hypertrophic obstructive cardiomyopathy, constrictive pericarditis or cardiac tamponade.

Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates. Therefore, Nitorol must not be given to patients receiving phosphodiesterase-5 inhibitors.

Use of Nitorol 0.05%is contra-indicated in patients with known hypersensitivity to nitrates, marked anaemia, cerebral haemorrhage, trauma, hypovolaemia and severe hypotension.

Nitorol 0.05% must not be used in cases of circulatory collapse or low filling pressure.

Treatment of cardiogenic shock with Nitorol 0.05% should only be undertaken if means of maintaining an adequate diastolic pressure is available.

Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contra-indicated.

Nitorol should be used with caution and under medical supervision in patients who are suffering from:

- hypothyroidism,

- malnutrition,

- severe liver or renal disease

- hypothermia

- orthostatic syndrome

The development of tolerance (decrease in efficacy) as well as cross tolerance towards other nitrate-type drugs (decrease in effect in case of a prior therapy with another nitrate drug) has been described. For a decrease in, or loss of, effect to be prevented, continuously high dosages must be avoided.

Blood pressure and pulse rate should always be monitored and the dose adjusted according to the patient's response.

Nitorol contains 0.15mmol (3.54mg) of sodium per ml and should be taken into consideration by patients on a controlled sodium diet.

Nitorol 0.05% should be used with caution in patients who are predisposed to closed angle glaucoma, and in patients suffering from hypothyroidism, malnutrition, severe liver or renal disease or hypothermia.

As for other drugs which produce changes in blood pressure, patients taking Nitorol should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

None stated.

During administration of Nitorol the following undesirable effects may be observed:

Nervous system disorders: headache, dizziness, somnolence.

Cardiac disorders: tachycardia, angina pectoris aggravated.

Vascular disorders: orthostatic hypotension, collapse (sometimes accompanied by bradyarrhythmia and syncope).

Gastrointestinal disorders: nausea, vomiting, heartburn.

Skin and subcutaneous tissue disorders: allergic skin reactions (e.g. rash), flush, angioedema, Stevens-Johnson-Syndrome, in single cases: exfoliative dermatitis.

General disorders and administration site conditions: asthenia

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

During treatment with Nitorol 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.

Headache, nausea and tachycardia may occur during administration. Consistent with the known vasodilatory effects of Nitorol, a sharp fall in the systemic arterial pressure may occur requiring close attention to pulse and blood pressure during administration.

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.

o Symptoms:

- Fall of blood pressure ≤ 90 mmHg

- Pallor

- Sweating

- Weak pulse

- Tachycardia

- Postural dizziness

- Headache

- Asthenia

- Dizziness

- Nausea

- Vomiting

- Diarrhoea

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

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

General procedure:

- Stop delivery of the drug

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

- The patient must be laid down with lowered head and raised legs

- Supply oxygen

- Expand plasma volume (i.v. fluids)

- Specific shock treatment (admit patient to intensive care unit)

Special procedure:

- Raise the blood pressure if the blood pressure is very low.

- Vasopressors should be used only in patients who do not respond to adequate fluid resuscitation.

- Additional administration of noradrenaline or other vasoconstrictors.

- Treatment of methaemoglobinaemia

- Reduction therapy of choice with vitamin C, methylene-blue, or toluidine-blue

- Administer oxygen (if necessary)

- Initiate artificial ventilation

- Resuscitation measures

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

If arterial blood pressure drops below 99mmHg and if heart rate increases above 10% of its initial value, administration should be discontinued to allow a return to pre-treatment levels. If hypotension persists, measures should be taken to increase blood pressure.

Isosorbide dinitrate is an organic nitrate, which in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.

Isosorbide dinitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilatation of large epicardial vessels.

It reduces the requirement of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.

Nitorol is a potent venodilator and arterial dilator. It reduces systemic arterial pressure in a dose-related manner and, by causing peripheral venous pooling, reduces venous return and hence ventricular filling pressure and cardiac workload. Like all other nitrates, Nitorol dilates coronary arteries and relieves coronary artery spasm. An attenuation of the hypotensive and venodilator effects may be observed during long term therapy.

Isosorbide dinitrate (ISDN) is eliminated from plasma with a short half-life (about 0.7h). The metabolic degradation of ISDN occurs via denitration and glucuronidation, like all organic nitrates. The rate of formation of the metabolites has been calculated for isosorbide-5-mononitrate (IS-5-MN) with 0.57h^-1 followed by isosorbide-2-mononitrate (IS-2-MN) with 0.27h^-1and isosorbide (IS) with 0.16h^-1, IS-5-MN and IS-2-MN are the primary metabolites, which are also pharmacologically active. IS-5-MN is metabolised to isosorbide 5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5h) is shorter than that of IS-5-MN (about 5.1h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2h) lies in between.

Plasma protein binding of Nitorol is about 30% and the volume of distribution is large (reported at between 100 and 600 litres).

Mean half-life is about 1 hour but will be prolonged after chronic dosing. Metabolism of Nitorol occurs in the liver by denitration and glucuronidation. Both the 2- and the 5- mononitrates are biologically active. Only traces of the unchanged drug are eliminated in the urine.

About 80% of the dose of Nitorol can be recovered as metabolites in the urine within 24 hours.

Acute toxicity:

Acute toxicity of isosorbide dinitrate was related to an exaggerated pharmacodynamic effect. Animal studies showed good local tolerability of the undiluted isosorbide dinitrate solution.

Chronic toxicity:

In chronic oral toxicity studies in rats and dogs, toxic effects including CNS symptoms and an increase in liver weight, were observed at exposures considered sufficiently in excess of the maximum human exposure levels indicating little relevance to clinical use.

Reproduction studies:

There is no evidence from animal studies suggesting a teratogenic effect of isosorbide dinitrate. At high maternally toxic oral doses, isosorbide dinitrate was associated with increased post-implantation loss and reduced survival of offspring.

Mutagenicity and carcinogenicity:

No evidence for mutagenic effect was found in both in vitro and in vivo tests.

A long-term study in rats did not provide any evidence for carcinogenicity.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

Polyvinyl chloride (PVC) or polyurethane (PU) giving sets and containers should not be used since significant losses of the active ingredient by adsorption occur and it has not been verified how the dose can be adjusted to suit the patient's needs to account for this adsorption.

Materials made of glass, polyethylene (PE), polypropylene (PP) or polytetrafluoroethylene (PTFE) have been shown to be suitable for infusing Nitorol 0.5 mg/ml.

The use of PVC giving sets and containers should be avoided as significant losses of the active ingredient by adsorption can occur.

Nitorol contains isosorbide dinitrate in isotonic solution and is compatible with commonly employed infusion fluids, such as sodium chloride solution, 5-30% glucose solution, Ringer's solution and solutions containing albumin. No incompatibilities have so far been demonstrated.

Nitorol must be diluted under aseptic conditions immediately after opening. The diluted solution is to be used immediately. Any unused contents of the container should be discarded.

The injection is for single dose use only.

The injection should not be used if particles are present.

Nitorol 0.05% may be administered undiluted. Once opened, the product should be used immediately and any unused drug discarded.

Nitorol 0.05%is compatible with commonly employed infusion fluids. It is compatible with glass infusion bottles and infusion packs made from polyethylene. A syringe pump with a glass or plastic syringe may also be used for infusion.

Nitorol solutions diluted with Sodium Chloride Injection BP or Glucose Injection BP have been shown to be chemically and physically stable for 72 hours at 25°C, when stored in polypropylene or glass containers, protected from light.

From a microbiological point of view, the diluted 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 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.