1    NAME OF THE MEDICINAL PRODUCT

Minitran 10 mg/ 24 h, transdermal patch

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Minitran 10 has a surface area of 13.3 sq cm and contains 36 mg of glyceryl trinitrate. The average amount delivered in 24 hours is 10 mg.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Adhesive transdermal patch.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Minitran 10 is indicated for:

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

4.2 Posology and method of administration

Posology

Prophylaxis of angina pectoris

Adults:

The response to nitrates differs between individuals, and the minimum effective dose should be prescribed in each case. It is therefore recommended that treatment is started with one Minitran 5 patch per day, with upward dosage titration when necessary. Application can either be for a continuous period of 24 hours or intermittently, incorporating a patch free interval (usually at night). Attenuation of effect has occurred in some patients being treated with sustained release nitrate preparations. On the basis of current clinical studies it is recommended that in such cases Minitran should be applied daily with a patch free interval of 8 - 12 hours.

Special populations Elderly

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

Paediatric population:

The safety and efficacy of Minitran in children has yet to be established, and therefore recommendations for its use cannot be made.

Method of administration

Each Minitran patch is contained in a sealed sachet. The adhesive layer is covered by a protective film, which should be removed before application. The Minitran patch should be applied to a clean, dry healthy area of skin on the torso or the arms.

Subsequent patches should not be applied to the same area of skin until several days have elapsed. The Minitran patch adheres easily to the skin, and also stays in place whilst bathing or during physical exercise.

4.3 Contraindications

Minitran is contraindicated for patients with:

•    Known hypersensitivity to glyceryl trinitrate, and related organic nitrates or any excipient of Minitran.

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

•    Conditions associated with elevated intracranial and intra-ocular pressure.

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

•    Concomitant use of Minitran and phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra®) is contraindicated, because PDE5 inhibitors may amplify the vasodilatory effects of Minitran resulting in severe hypotension.

•    Severe anaemia

•    Severe hypotension (systolic blood pressure less than 90 mmHg).

•    Severe hypovolemia

4.4 Special warnings and precautions for use

Warnings

Minitran is not indicated for the treatment of acute angina attacks requiring rapid relief. Minitran should be used only under strict medical supervision in recent myocardial infarction or acute congestive cardiac insufficiency. Minitran should be used with caution in patients with hypoxaemia or ventilation perfusion imbalance.

The appearance of cross-tolerance with other nitrates is possible.

The use of products for topical application, especially if prolonged, may give rise to sensitisation phenomena, in which case treatment should be suspended, and suitable therapeutic measures adopted.

Minitran does not contain any metal components, and therefore it is not considered necessary to remove the patch prior to diathermy.

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 due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of glyeryl trinitrate is reduced. Similarly, caution is called for in patients with hypoxaemia and 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, glyeryl trinitrate 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 glyceryl trinitrate

As tolerance to glyceryl trinitrate patches develops, the effect of sublingual glyceryl trinitrate on exercise tolerance may be partially diminished.

Use for maintenance of venous patency at peripheral infusion sites

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

Interactions resulting in a concomitant use contraindicated

Concomitant administration of Minitran and other vasodilators (e.g. PDE5 inhibitors such as sildenafil [Viagra®]), potentiates the blood-pressure-lowering effect of Minitran.

Interactions to be considered

Concomitant treatment with calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants, neuroleptics and major tranquillisers may potentiate the blood-pressure-lowering effect of Minitran, as may alcohol.

Concurrent administration of Minitran with dihydroergotamine may increase the bioavailability of dihydroergotamine. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonizes the effect of glyceryl    trinitrate

and may lead to coronary vasoconstriction.

The non-steroidal anti-inflammatory drugs except acetyl salicylic acid may diminish the therapeutic response of Minitran.

Concurrent administration of Minitran with amifostine and acetyl salicylic acid may potentiate the blood pressure lowering effects of Minitran

4.6 Fertility, pregnancy and lactation Fertility

There is no data available on the effect of Minitran on fertility in humans.

Pregnancy

As with all drugs Minitran should not be prescribed during pregnancy, particularly during the first trimester, unless there are compelling reasons for doing so. It is not known whether the active substance passes into the breast milk. The benefits for the mother must be weighed against the risks for the child.

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 Minitran therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Minitran, 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

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories:

Very common (>1/10)

Common (>1/100 to <1/10) Uncommon (>1/1,000 to <1/100) Rare (>1/10,000 to <1/1,000) Very rare (<1/10,000)

Not known (The adverse drug reactions have been derived from post-marketing experience with Minitran 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)

Nervous system disorders

Common: Headache¹

Very rare: Dizziness Not known: Syncope Cardiac disorders

Rare: Tachycardia²

Not known: Palpitation, fainting

Vascular disorders

Rare: Orthostatic hypotension, flushing²

Very common: Nausea, vomiting

Skin and subcutaneous tissue disorders

Uncommon: Dermatitis contact Not known: Rash generalized

General disorders and administration site conditions

Uncommon: Application site erythema, pruritus, burning, irritation³

Investigations

Rare: Heart rate increase

¹    Like other nitrate preparations, Minitran 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 glyceryl trinitrate or discontinuing treatment.

²    A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.

³    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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs

High doses of glyceryl trinitrate 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 Minitran 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

Pharmacotherapeutic group: Vasodilators used in cardiac diseases, organic nitrates ATC Code: C01DA02

Mechanism of action

Nitroglycerin, the active constituent of Minitran is a dilator of smooth muscle, producing relaxation by an unknown mechanism. It has no direct effects on the inotropic or chronotropic state of the heart. It affects cardiac output only as a consequence of its effect on venous capacitance and arteriolar resistance vessels. These effects on preload and afterload reduce myocardial oxygen consumption and are primarily responsible for the mechanism by which nitroglycerin relieves the symptoms of angina pectoris. The drug’s principal side effects (headache, flushing, dizziness, postural hypotension and tachycardia) are also a result of its smooth muscle relaxing effects.

5.2 Pharmacokinetic properties

When Minitran is applied to the skin, nitroglycerin is absorbed continuously through the skin into the systemic circulation and thus reaches the target organs (heart, vascular system) before deactivation by the liver. Minitran gives continuous release of nitroglycerin over 24 hours maintaining constant plasma levels. Nitroglycerin is metabolised by hydrolysis to dinitrates and the mononitrate.

5.3 Preclinical safety data

Not applicable.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Isooctyl Acrylate/Acrylamide Copolymer (93:7)

Ethyl Oleate BP Glyceryl Monolaurate

Low Density Polyethylene Film

One Side Silicone Coated Polyester Film

6.2 Incompatibilities

None known.

Shelf life

3 years.

6.4    Special precautions for storage

Minitran must be stored at room temperature (below 25°C) under exclusion of light and moisture.

6.5    Nature and contents of container

Each patch is individually packed in a heat sealed foil sachet. Cartons contain 30 patches.

6.6 Special precautions for disposal and other handling

The patch is covered by a protective polyester film, which is detached and discarded before use.

7. MARKETING AUTHORISATION HOLDER

Meda Pharmaceuticals Ltd Skyway House Parsonage Road Takeley

Bishop’s Stortford CM22 6PU

8 MARKETING AUTHORISATION NUMBER(S)

PL 15142/0086

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION