Transiderm-Nitro 5
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Transiderm Nitro 5.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Nitroglycerin on lactose 250mg equivalent to nitroglycerin 25mg.
3. PHARMACEUTICAL FORM
Transdermal patch.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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 method of administration
For dermal administration
Adults:
Angina: Treatment should be initiated with one Transiderm Nitro 5 patch daily. If a higher dosage is required a Transiderm Nitro 10 patch may be substituted. The dosage may be increased to a maximum of two Transiderm Nitro 10 patches daily in resistant cases. 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 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 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 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 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 and phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra®) is contraindicated, because PDE5 inhibitors may amplify the vasodilatory effects of Transiderm Nitro resulting in severe hypotension.
• Severe hypotension (systolic blood pressure less than 90 mmHg)
• Severe hypovolemia
4.4 Special warnings and precautions 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 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 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. In Patients with alveolar hypoventilation a vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (Euler-Liljestrand mechanism). 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 in the prevention of phlebitis
The infusion site should be examined regularly. If phlebitis develops, it should be treated accordingly.
4.5. Interaction with other medicinal products and other forms of interaction
Concomitant administration of Transiderm Nitro and other vasodilators e.g PDE5 inhibitors such as sildenafil potentiates the blood pressure lowering effects of Transiderm 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 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 Nitro.
Concurrent administration of Transiderm Nitro with amifostine and acetyl salicylic acid may potentiate the blood pressure lowering effects of Transiderm Nitro.
4.6. Pregnancy and lactation
Women of child-bearing potential
There is no data supporting any special recommendations in women of child-bearing potential.
Pregnancy
Like any drug, Transiderm Nitro should be employed with caution during pregnancy, especially in the first 3 months.
Lactation
There is limited information on the excretion of the active substance in human or animal breast milk. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Transiderm Nitro therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
There is no data available on the effect of Transiderm Nitro on fertility in humans.
4.7. Effects on ability to drive and use machines
Transiderm 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 effects
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
|
Nervous System Disorders: Common: |
Headache |
|
Very rare: |
Dizziness |
|
Cardiac Disorders: Rare: |
Tachycardia |
|
Vascular Disorders: Rare: |
Orthostatic hypotension, flushing |
|
Gastrointestinal Disorders: Very Common: |
Nausea, vomiting |
|
Skin and subcutaneous tissue disorders: Uncommon: |
Contact dermatitis |
|
General disorders and administration site conditions: Uncommon: |
Application site erythema, pruritus, burning, irritation. |
|
Investigations: Rare: |
Heart rate increase |
Like other nitrate preparations, 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.
Reporting of suspected adverse reactions
Reporting 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.
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 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 PROPERTIES
5.1 Pharmacodynamic properties
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 properties
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 the plasma level falls rapidly. After repeated application of Transiderm Nitro no cumulation occurs.
5.3. Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, silicone oil, silica dioxide, ethylene-vinyl acetate copolymer, silicone-based adhesive (medical adhesive CH15).
6.2 Incompatibilities
None.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Store below 25°C.
6.5 Nature and contents of container
Individual patches in a sealed pouch (made of paper/PE/AL/surlyn1). 28 or 30 sealed patches in each cardboard container.
Instructions for use/handling
6.6
None stated.
7 MARKETING AUTHORISATION HOLDER
Novartis Pharmaceuticals UK Limited
Trading as Ciba Laboratories
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
8. MARKETING AUTHORISATION NUMBER
PL 00101/0464.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21 July 1997.
10 DATE OF REVISION OF THE TEXT
20/07/2015
Aluminium 12pm ± 10%, polyethylene 16G/m2 ± 20%, surlyn 20G/m2 ± 15%.