Section 1, 4.1, 4.2, 4.3, 4.4, 4.5, 4.7, 4.8, 4.9, 5.2 and 5.3 have been updated as shown below:
1. TRADE NAME OF THE MEDICINAL PRODUCT
TRANSIDERM NITRO®Transiderm Nitro 5.
4. CLINICAL PARTICULARS
4.1 Therapeutic iIndications
Prophylactic treatment of attacks of angina pectoris, as monotherapy or in combination with other anti-anginal agents.
Prophylactic treatment of phlebitis and extravasation secondary to venous cannulation for intravenous fluid and drug administration when the duration of treatment is expected to last for 2 days or longer.
4.2 Posology and mMethod of aAdministration
For dermal administration
Adults:
Angina: Treatment should be initiated with one Transiderm Nitro TRANSIDERM-NITRO 5 patch daily. If a higher dosage is required a Transiderm Nitro TRANSIDERM-NITRO 10 patch may be substituted. The dosage may be increased to a maximum of two Transiderm Nitro TRANSIDERM-NITRO 10 patches daily in resistant cases. Transiderm Nitro TRANSIDERM-NITRO may be given either continuously, or intermittently with a patch off period of 8-12 hours, usually at night, during each 24 hour period. Development of tolerance or attenuation of therapeutic effect commonly occurs with prolonged or frequent administration of all long-acting nitrates. Recent evidence suggests that intermittent therapy with Transiderm Nitro TRANSIDERM-NITRO may reduce the incidence of tolerance.
Prior to the use of intermittent therapy, the clinical benefits to the patients should be weighed against the risks of angina in the patch-free interval. In patients considered to be at risk, concomitant anti-anginal therapy should be implemented (see “Precautions”).
It is recommended that the patch is applied to the lateral chest wall. The replacement patch should be applied to a new area of skin. Allow several days to elapse before applying a fresh patch to the same area of skin. If acute attacks of angina pectoris occur, rapidly acting nitrates may be required.
Phlebitis and extravasation: One Transiderm Nitro TRANSIDERM-NITRO 5 patch is to be applied distal to the site of intravenous cannulation at the time of venepuncture. The patch should be removed after 3-4 days and a new replacement patch applied to a different area of skin. Treatment with Transiderm Nitro TRANSIDERM-NITRO should be discontinued once intravenous therapy has stopped.
Use in the elderly
No specific information on use in the elderly is available; however no evidence exists to suggest that an alteration in dosage is required.
Use in children
There is insufficient knowledge of the effects of Transiderm Nitro TRANSIDERM-NITRO in children and therefore recommendations for its use cannot be made.
4.3 Contraindications
· Known hypersensitivity to nitroglycerin, and related organic nitrates or any excipient.
· Acute circulatory failure associated with marked hypotension (shock).
· Conditions associated with elevated intracranial pressure.
· Myocardial insufficiency due to obstruction, as in aortic or mitral stenosis or constrictive pericarditis.
· Concomitant use of Transiderm Nitro TRANSIDERM-NITRO and phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra®) is contraindicated, because PDE5 inhibitors may amplify the vasodilatory effects of Transiderm Nitro TRANSIDERM-NITRO resulting in severe hypotension.
4.4 Special wWarnings and pPrecautions for use
Warnings
As with other nitrate preparations, when transferring the patient on long-term therapy to another form of medication, nitroglycerin should be gradually withdrawn and overlapping treatment started.
The Transiderm Nitro TRANSIDERM-NITRO patch contains an aluminium layer. Therefore the patch must be removed before applying magnetic or electrical fields to the body during procedures such as MRI (Magnetic Resonance Imaging), cardioversion, DC defibrillation or diathermy treatment.
In cases of recent myocardial infarction or acute heart failure, treatment with Transiderm Nitro TRANSIDERM-NITRO should be carried out cautiously under strict medical surveillance and/or haemodynamic monitoring.
Removal of the patch should be considered as part of the management of patients who develop significant hypotension.
Precautions
Hypoxaemia
Caution should be exercised in patients with arterial hypoxaemia (including G6PD deficiency induced forms) due to severe anaemia because, in such patients the biotransformation of nitroglycerin is reduced. Similarly, caution is called for in patients with hypoxaemia and a 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. 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.
Hypertrophic cardiomyopathy
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Increased angina
The possibility of increased frequency of angina during patch-off periods should be considered. In such cases, the use of concomitant anti-anginal therapy is desirable.
Tolerance to sublingual nitroglycerin
If tolerance to nitroglycerin patches develops, the effects of sublingual nitroglycerin on exercise tolerance may be partially diminished.
Use of Transiderm Nitro TRANSIDERM NITRO in the prevention of phlebitis
The infusion site should be examined regularly. If phlebitis develops, it should be treated accordingly.
4.5 Interactions with other medicinal productsMedicaments and other forms of Iinteraction
Concomitant administration of Transiderm Nitro and treatment with other vasodilators (e.g PDE5 inhibitors such as sildenafil [Viagra®]), calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers, as well as the consumption of alcohol, may potentiates the blood pressure lowering effects of Transiderm NitroTRANSIDERM-NITRO.
Concomitant treatment with calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers may potentiate the blood pressure-lowering effect of Transiderm Nitro, as may alcohol.
Concurrent administration of Transiderm Nitro TRANSIDERM-NITRO with dihydroergotamine may increase the bioavailability of dihydroergotamine. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises the effect of nitroglycerin and may lead to coronary vasoconstriction.
The non-steroidal anti-inflammatory drugs except acetyl salicylic acid may diminish the therapeutic response of Transiderm NitroTRANSIDERM-NITRO.
Concurrent administration of Transiderm Nitro TRANSIDERM-NITRO with amifostine and acetyl salicylic acid may potentiate the blood pressure lowering effects of Transiderm NitroTRANSIDERM-NITRO.
4.7 Effects on aAbility to dDrive and use mMachinesry
Transiderm NitroTRANSIDERM-NITRO, especially at the start of treatment or dose adjustments, may impair the reactions or might rarely cause orthostatic hypotension and dizziness (as well as exceptionally syncope after overdosing). Patients experiencing these effects should refrain from driving or using machines.
4.8 Undesirable eEffects
Adverse drug reactions are ranked in descending order of frequency, as follows: Very common (=1/10); common (=1/100, <1/10); uncommon (=1/1000, <1/100); rare (=1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1
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Nervous System Disorders:
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Common:
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Headache
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Very rare:
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Dizziness
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Cardiac Disorders:
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Rare:
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Tachycardia
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Vascular Disorders:
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Rare:
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Postural Orthostatic hypotension, flushing
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Gastrointestinal Disorders:
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Very Common:
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Nausea, vomiting
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Skin and subcutaneous tissue disorders:
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Uncommon:
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Contact dermatitis
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General disorders and administration site conditions:
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Uncommon:
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Application site Eerythema, pruritus, burning, irritation.
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Investigations:
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Rare:
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Heart rate increase
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Like other nitrate preparations, Transiderm Nitro TRANSIDERM-NITRO commonly causes dose-dependent headaches due to cerebral vasodilatation. 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 nitroglycerin 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.
Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.
The following adverse drug reactions have been derived from post-marketing experience with Transiderm Nitro via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.
- Cardiac disorders: palpitation.
- Skin and subcutaneous tissue disorders: rash generalized.
A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.
4.9 Overdose
Signs
High doses of nitroglycerin may lead to severe hypotension and reflex tachycardia or to collapse and syncope. Methaemoglobinaemia has also been reported following accidental overdosage.
Management
The nitrate effect of Transiderm Nitro TRANSIDERM NITRO can be rapidly terminated simply by removing the system(s).
Hypotension or collapse can be treated by elevation or, if necessary, compression bandaging of the patient’s legs.
5. PHARMACOLOGICAL PARTICULARS
5.1 Pharmacodynamic pProperties
ATC code: C01DA02
Nitroglycerin relaxes smooth muscle. It acts chiefly on systemic veins and large coronary arteries, with more predominant effects on the former. In angina pectoris the fundamental mechanism of action of nitroglycerin is based on an increase in venous capacitance leading to a decreased return of blood to the heart. Owing to this, preload and hence filling volume diminishes, resulting in a decreased myocardial oxygen requirement at rest and especially during exercise.
In the coronary arterial circulation nitroglycerin dilates extramural conductance and small resistance vessels. It appears to cause redistribution of coronary blood flow to the ischaemic subendocardium by selectively dilating large epicardial vessels and also relaxes vasospasm.
Nitroglycerin dilates the arteriolar vascular bed, as a result of which afterload and left ventricular systolic wall tension decrease, leading to a reduction in myocardial oxygen consumption.
5.2 Pharmacokinetic pProperties
Following a single application, plasma concentrations of nitroglycerin reach a plateau within 2 hours, which is maintained throughout the day until patch removal. The height of this plateau is directly proportional to the size of the system’s drug-releasing area.
The same plasma levels are attained regardless of whether the system is applied to the skin of the upper arm, pelvis or chest. Upon removal of Transiderm Nitro TRANSIDERM-NITRO the plasma level falls rapidly. After repeated application of Transiderm Nitro TRANSIDERM-NITRO no cumulation occurs.
5.3 Preclinical sSafety dData
None stated.Mutagenicity
Standard mutagenicity tests provided contradictory results in vitro. Cell culture and in vivo studies revealed no evidence of mutagenic activity of nitroglycerin, and therefore its use is considered devoid of genotoxic potential at exposures relevant to man.
Carcinogenicity
Dietary studies in rodents led to the conclusion that nitroglycerin has no carcinogenic effects relevant for the therapeutic dose range in man.
Reproduction toxicity
Animal teratology studies have not been conducted with nitroglycerin transdermal systems. Conventional reproduction studies involving the oral, intravenous, intraperitoneal and dermal (as ointment) administration routes of nitroglycerin have been performed in rats and rabbits. Nitroglycerin showed no teratogenic potential in these animals.
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