NITROCINE Solution for infusion Ref.[50442] Active ingredients: Glyceryl trinitrate

Nitrocine must be used only with particular caution and under medical supervision in:

• Low filling pressures e.g. in acute myocardial infarction, impaired left ventricular function (left ventricular failure). Reducing systolic blood-pressure below 90 mmHg must be avoided.
• Orthostatic dysfunction.
• Hypertrophic cardiomyopathy (nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy).

The development of tolerance and cross tolerance to other nitro compounds has been described.

Nitrocine must not be used in patients known to be taking phosphodiesterase inhibitor-containing products (e. g. sildenafil, vardenafil, tadalafil) in the intervening 24h (48h for tadalafil). Patients who receive GTN solution therapy must be warned not to take phosphodiesterase inhibitor-containing products (e. g. sildenafil, vardenafil, tadalafil) (see sections 4.3 and 4.5).

Materials made of polyethylene (PE), polypropylene (PP) or polytetrafluorethylene (PTFE) have proven to be suitable for infusing GTN solution. However, infusion material made of polyvinyl chloride (PVC) or polyurethane (PU) has been shown to induce a loss of the active substance due to adsorption. If these materials are used the dose must be adjusted to suit patient’s needs (see also section 6.2).

The solution contains glucose; this should be taken into account in patients with diabetes mellitus.

During treatment with GTN alcohol should be avoided as it may potentiate the hypotensive and vasodilating effect of GTN (see section 4.5)

Hypoxaemia

Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is reduced.

Similarly, caution is called for in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.

Patients with angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia).

Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (see also section 4.8). As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.

Methemoglobinemia

Following treatment with Nitrocine, methemoglobinemia has been reported. Treatment of methaemoglobinemia with methylene blue is contraindicated in patients with glucose-6-phosphate deficiency or methemoglobin-reductase deficiency (see also section 4.9).

Concomitant treatment with other drugs with blood pressure lowering properties e.g. vasodilators (e.g. PDE5 inhibitors such as Sildenafil), calcium channel antagonists, ACE-inhibitors, monoamine oxidase inhibitors, beta-blockers, diuretics, tricyclic antidepressants and neuroleptics, as well as the consumption of alcohol, may potentiate the hypotensive effect of the preparation.

The blood pressure lowering effect of Nitrocine will be increased if used together with phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) which are used for erectile dysfunction (see Section 4.3). This might lead to life threatening cardiovascular complications. Patients who have recently taken phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) therefore must not be treated with Nitrocine solution in the intervening 24h (48h for tadalafil). Patients who are on Nitrocine therapy therefore must not use phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil). To assure that the risk of adverse events with concomitant use is minimised, patients taken Nitrocine or PDE5 inhibitors must wait until either one is washed out.

The use of Nitrocine with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.

Simultaneous intravenous infusions of tissue plasminogen activator (tPA) and glyceryl trinitrate may accelerate plasma clearance of tPA by increasing hepatic blood flow.

Reports suggest that, when administered concomitantly, nitrocine may increase the blood level of dihydroergotamine and its effect. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises the effect of Nitrocnine and may lead to coronary vasoconstriction.

The use of heparin and nitrocine solution can lead to a partial loss of action of heparin when both drugs are given simultaneously by intravenous route. Concurrent administration of Nitrocine with acetyl salicylic acid may potentiate the blood pressure lowering effects of Nitrocine.

The non-steroidal anti-inflammatory drugs except acetyl salicylic acid may diminish the therapeutic response of Nitrocine.

Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).

Fertility

Reproduction toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on mating, fertility and general reproductive parameters.

There is no data available on the effect of Nitrocine on fertility in humans.

Pregnancy

Developmental toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on the embryos, fetuses or the young animals even at toxic doses for the dam.

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.

Lactation

Available evidence is inconclusive or inadequate for determining infant risk when used during breastfeeding. There is data that nitrates are excreted in breast milk and may cause methemoglobinemia in infants. The extent of excretion of nitroglycerin in human breast milk has not been determined. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Nitrocine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Nitrocine may affect the patient’s reactivity to an extent that her/his ability to drive or to operate machinery is impaired. This effect is increased in combination with alcohol.

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

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

During treatment with Nitrocine, 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. Like other nitrate preparations, Nitrocine commonly causes dose-dependent headaches due to cerebral vasodilation. These often regress after a few days despite the maintenance of therapy. If headaches persist during intermittent therapy, they should be treated with mild analgesics. Unresponsive headaches are an indication for reducing the dosage of Nitrocine or discontinuing treatment.

A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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 (see also section 4.4).

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.