SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Nicorette invisipatch 25 mg/16 h transdermal patch

Nicorette invisipatch 15 mg/16 h transdermal patch Nicorette invisipatch 10 mg/16 h transdermal patch

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each transdermal patch contains nicotine 1.75 mg/cm2.

Nicorette invisipatch 25 mg/16 h, of 22.5 cm2 size contains nicotine 39.37 mg and releases nicotine 25 mg /16 hours Nicorette invisipatch 15 mg/16 h, of 13.5 cm2 size contains nicotine 23.62 mg and releases nicotine 15 mg /16 hours Nicorette invisipatch 10 mg/16 h, of 9.0 cm2 size contains nicotine 15.75 mg and releases nicotine 10 mg /16 hours

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Transdermal patch

Beige, semi-transparent, rectangular patch with rounded edges and light-brown “Nicorette” printing, is placed on an easily removable layer coated with aluminium and silicon and is formed by nicotine layer and adhesive acrylate layer.

4. CLINICAL PARTICULARS

4.1. Therapeutic indication

Nicorette invisipatch is to be used for the treatment of tobacco dependence in adults by relief of nicotine withdrawal symptoms, including cravings, during a quit attempt. Permanent cessation of tobacco use is the eventual objective.

Nicorette invisipatch is indicated in adults.

Nicorette invisipatch should preferably be used in conjunction with a behavioral support program.

4.2. Posology and method of administration

Posology Subjects should stop smoking completely during the course of treatment with Nicorette invisipatch. Administration of nicotine should be stopped immediately if any symptoms of overdose listed in Section 4.9 occur.

Professional advice and support usually improve the success rate.

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Treatment with Nicorette invisipatch simulates variation of plasma nicotine level observed in smokers without nicotine intake during sleep. Nicotine released from Nicorette patches that are used only during the active part of a day (during 16 hours), does not cause sleep disorders that are observed when nicotine is applied during sleep.

Monotherapy

Adults Treatment with Nicorette invisipatch is usually 12 weeks, 8 weeks treatment with a sufficient therapeutic dose, followed by 4 weeks tapering.

Smokers with high nicotine dependence (Fagerström score of nicotine dependence  6 or  20 cigarettes a day) are recommended to start the treatment with Nicorette invisipatch 25 mg/16 h, one patch a day (Step 1 in Table 1) for 8 weeks. After 8 weeks, the nicotine dose should be decreased gradually. Therefore, Nicorette invisipatch 15 mg/16 h should be used for 2 weeks, one patch a day (Step 2 in Table 1) followed by Nicorette invisipatch 10 mg/16 h used for 2 weeks as well, one patch a day (Step 3 in Table 1).

Smokers with lower nicotine dependence (Fagerström score of nicotine dependence < 6 or ≤ 20 cigarettes a day) are recommended to start their treatment with Nicorette invisipatch 15 mg/16 h, one patch a day (step 1 in Table 2) for 8 weeks. After 8 weeks, the nicotine dose should be decreased gradually. Therefore, Nicorette invisipatch 10 mg/16 h should be used for 4 weeks, one patch a day (Step 2 in Table 2).

Using patches longer than 6 months is generally not recommended. Some ex-smokers may need treatment with the patch longer to avoid returning to smoking.

Table 1) Dosage scheme in smokers with high nicotine dependence

Dosage Treatment period Step 1 Nicorette invisipatch 25 mg/16 h one patch a day first 8 weeks – initial phase Step 2 Nicorette invisipatch 15 mg/16 h one patch a day following 2 weeks Step 3 Nicorette invisipatch 10 mg/16 h one patch a day last 2 weeks

Table 2) Dosage scheme in smokers with lower nicotine dependence

Dosage Treatment period Step 1 Nicorette invisipatch 15 mg/16 h one patch a day first 8 weeks – initial phase Step 2 Nicorette invisipatch 10 mg/16 h one patch a day following 4 weeks

Combination therapy

Smokers who experience `breakthrough' cravings with single nicotine replacement therapy (NRT) or those who have failed with single NRT treatment, can use Nicorette invisipatches in combination with an oromucosal NRT product for fast relief of cravings.

The oromucosal format to consider in combination with the Nicorette invisipatches are [to be completed nationally depending on local product names and licences granted amongst: the Nicorette 2mg gums (any flavour) or Nicorette 1mg/spray mouthspray].

2/12 The user needs to also refer to the product information of the chosen flexible format.

Smokers should stop smoking completely during the course of treatment.

For combination therapy use of only one flexible format over a 24h period is recommended.

Recommended use of transdermal patch in combination with chewing gum 2mg / oromucosal spray 1mg/spray in tabular form:

High level of dependence: Smokers with high nicotine dependence (Fagerström score of nicotine dependence  6 or  20 cigarettes a day) who experience `breakthrough' cravings or those who have failed with single NRT treatment

Dose Time 2mg Gums Oromucosal spray 1mg/spray period Step 1 1 patch First 8 As needed but not more than 16 As needed but not more than 32mg 25mg/16h weeks gums a day. a day (2 sprays per hour over 16h). Usual dose is 5-6 gums per day Start reducing from week 7. Step 2 1 patch Next 2 As needed but not more than 16 As needed but not more than 32mg 15mg/16h weeks gums a day. a day (2 sprays per hour over 16h). Continue reducing the number of spray per day. By the end of week 9, users should be using half the average of sprays per day that was used until week 6. Step 3 1 patch Last 2 As needed but not more than 16 Continue reducing the number of 10mg/16h weeks gums a day. spray per day so users are not using more than 4 sprays per day during week 12. When users have reduced to 2-4 sprays per day, oromucosal spray should be discontinued. Do not use more than 32 mg a day (2 sprays per hour over 16h).

Beyond None After If needed but reduce the If needed but continue reducing the Step 3 Week 12 number of gums. Treatment number of spray per day. When should be stopped when the users have reduced to 2-4 sprays dose is reduced to 1-2 chewing per day, oromucosal spray should gums per day. be discontinued. Do not take more than 16 gums Do not use more than 32 mg a day a day. (2 sprays per hour over 16h).

Up to maximum 12 months Up to maximum 6 months

Low level of dependence: Smokers with lower nicotine dependence (Fagerström score of nicotine dependence < 6 or ≤ 20 cigarettes a day) who experience `breakthrough' cravings or those who have failed with single NRT treatment

Dose Time 2mg Gums Oromucosal spray 1mg/spray

3/12 period Step 1 1 patch First 8 As needed but not more than 16 As needed but not more than 32 mg 15mg/16h weeks gums a day. a day (2 sprays per hour over 16h). Usual dose is 5-6 gums per day Start reducing from week 7. Step 2 1 patch Last 4 As needed but not more than 16 Continue reducing the number of 10mg/16h weeks gums a day. spray per day. By the end of week 9, users should be using half the average of sprays per day that was used until week 6. Users should not be using more than 4 sprays per day during week 12. When users have reduced to 2-4 sprays per day, oromucosal spray should be discontinued. Do not use more than 32mg a day (2 sprays per hour over 16h).

Beyond None After If needed but reduce the If needed but continue reducing the Step 2 Week 12 number of gums. Treatment number of spray per day. When should be stopped when the users have reduced to 2-4 sprays dose is reduced to 1-2 chewing per day, oromucosal spray should gums per day. be discontinued. Do not take more than 16 gums Do not use more than 32mg a day a day. (2 sprays per hour over 16h).

Up to maximum 12 months Up to maximum 6 months

Paediatric population The safety and efficacy of Nicorette invisipatch in children under 18 years of age, have not been established. No data are available. Method of administration: The patch is applied in the morning and taken off when going to bed, so that approximate 16 hour effect is ensured. The patch is applied on a clean, dry, hairless and intact area of skin (for example on the trunk, hip, upper arms or chest). These areas should be varied each day and the same site should not be used on consecutive days. 1. Wash your hands before applying a patch. 2. Cut open the pouch with scissors along the side, as indicated. 3. Remove one part of a silver aluminium layer as far as possible. Avoid touching the sticky surface of the patch with your fingers! 4. Firmly apply the patch by pressing the sticky side of the patch onto your skin and remove the silver aluminium layer. 5. Firmly press the patch onto the skin, with your fingers or palm. 6. Rub firmly round the edge to ensure that the patch sticks firmly. 7. If the patch comes off, replace with a new one.

After removal, used patches should be disposed of safely.

Do not use patches during night, i.e. not longer than 16 hours.

4.3 Contraindications 4/12

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Children under the age of 18 years. Those who have never smoked.

4.4 Special warnings and precautions for use

Nicorette invisipatch should not be used by non-smokers.

The benefits of quitting smoking outweigh any risks associated with correctly administered nicotine replacement therapy (NRT).

Users should be informed that if they continue to smoke while using the patches, they may experience increased adverse effects due to the hazards of smoking, including cardiovascular effects.

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

• Cardiovascular disease: Dependent smokers with a recent myocardial infarction, unstable or worsening angina including Prinzmetal’s angina, severe cardiac arrhythmias, recent cerebrovascular accident and/or who suffer with uncontrolled hypertension should be encouraged to stop smoking with non-pharmacological interventions (such as counselling). If this fails, the patch may be considered but as data on safety in this patient group 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 NRT is initiated as reduction in nicotine induced catecholamine release can affect carbohydrate metabolism.

• 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.

• Gastrointestinal disease: Nicotine may exacerbate symptoms in patients suffering from oesophagitis, gastric or peptic ulcers and NRT preparations should be used with caution in these conditions.

Magnetic Resonance Imaging (MRI): Nicorette invisipatch should be removed prior to undergoing any MRI procedures to prevent the risk of burns.

Danger in children: Doses of nicotine tolerated by smokers can produce severe toxicity in children that may be fatal. Products containing nicotine, unused or used patches, should not be left where they may be handled or ingested by children, see section 4.9.

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

5/12 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.

Combination therapy: The warnings and precautions for use for the combination of Nicorette invisipatch with the chosen flexible format are those of each treatment used alone. For the warning and precautions for use for the flexible format, refer to its product information.

4.5 Interactions 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 hemodynamic 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

Combination therapy should not be used in pregnancy and lactation.

Women of childbearing potential/ contraception in males and females In contrast to the well known adverse effects of tobacco smoking on human conception and pregnancy, the effects of therapeutic nicotine treatment are unknown. Thus, whilst to date no specific advice regarding the need for female contraception has been found to be necessary, the most prudent state for women intending to become pregnant is to be both non-smoking, and not using NRT. Whilst smoking may have adverse effects on male fertility, no evidence exists that particular contraceptive measures are required during NRT treatment by males.

Pregnancy Smoking during pregnancy is associated with risks such as intra-uterine growth retardation, premature birth or stillbirth. Stopping smoking is the single most effective intervention for improving the health of both pregnant smoker and her baby. The earlier abstinence is achieved the better. Nicotine passes to the foetus and affects its breathing movements and circulation. The effect on the circulation is dose-dependent.

Therefore the pregnant smoker should always be advised to stop smoking completely without use of nicotine replacement therapy. The risk of continued smoking may pose greater hazard to the foetus as compared with the use of nicotine replacement products in a supervised smoking cessation programme. Use of Nicorette invisipatch by the pregnant smoker should only be initiated after advice from a healthcare professional.

Breastfeeding Nicotine passes freely into breast milk in quantities that may affect the child even with therapeutic doses. Nicorette invisipatch should therefore be avoided during breast-feeding. Should smoking cessation not be achieved, use of Nicorette invisipatch by breast feeding smokers should only be initiated after advice from a healthcare professional.

Fertility In females, tobacco smoking delays time to conception, decreases in-vitro fertilization success rates, and significantly increases the risk of infertility.

6/12 In males, tobacco smoking reduces sperm production, increases oxidative stress, and DNA damage. Spermatozoa from smokers have reduced fertilizing capacity. The specific contribution of nicotine to these effects in humans is unknown.

4.7 Effects on ability to drive and use machines

Nicorette invisipatch has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Effects of smoking cessation Regardless of the means used, a variety of symptoms are known to be associated with quitting habitual tobacco use. These include emotional or cognitive effects such as dysphoria or depressed mood; insomnia; irritability, frustration or anger; anxiety; difficulty concentrating, and restlessness or impatience. There may also be physical effects such as decreased heart rate; increased appetite or weight gain, dizziness or presyncopal symptoms, cough, constipation, gingival bleeding or aphthous ulceration, or nasopharyngitis. In addition, and of clinical significance, nicotine cravings may result in profound urges to smoke.

As would be expected, the types of adverse reactions seen for the patch in clinical trials are similar to those associated with nicotine administered by other means.

The adverse reactions observed in patients treated with patch formulations during clinical trials and post- marketing experience are listed below by system organ class.

Frequencies are provided according to the following convention: Very common ≥1/10 Common ≥1/100 and <1/10 Uncommon ≥1/1,000 and <1/100 Rare ≥1/10,000, <1/1,000 Very rare <1/10,000 Not known (cannot be estimated from the available data)

System Organ Class Reported adverse reactions Immune system disorders Uncommon Hypersensitivity a* Not known Anaphylactic reaction a¶ Psychiatric disorders¶ Uncommon Abnormal dream a¶ Nervous system disorders Common Headache a# Common Dizzinessa Uncommon Paraesthesia a* Cardiac disorders¶ Uncommon Palpitations a¶, tachycardia a¶ Very rare Reversible atrial fibrillation Vascular disorders¶ Uncommon Flushing a¶, hypertension a¶ Respiratory, thoracic and mediastinal disorders¶ 7/12 Uncommon Dyspnoea a¶ Gastrointestinal disorders Common Nausea a#, vomiting a, Gastrointestinal discomforta Skin and subcutaneous tissue disorders Very common Pruritus Common Rash a¶, urticaria a¶, Erythema a¶ Uncommon Hyperhidrosis a¶ Not known Angioedema a¶ Musculoskeletal and connective tissue disorders Uncommon Myalgia&¶ Not known Pain in extremity¶ General disorders and administration site conditions Uncommon Application site reactions¶, asthenia a¶, chest discomfort and pain a¶, fatigue a*#, malaise a¶ a: Systemic effects * Although the frequency is <1%, the PT occurred at a frequency ≥1% in another formulation in which the PT was identified as a systemic ADR. # Although the frequency in the active group is less than that of the placebo group, the frequency in the specific formulation in which the PT was identified as a systemic ADR was greater in the active group than the placebo group. & In vicinity/region of patch ¶ ADRs identified from Post-Marketing Data.

Combination therapy: Undesirable effects occurring during the use of a combination NRT only differ from those of each treatment alone in terms of local adverse effects related to the pharmaceutical forms. The frequency of these undesirable effects is comparable to that listed in the SmPCs of each product.

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 in Appendix V.

4.9 Overdose

Excessive use of nicotine replacement therapy products and/or smoking may cause symptoms of overdose.

Overdose with nicotine can occur if many patches are used simultaneously, contemporary smoking or uses other forms of nicotine replacement therapy at the same time or if the users have very low nicotine dependence.

Symptoms of overdose Symptoms of overdose are similar to those of acute nicotine poisoning and include nausea, vomiting, increased salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and a profound feeling of weakness. Acute minimal lethal dose for a man is 40 - 60 mg of nicotine. At high doses these symptoms may be accompanied by hypotension, weak and irregular pulse, breathing difficulties, exhaustion, circulatory collapse and general convulsions.

Paediatric population 8/12 Doses of nicotine that are tolerated by adult smokers during treatment may cause serious symptoms of poisoning in children that may have a fatal outcome. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Management of overdosage

Immediate stop of nicotine administration and initiation of symptomatic treatment. The skin surface may be washed with water and dried (no soap should be used). If necessary, oxygen application and pulmonary ventilation must be initiated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drug used in nicotine dependence ATC code: N07B A01

Pharmacological effects of nicotine are well documented. The main pharmacological effect is central stimulation and/or decline, transient hyperpnoe, peripheral vasoconstriction (leading to increased systolic pressure), appetite reduction and peristalsis stimulation.

When used as recommended, Nicorette invisipatch helps to control weight gain after stopping smoking.

Clinical studies have shown that nicotine replacement products help smokers to refrain from smoking by relieving the abstinence syndromes.

5.2 Pharmacokinetic properties

Content of nicotine stated in the name of the medicinal product refers to the average amount of nicotine released from a patch within 16 hours.

Absorption The peak nicotine plasma concentration is reached in approximately 9 hours (tmax) after patch application, i.e. in the afternoon or in the evening when the risk of relapse is at its highest.

Linear relationship exists between released amount of nicotine (dose) and nicotine plasma levels over the therapeutic dose range, 10-25 mg/16 hours. The mean peak nicotine plasma levels (Cmax ) achieved is calculated as follows:

Nicotine dose (mg/16 hours) Cmax (ng/ml) 10 10 15 15,5 25 26,5

The calculated nicotine plasma levels correspond to the real plasma concentrations measured: 11 ng/mL for the 10 mg patch and 25 ng/mL for the 25 mg patch. Interpolation yields the peak plasma concentration of 16 ng/mL for the 15 mg patch.

The kinetics of nicotine is not affected by the location of the patch (either the thigh or upper arm).

9/12 Variations in the absorption of nicotine in extreme conditions have not been studied, but are not considered to constitute a safety hazard.

Pharmacokinetic studies have shown that there is no significant accumulation of nicotine when a patch remains stuck for more than 16 hours and is followed by a new patch. If a patient forgets (exceptionally) to remove a patch in the evening, he/she can remove it in the morning and continue with a new patch without interrupting the treatment.

Distribution The volume of distribution of nicotine is about 2-3 L/kg.

Plasma protein binding of nicotine is less than 5%. Therefore, variations in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states are not expected to have significant effects on nicotine kinetics.

Biotransformation The major elimination organ is liver, but is also metabolized by kidney and lungs. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound.

The primary metabolite of nicotine in plasma, cotinine, has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10 times.

Elimination The average plasma clearance is about 70 L/hour and the half-life of approximately 3 hours.

The primary urinary metabolites are cotinine (12 % of a dose) and trans-3-hydroxycotinine (37 % of a dose). Less than 10% of nicotine is excreted unchanged via urine. Up to 30 % may be excreted via urine through the increased diuresis and acidification below pH 5.

Linearity/non-linearity Plasma nicotine concentrations show dose proportionality for all three patch doses.

Renal impairment Progressive severe renal impairment is associated with decreased total clearance of nicotine. Increased nicotine levels have been observed in patients-smokers undergoing hemodialysis.

Hepatic impairment The pharmacokinetics of nicotine is unaffected in cirrhotic patients with mild liver impairment (Child-Pugh score 5) and nicotine clearance is decreased in cirrhotic patients with moderate liver impairment (Child-Pugh score 7).

Elderly patients A minor reduction in total clearance of nicotine has been demonstrated in healthy elderly patients, however not justifying adjustment of dosage.

No differences in nicotine kinetics have been observed between men and women.

5.3 Preclinical safety data

Non-clinical studies with Nicorette invisipatch supported well established safety of the active substance and documented safety profile for the excipients. 10/12

There is no clear evidence of nicotine being genotoxic or mutagenic.

The well known carcinogenicity of tobacco smoke is related to substances formed by the pyrolysis of tobacco. None of these substances occur in Nicorette patches.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The active substance layer: Polyethylenterephthalate (PET) film, triglycerides, medium-chain, basic butylated methacrylate-copolymer.

The acrylate layer: Acrylic adhesive solution, potassium hydroxide, croscarmellose sodium, aluminium acetylacetonate.

The release liner: Polyethylenterephthalate (PET) film, single side aluminised, both sides siliconised.

6.2 Incompatibilities

Not known.

6.3. Shelf life

3 years

6.4. Special precautions for storage

Store below 25ºC, keep the pouch tightly closed in order to protect from moisture.

6.5. Nature and content of container

Multilayer pouch made of paper, PET film, aluminium and acrylnitrilcopolymer or cyclo olefine copolymer coextrudate, a box.

Pack sizes Nicorette invisipatch 25 mg/16 h: 7, 14, 28 patches Nicorette invisipatch 15 mg/16 h: 7, 14, 28 patches Nicorette invisipatch 10 mg/16 h: 7, 14 patches

Not all pack sizes may be marketed.

6.6. Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Use of medicine has been considered to result in insignificant environmental risk.

7. MARKETING AUTHORIZATION HOLDER 11/12

McNeil AB Norrbroplatsen 2 251 09 Helsingborg Sweden

8. MARKETING AUTHORIZATION NUMBERS(S)

Nicorette invisipatch 25 mg/16 h: [To be completed nationally] Nicorette invisipatch 15 mg/16 h: [To be completed nationally] Nicorette invisipatch 10 mg/16 h: [To be completed nationally]

9. DATE OF THE FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION

Date of first authorisation: <[To be completed nationally>] Date of latest renewal: <[To be completed nationally>]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

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