This information is intended for use by health professionals

1. Name of the medicinal product

Deponit 10

2. Qualitative and quantitative composition

One patch contains glyceryl trinitrate 37.4 mg

The average amount of glyceryl trinitrate absorbed from each patch in 24 hours is 10 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Transdermal patch

White, translucent square patch with convex round corners with “Deponit 10” marked on the outer face.

4. Clinical particulars
4.1 Therapeutic indications

Prophylaxis of angina pectoris alone or in combination with other anti-anginal therapy.

4.2 Posology and method of administration

Posology

Dermal

Adults: Treatment should be initiated with one patch daily. If necessary the dosage may be increased to two patches.

Method of Administration

It is recommended that the patch is applied to healthy, undamaged, relatively crease free and hairless skin. The best places to apply Deponit patches are the easily reached, fairly static areas at the front or side of the chest. However, Deponit patches may also be applied to the upper arm, thigh, abdomen or shoulder. Skin care products should not be used before applying the patch. 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.

Tolerance may occur during chronic nitrate therapy. Tolerance is likely to be avoided by allowing a patch-free period of 8-12 hours each day, usually at night. Additional anti-anginal therapy with drugs not containing nitro compounds should be considered for the nitrate-free interval if required.

As with any nitrate therapy, treatment with these patches should not be stopped abruptly. If the patient is being changed to another type of treatment, the two should overlap.

Older people

Elderly: No specific information on use in the elderly is available, however there is no evidence to suggest that an alteration in dose is required.

Paediatric population

Children: The safety and efficacy of this patch in children has yet to be established

4.3 Contraindications

• Known hypersensitivity to nitrates or to the adhesives used in the patch

• Raised intracranial pressure including that caused by head trauma or cerebral haemorrhage

• Acute circulatory failure associated with marked hypotension (shock).

• Myocardial insufficiency due to obstruction, as in aortic or mitral stenosis or constrictive pericarditis.

• Marked anaemia

• Closed angle glaucoma

• Severe Hypotensive conditions (systolic blood pressure less than 90mmHg)

• Severe hypovolaemia

• Hypertrophic obstructive cardiomyopathy

• Aortic stenosis and mitral stenosis

• Constrictive pericarditis

• Cardiac tamponade

• Concomitant use of phosphodiesterase type-5 inhibitors. Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contra-indicated.

• During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).

4.4 Special warnings and precautions for use

Warnings:

In cases of recent myocardial infarction or acute heart failure, treatment with the preparation 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:

This patch should be used with caution in patients with

• Severe hepatic or renal impairment

• Hypothyroidism

• Hypothermia

• Malnutrition

• A recent history of myocardial infarction

• Hypoxaemia or a ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.

• Arterial Hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is reduced.

• 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).

• 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.

• Methemoglobinemia

Following treatment with GTN, 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).

The patch is not indicated for use in acute angina attacks. In the event of an acute angina attack, sublingual treatment such as a spray or tablet should be used.

As with all nitrate preparations withdrawal of long-term treatment should be gradual by replacement with decreasing doses of long acting oral nitrates.

Also when transferring the patient on long-term therapy to another form of medication, nitroglycerin should be gradually withdrawn and overlapping treatment started.

If the patches are not used as indicated (see Section 4.2) tolerance to the medication could develop.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers, as well as the consumption of alcohol, may potentiate the hypotensive effect of the preparation.

The blood pressure lowering effect of these patches will be increased if used together with phosphodiesterase inhibitors (e.g. sildenafil) which are used for erectile dysfunction (see Section 4.3). This might lead to life threatening cardiovascular complications. Patients who are on nitrate therapy must not use phosphodiesterase inhibitors (e.g. sildenafil).

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

If administered concurrently, these patches may increase the blood level of dihydroergotamine and lead to coronary vasoconstriction.

The possibility that ingestion of non-steroidal anti-inflammatory drugs except Acetyl Salicylic acid might diminish the therapeutic response to the patch cannot be excluded.

Concurrent administration with Amifostine and acetyl salicylic acid may potentiate the hypotensive effect of the preparation.

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).

4.6 Fertility, pregnancy and lactation

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 Deponit 10 on fertility in humans.

Pregnancy and Lactation

Like any drug, Deponit 10 should be employed with caution during pregnancy, especially in the first 3 months.

These patches should not be used during pregnancy or lactation unless considered absolutely essential by the physician.

It is not known whether the active substance passes into the breast milk. Benefits to the mother must be weighed against risk to the child.

4.7 Effects on ability to drive and use machines

Glyceryl trinitrate can cause postural hypotension and dizziness. Patients should not drive or operate machinery if they feel affected.

4.8 Undesirable effects

A very common (>10% of patients) adverse reaction to the patch is headache. The incidence of headache diminishes gradually with time and continued use.

At start of therapy or when the dosage is increased, hypotension and/or light-headedness on standing are observed commonly (i.e. in 1-10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachycardia, and a feeling of weakness.

Infrequently (i.e. in less than 1% of patients), nausea, vomiting, flushing and allergic skin reaction (e.g. rash), which may be severe can occur. Exfoliative dermatitis has been reported

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.

A few reports of heartburn, most likely due to a nitrate-induced sphincter relaxation, have been recorded.

Allergic skin reactions to glyceryl trinitrate and ingredients can occur, but they are uncommon (i.e. >0.1% but <1%). Patients may commonly experience slight itching or burning at the site of application. Slight reddening usually disappears without therapeutic measures after the patch has been removed. Allergic contact dermatitis and application site erythema, Pruritus, Burning, Irritation are uncommon.

During the treatment with these patches, a temporary hypoxaemia 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, GTN 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 GTN 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.

Cardiac disorders like palpitation and disorders related to Skin and subcutaneous tissue like generalized rash might occur in some population which is not known

Investigations

Not known: Heart rate increase

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.

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 listed below.

The Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In view of the transdermal mode of delivery, an overdose of glyceryl trinitrate is unlikely to occur. However, in the unlikely event of an overdose, the symptoms could include the following:

• Fall in blood pressure ≤ 90 mmHg

• Collapse or syncope

• Paleness

• Sweating

• Weak pulse

• Reflex tachycardia

• Flushing

• Light-headedness on standing

• Headache

• Weakness

• Dizziness

• Nausea

• Vomiting

• Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During glyceryl trinitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It can not be excluded that an overdose of glyceryl trinitrate may cause this adverse reaction

• In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms

General procedure:

• Since these patches are applied to the skin, removing the patch immediately stops delivery of the drug.

• General procedures in the event of nitrate-related hypotension

- Patient should be kept horizontal with the head lowered and legs raised or, if necessary, compression bandaging of the patient's legs.

- Supply oxygen

- Expand plasma volume

- For specific shock treatment admit patient to intensive care unit

Special procedure:

• Raising the blood pressure if the blood pressure is very low

• Treatment of methaemoglobinaemia

Treatment with intravenous methylene blue

- Initially 1 to 2 mg/kg, not exceeding 4 mg/kg of a 1% solution over 5 minutes.

- Repeat dose in 60 minutes if there is no response.

- Administer oxygen (if necessary)

- Initiate artificial ventilation

Treatment with methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or methaemaglobin reductase deficiency. (see also section 4.4).

Where treatment with methylene blue is contraindicated or is not effective, exchange transfusion and / or transfusion of packed red blood cells is recommended.

Resuscitation measures:

In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group

Pharmacotherapeutic group: Vasodilators used in Cardiac Diseases, organic nitrates.

ATC Code: C01DA02

Pharmacodynamics

The main pharmacological activity of organic nitrates is the relaxation of smooth vascular muscles. The systemic vasodilation induces an increase of venous capacitance. Venous return is reduced. Ventricular volume, filling pressures and diastolic wall tension are diminished (preload reduction).

A diminished ventricular radius and reduced wall tension, lower myocardial energy and oxygen consumption, respectively.

The dilation of the large arteries near the heart leads to a decrease in both the systemic (reduction of afterload) and the pulmonary vascular resistance. In addition, this relieves the myocardium and lowers oxygen demands.

By dilating the large epicardial coronary arteries, glyceryl trinitrate enhances blood supply to the myocardium, improving its pump function and increasing the oxygen supply.

At molecular level, nitrates form nitric oxide (NO), which corresponds to the physical EDRF (endothelium derived relaxing factor). EDRF mediated production of cyclic guanosine monophosphate (CGMP) leads to relaxation of smooth muscle cells.

5.2 Pharmacokinetic properties

(a) General characteristics of the active substance

The transdermal absorption of glyceryl trinitrate circumvents the extensive hepatic first pass metabolism so the bioavailability is about 70% of that achieved after i.v. administration.

The steady-state concentration in the plasma depends on the patch dosage and the corresponding rate of absorption. At a rate of absorption of 0.4 mg/h, the steady-state concentration is about 0.2 µg/l on average. Plasma protein binding is about 60%. Glyceryl trinitrate is metabolized to 1,2- and 1,3-dinitroglycerols. The dinitrates exert less vasodilatory activity than glyceryl trinitrate. The contribution to the overall effect is not known. The dinitrates are further metabolized to inactive mononitrates, glyceryl and carbon dioxide.

The elimination half-life of glyceryl trinitrate is 2-4 min. The metabolism of glyceryl trinitrate, which is effected in the liver, but also in many other cells, e.g. the red blood cells, includes the separation of one or more nitrate groups. In addition to the metabolism of glyceryl trinitrate, there is a renal excretion of the catabolites.

5.3 Preclinical safety data

Glyceryl trinitrate is a well-known active substance, established for more than a hundred years. Thus new preclinical studies have not been carried out with Deponit 10.

6. Pharmaceutical particulars
6.1 List of excipients

Acrylate/vinyl acetate copolymer (adhesive matrix)

Polypropylene (backing foil)

Polyethylene (siliconised release liner)

6.2 Incompatibilities

No incompatibilities have so far been demonstrated.

6.3 Shelf life

Shelf life of the product as packaged for sale: 48 months.

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Multilaminate film/foil pouch with heat-sealed edges.

28 patches per carton.

6.6 Special precautions for disposal and other handling

The patch should be removed from the package just before application. After removal of the protective foil, the patch should be applied to unbroken, clean and dry skin that is smooth and with few hairs. The same area of skin should not be used again for some days.

7. Marketing authorisation holder

Merus Labs Luxco II S.à r.l.

26-28, rue Edward Steichen

L-2540 Luxembourg

Luxembourg

8. Marketing authorisation number(s)

PL 44374/0011

9. Date of first authorisation/renewal of the authorisation

28 February 2008

10. Date of revision of the text

August 2016