SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nitro-Dur 0.4mg/h Transdermal Patch

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Glyceryl trinitrate 37.4 % w/w For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Transdermal Patch

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Adults, including elderly patients :

The recommended initial dose is one 0.2mg/h Nitro-Dur patch daily. In some patients dose titration to higher or lower doses may be necessary to achieve optimum therapeutic effect.

Maximum dose : 15 mg in 24 hours.

Nitro-Dur is suitable for continuous or intermittent use. Patients already receiving continuous 24-hour nitrate therapy without signs of nitrate tolerance may continue on this regimen provided clinical response is maintained. Attenuation of effect has however occurred in some patients being treated with sustained release nitrate preparations. In such patients intermittent therapy may be more appropriate. Under these circumstances Nitro-Dur is applied daily for a period of approximately 12 hours. The patch is then removed to provide a nitrate-free interval of 12 hours which may be varied between 8-12 hours to suit individual patients (see section 4.4).

Patients experiencing nocturnal angina may benefit from overnight treatment with a nitrate-free interval during the day. In this patient group additional anti-anginal therapy may be needed during the day.

Patients with severe angina may need additional anti-anginal therapy during nitrate-free intervals.

Nitro-Dur Transdermal patches may be applied to any convenient skin area; the recommended site is the chest or outer upper arm. Application sites should be rotated and suitable areas may be shaved if necessary. Nitro-Dur patches should not be applied to the distal part of the extremities.

Children :

Not recommended.

4.3 Contraindications

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

•    Marked anaemia.

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

•    Conditions associated with elevated intracranial pressure, cerebral haemorrhage and head trauma.

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

•    Closed-angle glaucoma.

•    Concomitant use of Nitro-Dur and phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra®), tadalafil (Cialis), or vardenafil (Levitra) is contraindicated, because PDE5 inhibitors may amplify the vasodilatory effects of Nitro-Dur resulting in severe hypotension.

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

•    Severe hypovolemia.

•    Do not use Nitro-Dur in patients who are taking the soluble guanylate cyclase stimulator riociguat (Adempas) for chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension. Concomitant use can cause hypotension.

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, glyceryl trinitrate should be gradually withdrawn and overlapping treatment started. Nitro-dur is not indicated for the immediate treatment of acute angina attacks.

Nitro-Dur patch must be removed before procedures such as cardioversion or DC defibrillation, to avoid the possibility of electrical arching, before diathermy.

In cases of recent myocardial infarction or acute heart failure, treatment with Nitro-Dur 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

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.

In some patients severe hypotension may occur particularly with upright posture, even with small doses of glyceryl trinitrate. Thus Nitro-Dur should be used with caution in patients who may have volume depletion from diuretic therapy and in patients who have low systolic blood pressure (e.g. below 90mm Hg).

Paradoxical bradycardia and increased angina may accompany glyceryl-trinitrate-induced hypotension.

The lowest effect dose should be used.

Attenuation of effect has occurred in some patients being treated with sustained release preparations. In such patients intermittent therapy may be more appropriate (see section 4.2).

Caution should be exercised in patients suffering from hypothyroidism, malnutrition, severe renal or hepatic impairment, hypothermia and recent history of myocardial infarction.

Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

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 glyceryl 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-Liliestrand 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, glyceryl 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.

4.5 Interactions with other medicinal products and other forms of interaction

Interactions resulting in a concomitant use contraindicated

Concomitant administration of Nitro-Dur with phosphodiesterase inhibitors (e.g. sildenafil [Viagra®], tadalafil [Cialis] and vardenafil [Levitra]) in any form is contraindicated. Concomitant use potentiates the blood pressurelowering effect of Nitro-Dur.

Concomitant use of Nitro-Dur with soluble guanylate cyclase stimulators is contraindicated.

Interactions to be considered

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

Concurrent administration of Nitro-Dur with dihydroergotamine may increase the bioavailability of dihydroergotamine. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises 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 Nitro-Dur.

Concurrent administration of Nitro-Dur with amifostine and acetyl salicyclic acid may potentiate the blood pressure lowering effects of Nitro-Dur.

4.6 Fertility, pregnancy and lactation

Fertility

There is no data available on the effect of Nitro-Dur on fertility in humans.

Pregnancy

Like any drug, Nitro-Dur 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 Nitro-Dur therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Nitro-Dur, especially at the start of treatment or dose adjustments, may impair the reactions, cause blurred vision, 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

Headache is the most common side-effect, especially at higher doses.

Transient episodes of dizziness and light-headedness which may be related to blood pressure change may also occur. Hypotension occurs infrequently but may be severe enough to warrant discontinuation of therapy. Syncope and reflex tachycardia have been reported but are uncommon. Application site reactions (including erythema, rash, burning and purpura may occur but are rarely severe. Contact dermatitis has been reported. Hypersensitivity reactions may occur.

Adverse 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

Table 1

¹Like other nitrate preparations, Nitro-Dur 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.

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

³Upon 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 Nitro-Dur 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 therefore categorized as not known. Within each System- Organ Class, adverse drug reactions are presented in order of decreasing seriousness.

•    Cardiac disorders: palpitation.

•    Skin and subcutaneous tissue disorders: rash generalized.

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

Increased intracranial pressure with associated cerebral symptoms may occur. Treatment is by removal of the patch or reduction of dose, depending on severity. Thorough scrubbing of underlying skin may reduce absorption more quickly after removal. Intravenous infusion of normal saline or similar fluid may be necessary to increase the central fluid volume. Any fall in blood pressure or signs of collapse that may occur may be managed by general supportive or resuscitative measures. Adrenaline and related products are ineffective in reversing the severe hypotensive events associated with 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 Nitro-Dur 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

Glyceryl trinitrate, (as other organic nitrates), is a potent dilator of vascular smooth muscle. The effect on veins predominates over that on arteries resulting in decreased cardiac preload. Systemic vascular resistance is relatively unaffected, heart rate is unchanged or slightly increased and pulmonary vascular resistance is consistently reduced.

In normal individuals or those with coronary artery disease (in the absence of heart failure) glyceryl trinitrate decreases cardiac output slightly. Doses which do not alter systemic arterial pressure often product arteriolar dilatation in the face and neck resulting in flushing. Dilatation of the meningeal arterioles may explain the headache which is often reported. Rapid administration of high doses of glyceryl trinitrate decreases blood pressure and cardiac output resulting in pallor, weakness, dizziness and activation of compensatory sympathetic reflexes. A marked hypotensive effect may occasionally occur especially in the upright position.

5.2 Pharmacokinetic properties

Glyceryl trinitrate is rapidly hydrolysed by liver enzymes which are a major factor in bioavailability. Orally administered glyceryl trinitrate is ineffective as a therapeutic agent due to first-pass metabolism and administration has therefore routinely been via the sub-lingual route thus bypassing the hepatic circulation initially. Peak concentrations of glyceryl trinitrate following sub-lingual administration occur within 4 minutes in man with a half-life of 1 to 3 minutes. Transdermal administration, initially with ointment preparations but more recently with sustained-release delivery systems provide an alternative route to bypass the hepatic circulation with longer term concentrations of approximately 200pg/ml are achieved within approximately 2h or application of Nitro-Dur and are maintained for 24 h. Rate of absorption is controlled by the skin.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Butylacrylate Polymer (Polymer C);

Butylacrylate Polymer (Polymer D);

Sodium Polyacrylate (Polymer A);

Melamine Formaldehyde Resin (Polymer B);

Purified Water.

Coated onto tan-coloured Saranex® 2014 extruded thermoplastic film Adhesive layer covered by PVC Release Liner.

6.2 Incompatibilities

None known.

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store below 30°C. Do not refrigerate.

6.5 Nature and contents of container

Sealed pouches consisting of paper lined with polyethylene/foil laminate enclosing individual transdermal patches; 28 patches are contained in a cardboard carton.

6.6 Special precautions for disposal and other handling

Nitro-Dur patches are applied after removal from the protective pouch. With the brown lines on the backing cover facing the user, edges are bent away to break open the cover along the brown line.

The halves of the cover are peeled off and the patch applied firmly to the skin. Hands should be washed thoroughly after application.

Patients should be advised to dispose of patches carefully to avoid accidental application or use.

7    MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited Hertford Road

Hoddesdon Hertfordshire EN11 9BU UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 00025/0581

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/01/2011

10 DATE OF REVISION OF THE TEXT

14/01/2015