NITRIDERM TTS 15 mg/24 h Transdermal disp 30 sachet

Trinitrin on lactose ...................................................................................................................750,0 mg

For a transdermal system of 30 cm².

One transdermal system at 15 mg/24 h contains 75 mg of trinitrin and releases 15 mg of trinitrin per 24 h.

Preventive treatment of angina attacks.

Reserved for adults.

NITRIDERM TTS is not intended for the immediate relief of acute angina attacks, which must be treated with fast-acting nitrate derivatives.

Dosage

Nitrate derivatives are administered intermittently over the nychthemeron, creating a daily free interval in order to avoid the phenomenon of therapeutic escape (attenuation of the therapeutic effect), which is well established when nitrate derivatives are administered continuously. This free interval should be chosen during the period when the patient does not have attacks, usually at night. The recommended duration of the free interval is 8 to 12 h.

The timing of doses of the associated antianginal treatment (ß blocker and/or calcium antagonist) should be chosen to ensure therapeutic coverage during this free interval.

Patients suffering from nocturnal angina will benefit from treatment at night followed by a free interval during the day.

In these patients, an associated antianginal treatment may be necessary during the day.

Patients suffering from severe angina may also require an associated antianginal treatment during the free interval.

In the preventive treatment of angina attacks, the phenomenon of therapeutic escape is well established. Mastery of prescribing methods respecting a free interval ensures nitrate derivatives recognised therapeutic efficacy.

The times of application and removal of the transdermal system must be clearly stated on the prescription.

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 : placement of one patch per day, starting with the least dosed patch 5 mg/24 h per day, i.e. 0,2 mg per hour.

In case of insufficient efficacy, the dosage will be increased to a transdermal patch 10 mg/24 h per day, i.e. 0,4 mg per hour, then if necessary to a transdermal patch 15 mg/24 h per day, i.e. 0,6 mg per hour.

Paediatric population

NITRIDERM TTS is not recommended in children and adolescents under 18 years of age.

Elderly subject

No dosage adjustment is recommended in elderly subjects, as no studies have been conducted in this population.

Renal and/or hepatic impairment

As no studies have been conducted in patients with impaired renal and/or hepatic function, no dosage recommendation can be made.

Method of administration

The patch must be applied to the skin in a healthy, dry and clean area where hair is sparse (lateral chest wall, for example). For good adhesion, it is useful to apply the patch well by pressing with the palm of the hand for about ten seconds.

After the prescribed application period, remove and discard the used patch, then take care to apply the new patch to another site. Do not reapply a patch to the same site until several days later, to avoid local irritation phenomena.

In case of spontaneous detachment, a new patch should be put in place (at another site).

Do not cut the patches.

• Hypersensitivity to the active substance and to nitrated derivatives or to any of the excipients mentioned in the section Composition.
• Acute circulatory failure associated with significant hypotension (shock).
• Situations of intracranial hypertension, including head trauma.
• Obstructive cardiac failure (for example, in the presence of mitral or aortic stenosis or constrictive pericarditis).
• Severe hypotension (systolic blood pressure below 90 mm Hg).
• Severe hypovolaemia.
• Severe anaemia.
• Toxic pulmonary oedema.
• In combination with a phosphodiesterase type 5 inhibitor (see sections Warnings and precautions and Interactions) :
  • in any patient treated with a nitrate derivative, in any form whatsoever, a phosphodiesterase type 5 inhibitor must not be prescribed as long as the patient is under the effect of the nitrated derivative.
  • in case of treatment with a phosphodiesterase type 5 inhibitor, nitrated derivatives are contraindicated in any form whatsoever. In particular, it is advisable to warn any 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 a first anginal episode following sexual activity, it is advisable to check by questioning whether a phosphodiesterase type 5 inhibitor may have been taken (most often, within the hour preceding sexual activity) and if so to refrain from any nitrated treatment. In general, according to the available data, the time interval to observe before administering a nitrated derivative to a patient exposed to a phosphodiesterase type 5 inhibitor is not precisely known, but may be estimated at a minimum of 24 hours.

Warnings

As with all nitrate derivatives, when switching from long-term treatment with NITRIDERM TTS to another medicinal product, discontinuation of trinitrin must be carried out gradually and a replacement treatment must be introduced during the trinitrin withdrawal period.

The NITRIDERM TTS transdermal system must be removed before the application of any magnetic or electric field to the body during procedures such as MRI (Magnetic Resonance Imaging), cardioversion or direct current defibrillation, or diathermy treatment.

In cases of recent myocardial infarction or acute heart failure, treatment with NITRIDERM TTS must be started with caution, under strict medical supervision and/or haemodynamic monitoring.

Removal of the transdermal device should be considered an integral part of the management of patients presenting with significant hypotension.

NITRIDERM TTS is not the treatment for acute angina attacks, unstable angina or myocardial infarction.

The transdermal system must be removed in cases of collapse or shock.

It is advisable to increase the dose gradually until the optimal effect is achieved: if the initial dose used is too high, severe headaches or hypotension may occur in some patients. The occurrence of these undesirable effects is rarer when switching from injectable to transdermal forms of nitrate derivatives.

Cross-tolerance with other nitrate derivatives is possible.

Paradoxical bradycardia and an increase in the frequency of angina may occur in patients with trinitrin-induced hypotension.

NITRIDERM TTS must be used with the utmost caution in patients at risk of angle-closure glaucoma.

Association of nitrate derivatives with a type 5 phosphodiesterase inhibitor:

The association of a nitrate derivative, whatever its nature or mode of administration, with a type 5 phosphodiesterase inhibitor risks causing a significant and sudden fall in blood pressure which may in particular lead to lipothymia, syncope or acute coronary accident (see sections Contraindications and Interactions).

Precautions for use

Hypoxemia

Caution is advised in patients presenting with arterial hypoxemia secondary to severe anemia (including forms induced by G6PD deficiency) because the biotransformation of trinitrin is reduced in these patients.

Likewise, caution is required in patients with hypoxaemia and a ventilation/perfusion ratio imbalance due to lung disease or ischaemic heart failure. In patients with alveolar hypoventilation, intrapulmonary vasoconstriction occurs in order to divert perfusion from areas of alveolar hypoxia towards better-ventilated regions of the lung (Euler-Liljestrand mechanism).

Patients suffering from angina pectoris, myocardial infarction, or cerebral ischaemia often present abnormalities of the small airways (in particular alveolar hypoxia). In this case, intrapulmonary vasoconstriction occurs in order to divert perfusion from areas of alveolar hypoxia towards better-ventilated regions of the lung. Since trinitrin is a powerful vasodilator, it could reverse this protective vasoconstriction and, consequently, result in increased perfusion of poorly ventilated areas, worsening the ventilation/perfusion imbalance and leading to a further decrease in arterial partial pressure of oxygen.

Hypertrophic cardiomyopathy

Treatment with nitrate derivatives may worsen angina caused by hypertrophic cardiomyopathy.

Worsening of angina

The frequency of angina attacks during periods when the transdermal system is removed may increase.

In these cases, the use of an additional anti-anginal treatment is advisable.

Tolerance to sublingual trinitrin

When tolerance to transdermal trinitrin devices occurs, the effect of sublingual trinitrin on exercise tolerance may be partially diminished.

It is not logical to combine trinitrin with molsidomine or nicorandil since their mechanisms of action are similar.

Contraindicated combinations

+ Type 5 phosphodiesterase 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.

Associations to be taken into account

+ Dapoxetine

Risk of increased adverse effects, notably dizziness or syncope.

Pregnancy

As with any medicine, NITRIDERM TTS should be used with caution during pregnancy, particularly during the first trimester.

Breast-feeding

There is little information on the passage of the active substance into breast milk. During breastfeeding, risks to the child cannot be excluded.

The decision whether to continue or not breastfeeding or to continue or not treatment with NITRIDERM TTS must take into account the benefit of breastfeeding for the child and the benefit of treatment for the mother.

Fertility

There is no data on the effect of NITRIDERM TTS on fertility.

NITRIDERM TTS, particularly at the start of treatment or during dose adjustments, may reduce reactivity or, in rare cases, cause orthostatic hypotension and dizziness (or exceptionally syncope in case of overdose). It is preferable for patients who have experienced such effects to limit driving vehicles or using machines.

The undesirable effects of the medicine are listed by MedDRA system organ class (SOC). Within each class, the undesirable effects of the medicine are ranked by frequency, the most frequent appearing first. In addition, within each frequency group, the undesirable effects of the medicine are presented in order of decreasing seriousness. Finally, the frequency of undesirable effects is also given according to the CIOMS III classification: 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 reports.

1) Like other nitrate derivatives, NITRIDERM TTS frequently causes dose-dependent headaches due to cerebral vasodilation. These headaches often regress after a few days despite continued treatment. If headaches persist during intermittent treatment, they should be treated with mild analgesics. In case of headaches not responding to analgesic treatment, the dose of trinitrine should be reduced or treatment discontinued.

2) A slight reflex increase in heart rate can be controlled, if necessary, by combining a beta-blocker.

3) Upon removal of the transdermal system, mild skin redness usually disappears within a few hours. The application site should be changed regularly to avoid local irritation.

The following adverse effects have been reported during the post-marketing experience and come from spontaneous reports and published cases. As these effects were reported voluntarily by a population of imprecisely defined size, their frequency cannot be reliably estimated, hence their classification in the category "Frequency not known". Within each system organ class, adverse drug effects are presented in order of decreasing seriousness.

• Cardiac disorders: palpitations.
• Skin and subcutaneous tissue disorders: generalised rash.

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/.

Signs

High doses of trinitrine may cause severe hypotension and reflex tachycardia or collapse and syncope. Methaemoglobinaemia has also been reported after accidental overdose.

Management

The nitrate effect of NITRIDERM TTS can be rapidly stopped by simply removing the transdermal system.

Hypotension or collapse can be managed by elevating the patient's legs or, if necessary, applying a compression bandage.

Pharmacotherapeutic class: Vasodilator used in cardiology, ATC code: C01DA02

Mechanism of action

Trinitrine causes relaxation of smooth muscles. Vascularly, this effect is exerted primarily on systemic veins and, to a lesser extent, on coronary arteries.

In angina pectoris, the mechanism of action of trinitrine is based on an increase in venous capacitance (venous pooling) resulting in a reduction of venous return to the heart. This phenomenon causes a decrease in left ventricular end-diastolic pressure (preload) and thus of filling volume; this results in a reduction of myocardial oxygen demand at rest and especially on exertion, hence an improvement in exercise capacity.

By selective dilation of large epicardial vessels, the medicinal product leads to a redistribution of coronary circulation towards subendocardial zones, which are particularly vulnerable to ischaemia.

Trinitrine also has an antispasmodic action at the coronary level.

Depending on the dose, trinitrine dilates the arteriolar vascular bed, thereby decreasing systemic vascular resistance (afterload) and left ventricular systolic wall tension, which reduces myocardial oxygen consumption.

The decrease in cardiac venous return, accompanied by a decrease in pulmonary capillary pressures, combined with the reduction in afterload at high doses of nitrate derivatives, are the basis for the indications of certain derivatives in left or global heart failure.

This system allows constant-rate transdermal delivery of trinitrine directly into the bloodstream.

Absorption

After a single application of NITRIDERM TTS, the plasma concentration of trinitrine reaches a plateau in 2 hours, which is maintained for the entire recommended duration of application, despite the very short half-life of trinitrine. The plateau level is directly proportional to the surface area of the system releasing the product. Identical plasma concentrations are reached whether the system is applied to the skin of the arm, the pelvic region or the chest.

After removal of this system, the plasma concentration falls rapidly to become negligible within 2 hours.

There is no accumulation even with repeated applications.

NITRIDERM TTS delivers trinitrine transdermally directly into the bloodstream, avoiding variations in intestinal absorption and first-pass hepatic metabolism, and allows the use of lower doses of trinitrine to obtain more constant plasma concentrations of trinitrine than with conventional forms.

Distribution

Between 61 % and 64 % of trinitrin binds to plasma proteins. This fraction is 23 % for glyceryl 1,2-dinitrate and 11 % for glyceryl 1,3-dinitrate.

Biotransformation

Trinitrin is rapidly converted into mononitrated and dinitrated metabolites (glyceryl 1,2-dinitrate and glyceryl 1,3-dinitrate), ultimately yielding nitric oxide (NO) or a related substance.

Elimination

Trinitrin is eliminated by the kidneys in the form of mononitrated and dinitrated metabolites, glucuronoconjugates and glycerol. The elimination half-life of trinitrin is 10 minutes, 30-60 minutes for glyceryl 1,2-dinitrate and 5-6 minutes for glyceryl mononitrate.

Mutagenicity

Standard mutagenicity tests gave contradictory results in vitro. Cell culture and in vivo studies did not show any mutagenic activity of trinitrin; its use is therefore considered to be devoid of genotoxic potential at the doses usually recommended in humans.

Carcinogenicity

Dietary toxicity studies conducted in rodents led to the conclusion that trinitrin had no significant carcinogenic effect at the doses usually recommended in humans.

Reproductive toxicity

Teratogenicity studies in animals with transdermal trinitrin systems were not performed. In standard reproduction studies conducted in rats and rabbits, trinitrin was administered topically (as an ointment), intraperitoneally, intravenously and orally. No teratogenic potential of trinitrin was observed in these animals.

3 years.

Store at a temperature not exceeding 25 °C

Any device, whether used or not, must be kept out of the reach of children.