TRINIPATCH 5 mg/24 h Transdermal patch (22,4 mg / 7 cm²) 30Sachet/1dispenser

Transdermal system.
Sachet. Box of 30.

Trinitrine 22,4 mg, for a transdermal device of 7 cm².

Preventive treatment of angina attacks.

TRINIPATCH is indicated in adults.

Dosage

Paediatric population

The safety and efficacy of TRINIPATCH in children have not yet been established.

Adults

• Nitrate derivatives are administered intermittently over the nycthemeral cycle, with a daily nitrate-free interval, in order to avoid the phenomenon of therapeutic tolerance, which is well established when nitrate derivatives are administered continuously.
• This symptom-free interval will be chosen within the period when the patient does not present with an attack. The duration of the symptom-free interval is at least 8 hours. The timing of the associated antianginal treatment (β beta-blocker and/or calcium antagonist) should be chosen to ensure therapeutic coverage during this symptom-free interval.
• In the preventive treatment of angina attacks, the phenomenon of tolerance is well established. Controlling prescription methods so as to respect a nitrate-free interval ensures nitrate derivatives have recognised therapeutic efficacy. The times of application and removal of the transdermal patch must be clearly stated on the prescription. The response to nitrate derivatives varies from patient to patient, and the lowest effective dose should be prescribed at the start of treatment.
• The treatment regimen is as follows: application of one patch per day, starting with the least dosed patch, i.e. 5 mg/24 h per day. In case of insufficient efficacy, the dosage will be increased to one transdermal patch of 10 mg/24 h per day, i.e. 0,4 mg per hour, then if necessary to one transdermal patch of 15 mg/24 h per day, i.e. 0,6 mg per hour.

Method of administration

• The patch must be applied to the skin at a healthy, dry and clean site where hair is sparse (lateral chest wall, for example). For good adhesion, it is useful to apply the system well by pressing with the palm of the hand for about ten seconds. The double-tab system allows the patch to be applied without fingers contacting the trinitrine.
• After the prescribed application duration, remove and discard the used system, then take care to apply the new system at a different site. Do not reapply a system to the same site until several days have passed, in order to avoid local irritation phenomena.
• In case of spontaneous detachment, a new system should be put in place (at a different site).

This medicine MUST NEVER BE USED in the following cases:

• hypersensitivity to the active substance or to any of the excipients mentioned in section Composition,
• shock state, severe hypotension,
• in association with phosphodiesterase 5 (PDE5) inhibitors (see sections Interactions and Warnings and precautions) :
  • in any patient treated with a nitrate derivative, in whatever form, a phosphodiesterase 5 (PDE5) inhibitor must not be prescribed while the patient is under the effect of the nitrate derivative, because of the risk of significant hypotension (synergistic effect) that may worsen the state of myocardial ischemia and notably cause an acute coronary event.
  • in case of treatment with phosphodiesterase inhibitors 5, nitrate derivatives are contraindicated in any form whatsoever. In particular, any patient should be warned coronary patient that, if during sexual activity they experience anginal pain, they must in no case take an immediate-acting nitrate derivative.
  • likewise, in a patient without coronary history presenting with a first episode of angina following sexual activity, the history should be used to look for possible intake of phosphodiesterase inhibitors 5 (most often within the hour preceding sexual activity) and, if this is the case, nitrate treatment should be avoided.
  • in general, according to available data, the interval to be observed before administering a nitrate derivative to a patient exposed to phosphodiesterase inhibitors 5 is not precisely known, but can be estimated at a minimum of 24 hours.
• in combination with riociguat (see section Interactions)

This medicine should GENERALLY NOT BE USED in cases of:

• obstructive cardiomyopathy,
• inferior-wall myocardial infarction with extension to the right ventricle, in the acute phase,
• intracranial hypertension,
• breastfeeding.

Special warnings

• This medicine is not a curative treatment for an angina attack, nor is it indicated as initial treatment for unstable angina or myocardial infarction, either in the pre-hospital phase or during the first days of hospitalization.
• In case of collapse or a state of shock, remove the device (see section Contraindications).
• If an angina attack occurs during the symptom-free interval (as well as outside it), a reassessment of the coronary artery disease is required, and an adjustment of treatment should be discussed (drug treatment and possibly revascularization).
• Association of nitrate derivatives with a phosphodiesterase type 5 inhibitor: the combination of a nitrate derivative, whatever its nature or mode of administration, with a phosphodiesterase type 5 inhibitor may cause a significant and sudden fall in blood pressure, which may in particular lead to lipothymia, syncope or acute coronary accident (see section Interactions and Contraindications).
• The device must be removed before exposing the human body to a magnetic field during examinations such as MRI, or before performing external electrical cardioversion or diathermy treatment.

Precautions for use

• The effective dose should be reached gradually because of the risk of arterial hypotension and severe headaches in some subjects, except where the transdermal route is used following an intravenous form of nitrate derivatives.
• Vasodilator and antihypertensive substances, diuretics, and alcohol may increase the hypotension caused by nitrate derivatives, especially in elderly people.
• It is not logical to combine trinitrin with molsidomine or nicorandil since their mechanisms of action are similar.

Contraindicated combinations (see section Contraindications)

+ Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil)

Risk of significant hypotension (synergistic effect) which may worsen the state of myocardial ischaemia and in particular cause acute coronary accident.

+ Riociguat

The use of glyceryl trinitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section Contraindications), as concomitant use may cause hypotension

Associations to be taken into account

+ Medicines lowering blood pressure (antihypertensives, imipramine-type antidepressants, neuroleptics, alpha-blockers for urological use, amifostine, baclofen, beta-blockers in heart failure)

Increased risk of hypotension, particularly orthostatic hypotension.

Pregnancy

• There are no reliable data on teratogenicity in animals.
• In clinical practice, there are currently no sufficiently relevant data to assess a possible teratogenic or fetotoxic effect of trinitrin when administered during pregnancy.
• Consequently, except in acute situations, the use of trinitrin is not recommended during pregnancy.

Breast-feeding

• In the absence of data on passage into breast milk, breastfeeding is not recommended during the duration of treatment.

At the start of treatment, there is a risk of orthostatic hypotension, which may be accompanied by dizziness, presyncope, or, exceptionally, syncope.

Adverse effects are listed in decreasing order of frequency, as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1 000, < 1/100); rare (≥ 1/10 000, < 1/1 000); very rare (< 1/10 000), including isolated cases.

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 national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

The risk of overdose is very low. If several devices are applied, the occurrence of systemic side effects is possible: nausea, vomiting, methemoglobinemia. These manifestations can be rapidly treated by removing the devices and specialized management.

Pharmacotherapeutic class: Vasodilator used in cardiology/nitrated derivative, ATC code: C01DA02.

Mechanism of action

Nitrate derivatives are donors of nitric oxide (NO). NO, by stimulating the formation of cyclic GMP, leads to relaxation of vascular smooth muscle fibres.

The main actions of nitrated derivatives are as follows:

• predominant venous vasodilation responsible for a decrease in venous return to the heart, and therefore in cardiac preload;
• coronary vasodilation which, combined with a decrease in left ventricular telediastolic pressure linked to the decrease in venous return, leads to a redistribution of coronary perfusion towards the subendocardial zones, which are particularly vulnerable to ischaemia;
• an antispasmodic action at the coronary level;
• peripheral arteriolar vasodilation at high doses, resulting in a reduction of peripheral vascular resistance, and therefore of cardiac afterload.

Pharmacodynamic effects

These effects contribute to rest and exertion, to a decrease in myocardial oxygen requirements (decrease in cardiac workload related to pre- and post-load) and to an increase in oxygen supply (coronary vasodilation and redistribution), which are the basis for the indications of nitrated derivatives in angina.

Furthermore, the decrease in cardiac venous return, which is accompanied by a decrease in pulmonary capillary pressures, combined with the decrease in post-load in the case of high doses of nitrated derivatives, are the basis for the indications of certain derivatives in left or global heart failure.

Absorption

The transdermal system allows continuous and controlled release of trinitrine from an adhesive matrix containing the active ingredient.

Distribution

After application of the device to the skin, trinitrine passes directly into the circulation in active form (no first-pass effect in the liver).

Trinipatch 5 mg/24 hours releases an average dose of 5 mg of trinitrine per 24 hours, i.e. 0,2 mg per hour.

The plasma concentrations obtained are constant between 2 and 24 hours after application.

Upon removal of the system, plasma trinitrine levels decrease rapidly to become negligible after 1 hour.

Biotransformation

The main metabolites consist of dinitrated (1,3 and 1,2) and mononitrated derivatives; they are partially eliminated in the form of glucuronoconjugated derivatives.

Elimination

Elimination is essentially urinary.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenesis, and reproduction and developmental function studies revealed no particular risk for humans.

3 years

No special precautions for storage.

No special requirements for disposal.