SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Exmo 21 mg/24 hours Transdermal Patches

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each transdermal patch contains 47.27 mg of nicotine in a patch size of 29 cm², releasing 21 mg of nicotine per 24 hours.

Excipients:

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Transdermal patch.

Square patch with round corners, with “Nicotine 21 mg/day” printed randomly all over the patch.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Relief of nicotine withdrawal symptoms, in nicotine dependency as an aid to smoking cessation. Advice and support normally improve the success rate.

4.2 Posology and method of administration

Users should stop smoking completely during treatment with Exmo.

Transdermal patches should also not be used simultaneously with another pharmaceutical form of nicotine replacement therapy such as gums or lozenges except under strict medical supervision.

Posology

Exmo transdermal patch is available in three strengths: 7 mg/24 hours, 14 mg/24 hours, 21 mg/24 hours.

Adults

The degree of nicotine dependence is to be assessed by the number of cigarettes smoked daily, or by the Fagerstrom's Test for Nicotine Dependence (test available in package leaflet).

	Initial phase 3 to 4 weeks	Treatment follow-up 3 to 4 weeks	Treatment withdrawal 3 to 4 weeks
Score of 5 or more on Fagerstrom's test or smokers of 20 or more cigarettes / day	21 mg/24 hours	14 mg/24 hours or 21 mg/24 hours*	7 mg/24 hours or 14 mg/24 hours and then 7 mg/24 hours*
Score of less than 5 on Fagerstrom's test or smokers of less than 20 cigarettes / day	14 mg/24 hours or increase to 21 mg/ day*	7 mg/24 hours or 14 mg/24 hours*	Treatment discontinuation or 7 mg/24 hours*

depending on the results on withdrawal symptoms

The strength of the transdermal patch is to be adapted to individual response: increase strength if abstinence from smoking is not complete or if withdrawal symptoms are observed, decrease in the event of suspected overdose.

The treatment duration is about 3 months but may vary as a function of individual response.

This medicinal product should not be used for more than 6 months unless otherwise directed by a physician.

Paediatric population (< 18 years)

Exmo should not be used by smokers under 18 years of age without recommendation from a healthcare professional. There is no clinical experience in treating adolescents under the age of 18 years with Exmo.

Method of administration

The Exmo transdermal patch should not be removed from its sealed protective sachet until the user is ready to use it.

The patch should be placed on a non-hairy, clean, dry area of the body or the upper, outer part of an arm. An area that is free from lesions (cuts, scratches, burns or bruises) and not irritated in any way should be chosen. Mobile zones such as the joints subject to friction from clothes should be avoided.

Using a pair of scissors, the sachet should be cut open carefully and the patch removed. The patch should not be cut. The pre-cut protective liner which covers the sticky side of the patch should be removed. The patch should be held at the edge and the sticky side should be touched as little as possible. The complete and uncut patch should be placed on the selected area of skin immediately after removing the protective liner. The patch should be pressed firmly on the skin with the palm of the hands for about 10 seconds, making sure it sticks well to the skin, especially around the edges. The patch should be left in place for 24 hours.

The patch should be changed every 24 hours. A different place on the skin should be chosen to apply the next patch. At least one week should pass before returning to a previously used skin site.

If the patch falls off, a new one should be put on the skin. The patch should be removed at the regular time and the schedule kept the same. The new patch can also be left in place for 24 hours if the user wishes to change the time of application.

The patches should not come in contact with water.

When the patch has been removed from the skin, it must be must folded into two with the side that touched the skin folded inwards before being discarded in a secure place.

4.3 Contraindications

-    Non-smoker or occasional smoker.

-    Hypersensitivity to nicotine or any of the excipients.

4.4 Special warnings and precautions for use

Dependent smokers with a recent myocardial infarction, unstable or worsening angina pectoris including Prinzmetal’s angina, severe cardiac arrhythmias, uncontrolled hypertension or recent cerebrovascular accident should be encouraged to stop smoking with non-pharmacological interventions (such as counselling). If this fails, Exmo may be considered but as data on safety in these patient groups are limited, initiation should only be under close medical supervision.

Diabetes Mellitus. Patients with diabetes mellitus should be advised to monitor their blood sugar levels more closely than usual when smoking is stopped and nicotine replacement therapy is initiated as reduction in nicotine induced catecholamine release can affect carbohydrate metabolism.

Allergic reactions: Susceptibility to angioedema and urticaria.

A risk-benefit assessment should be made by an appropriate healthcare professional for patients with the following conditions:

Renal and hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment and/or severe renal impairment as the clearance of nicotine or its metabolites may be decreased with the potential for increased adverse effects.

Phaeochromocytoma and uncontrolled hyperthyroidism: Use with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

Exmo should be used with caution in patients with:

Severe hypertension, stable angina pectoris, cerebrovascular disease, occlusive peripheral arterial disease, heart failure

Active peptic ulcer.

Danger in small children: Doses of nicotine tolerated by adult and adolescent smokers can produce severe toxicity in small children that may be fatal. Products containing nicotine should not be left where they may be misused, handled or ingested by children, see section 4.9. Even used nicotine patches contain enough residual nicotine to be harmful to children. Exmo must be kept out of the reach and sight of children.

Transferred dependence: Transferred dependence can occur but is both less harmful and easier to break than smoking dependence.

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs metabolised by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops smoking, this may result in slower metabolism and a consequent rise in blood levels of such drugs. This is of potential clinical importance for products with a narrow therapeutic window, e.g. theophylline, tacrine, clozapine and ropinirole.

The plasma concentration of other medicinal products metabolised in part by CYP1A2 e.g. imipramine, olanzapine, clomipramine and fluvoxamine may also increase on cessation of smoking, although data to support this are lacking and the possible clinical significance of this effect for these drugs is unknown. Limited data indicate that the metabolism of flecainide and pentazocine may also be induced by smoking.

Exmo transdermal patches should be used with caution on diseased skin (please see section 4.2).

In the event of a severe or persistent skin reaction, discontinue treatment and use another pharmaceutical form.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically relevant interactions between nicotine replacement therapy and other drugs have definitely been established. However nicotine may possibly enhance the haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increase pain response (angina-pectoris type chest pain) provoked by adenosine administration (see section 4.4, Stopping smoking).

4.6 Fertility, pregnancy and lactation

Pregnancy

In pregnant women, complete cessation of tobacco consumption should always be recommended without nicotine substitution treatment.

Smoking in pregnant women can be the cause of delayed intra-uterine growth, in utero foetal death, premature birth and neonatal hypotrophy, which appear to be correlated with the extent of tobacco exposure during pregnancy as these effects are observed when tobacco exposure is continued during the third trimester.

Should smoking withdrawal not be achieved in heavily nicotine dependent pregnant smokers, a healthcare professional should be consulted before starting any nicotine substitution therapy. Quitting smoking, with or without nicotine replacement therapy, is not to be considered in isolation but in the context of overall management, taking into account the psychological and sociological context and any other associated substance dependencies. A specialized consultation on quitting smoking is therefore advisable.

The nicotine provided by substitution treatment is not without adverse reactions on the foetus, as evidenced by the hemodynamic impact observed in the third trimester (e.g. changes in heart rate), which may affect the foetus close to birth. However, the risk for the foetus is probably less than to be expected with continued smoking due to:

-    Lower maximal plasma concentrations compared to inhaled nicotine, resulting in a nicotine exposure less or not more than associated with smoking.

-    No exposure to polycyclic hydrocarbons and carbon monoxide.

Therefore, after the sixth month of pregnancy, the patch should only be used under medical supervision in pregnant smokers who have failed to stop smoking by the third trimester.

Lactation

Nicotine is excreted in breast milk in quantities that may affect the child even in therapeutic doses. Nicotine replacement therapy products, like smoking itself, should therefore be avoided during breast-feeding. Should smoking withdrawal not be achieved, use of oral forms should be preferred compared with patches. The use of the patch by breast-feeding smokers should only be initiated after advice from a doctor.

Fertility

There is no or limited data on the effect of nicotine on fertility in humans.

4.7 Effects on ability to drive and use machines

There is no evidence of any risks associated with driving or operating machinery when the patch is used following the recommended dose. Nevertheless one should take into consideration that smoking cessation can cause behavioural changes.

4.8 Undesirable effects

In principle, Exmo transdermal patch can cause adverse reactions similar to those associated with nicotine administered by smoking.

The listed undesirable effects and their frequencies are based mainly on literature data of similar products on the market.

System organ class (MedDRA classification)	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)
Immune system disorders				urticaria, rash, pruritus (sometimes generalised), angioedema
Psychiatric disorders		insomnia	abnormal dreams
Nervous system disorders		dizziness, headache
Cardiac disorders			palpitations
Gastrointestinal disorders		nausea	vomiting
Musculoskeletal and connective tissue disorders		localised muscle pain
General disorders and administration site conditions	application site reactions such as erythema and pruritus	application site reactions such as oedema and burning

Additional adverse reactions based on spontaneous notifications include paresthesia in the administration site, that can spread beyond the site of patch application. Its incidence is unknown.

The vast majority of these effects are moderate and regress spontaneously and rapidly after removal of the patch.

In the event of severe or persistent skin reaction, treatment should be discontinued and another form of nicotine replacement product used.

Some symptoms such as dizziness, headache and insomnia may be related to smoking cessation.

An increased occurrence of oral aphthae may occur after quitting smoking. No causal relationship has been clearly demonstrated.

4.9 Overdose

In overdose, symptoms corresponding to heavy smoking may be seen.

The acute lethal oral dose of nicotine is about 0.5-0.75 mg per kg bodyweight, corresponding in an adult to 40-60 mg. Even small quantities of nicotine are dangerous in children, and may result in severe symptoms of poisoning which may prove fatal. If poisoning is suspected in a child, a doctor must be consulted immediately.

Overdose with Exmo transdermal patch may occur when many pieces are applied simultaneously on the skin.

General symptoms of nicotine poisoning may include: weakness, perspiration, salivation, nausea, vomiting, diarrhoea, abdominal pain, hearing and visual disturbances, headache, tachycardia and cardiac arrhythmia, dyspnoea, prostration, circulatory collapse, coma and terminal convulsions.

Treatment of overdose:

Following overdose, symptoms may develop rapidly particularly in children.

Immediately discontinue nicotine administration and institute symptomatic treatment. Monitor vital signs.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in nicotine dependence, ATC code: N07BA01.

Nicotine, the primary alkaloid in tobacco products and a naturally occurring autonomous substance, is a nicotine receptor agonist in the peripheral and central nervous systems. On consumption of tobacco products, nicotine has proven to be addictive.

Quitting smoking abruptly after prolonged, daily consumption induces a withdrawal syndrome consisting of at least four of the following symptoms: dysphoria or depressive mood, insomnia, irritability, feelings of frustration or anger, anxiety, difficulty concentrating, agitation or impatience, slowed cardiac rhythm, increased appetite and weight gain. The craving for nicotine is considered as a recognised clinical symptom of the withdrawal syndrome.

Clinical trials have shown that nicotine replacement products may help smokers refrain from smoking or reduce their smoking habits by decreasing the withdrawal symptoms.

5.2 Pharmacokinetic properties

Nicotine is directly absorbed through the skin and enters the systemic circulation.

A single application of nicotine transdermal patch by a healthy smoker having quit smoking shows that absorption occurs progressively and that the first detectable nicotine levels are found 1 to 2 hours post-application. Plasma concentrations then gradually rise to a plateau reached about 8 to 10 hours post-application.

Following withdrawal of the patch, plasma nicotine levels fall more slowly than would be expected given the plasma elimination half-life of nicotine (after intravenous administration: 2 hours).

The probable existence of a cutaneous deposit explains why about 10% of the nicotine reaching the blood derives from the skin after patch withdrawal. The absolute bioavailability of the patch, compared to intravenous nicotine perfusion, is about 77%.

The area under the plasma concentration curve (0-24 h) increases in proportion to the dose of nicotine delivered by the patches: nicotine 7 mg, 14 mg and 21 mg per day.

The distribution volume of nicotine is high, between 1 and 3 l/kg.

Nicotine crosses the blood-brain barrier and placenta and is excreted in breast-milk. The plasma protein binding of nicotine is negligible (< 5%). Elimination is mainly by the hepatic route and the main metabolites are cotinine and nicotine 1 -N-oxide. The renal elimination of unchanged nicotine is pH-dependent and minimal in the event of an alkaline urinary pH.

5.3 Preclinical safety data

Nicotine has been shown positive in some in vitro genotoxicity tests but also negative in others. The in vivo studies indicated that nicotine potentially acts as a clastogen at high doses. Only limited information are available on the long term dosing of nicotine in animals to assess carcinogenicity risks. Male Syrian golden hamsters with subcutaneous injections of nicotine for the duration of their life did not develop tumours in any organs.

Nicotine is a neuroteratogen. Animal experiments have shown that nicotine induces postimplantation loss, reduces the growth of fetuses, results in behavioral changes and deficits in cognitive function.

Nicotine has a negative impact on embryo-fetal development in rodents and has long term behavioural and neurochemical changes in rats.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Backing film:

Polyester/ medium density polyethylene film (Scotchpak 9735)

Adhesive silicone layer (contains the nicotine):

Polydimethylsiloxane crosslinked with silicate resin (BIO-PSA SA7-4207) Adhesive Acrylic layer:

Acrylate-Vinylacetate copolymer solution (Duro-Tak 87-2194)

Removable release liner:

Polyester, silicone

Printing ink:

Titanium dioxide LT Isoparaffinic hydrocarbon Polyamide resin Polyethylene wax Polytetrafluoroethylene

6.2    Incompatibilities

To prevent interference with the adhesive properties of the transdermal patch, no cream, lotion or powder should be applied to the skin area where the medicinal product is to be applied.

6.3 Shelf life

3 years.

6.4    Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store the patch in the original sachet in order to protect from light.

6.5    Nature and contents of container

Carton of 7, 14, 21 or 28 transdermal patches. Each transdermal patch is packed in its own protective sachet.

The sachet material is a multi-laminate, child-resistant pouchstock composed of coated paper, adhesive, OPA (nylon), adhesive, aluminium, adhesive and polyacrylonitrile-copolymer (PAN). The PAN layer is in contact with the transdermal patch.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Used transdermal patches should be folded in half, with the adhesive side inwards and discarded safely and out of the sight and reach of children.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0384

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 08/01/2013

10 DATE OF REVISION OF THE TEXT

08/01/2013

DATE OF REVISION OF THE TEXT

08/01/2013