Legal Category: Products not subject to medical prescription. Supply through non-pharmacy outlets and pharmacies.

1. Name of the Medicinal Product

Nicorette Icy White 2mg Medicated Chewing Gum

2. Qualitative and Quantitative Composition

Each medicated chewing gum contains 2 mg nicotine as a resin complex.

Excipients with known effect:

Each piece contains 0.56mg Butylated hydroxytoluene (E321)

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

Medicated Chewing Gum.

A square, coated, white coloured chewing gum

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of tobacco dependence by relieving nicotine craving and withdrawal symptoms:

• thereby facilitating smoking cessation in smokers motivated to quit.

• helping smokers temporarily abstain from smoking

In certain circumstances, Nicorette Icy White 2mg Gum may be used in combination with Nicorette Invisi 10mg and 15mg Transdermal Patch for the treatment of tobacco dependence as part of a stop smoking programme.

In smokers currently unable or not ready to stop smoking abruptly, Nicorette Icy White 2mg gum may also be used as part of a programme to reduce smoking prior to stopping completely.

4.2 Posology and Method of Administration

Nicorette Icy White 2mg Gum should be chewed slowly.

Smoking cessation

Adults

The strength of gum to be used will depend on the smoking habit of the individual. In general, if the patient smokes fewer than 20 cigarettes a day, Nicorette Icy White 2mg Gum is indicated. If more than 20 cigarettes per day are smoked Nicorette Icy White 4mg Gum will be needed to meet the withdrawal of the high serum nicotine levels from heavy smoking. The patient should be urged to stop smoking completely when initiating therapy with Nicorette Icy White 2mg Gum.

The chewing gum should be used whenever there is an urge to smoke according to the “chew and rest” technique described on the pack. After about 30 minutes of such use, the gum will be exhausted. Not more than 15 pieces of the chewing gum may be used each day. Absorption of nicotine is through the buccal mucosa, any nicotine which is swallowed being destroyed by the liver.

Administration of nicotine should be stopped temporarily if any symptoms of nicotine excess occur. Nicotine intake should be decreased by lowering dosing frequency if nicotine excess symptoms persist (see Section 4.9).

Nicorette Icy White 2mg Gum may be used for up to 3 months during which time the habits associated with smoking will be lost. For those using the 4mg Gum, the 2mg will be helpful during withdrawal.

If not successful after 12 weeks the patient should be encouraged to make a fresh attempt to stop smoking. This may necessitate full or partial re-treatment with an NRT programme.

Temporary Abstinence

During periods of temporary abstinence, the patient should use Nicorette Icy White Gum when required to relieve nicotine cravings and withdrawal symptoms.

The strength of gum to be used will depend on the smoking habits of the individual. In general, if the patient smokes fewer than 20 cigarettes a day, Nicorette Icy White 2mg Gum is indicated. If more than 20 per day are smoked Nicorette Icy White 4mg Gum is indicated.

Not more than 15 pieces of the gum should be used per day.

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

Smoking reduction

For smokers who are unwilling or unable to quit abruptly.

Use the gum whenever there is a strong urge to smoke in order to reduce the number of cigarettes smoked as far as possible and to refrain from smoking as long as possible.

The number of pieces of gum is variable and depends on the patients needs. Not more than 15 pieces of the gum should be used per day.

If a reduction in number of cigarettes per day has not been achieved after 6 weeks, professional advice should be sought.

Reduced tobacco consumption should lead to complete cessation of smoking. A quit attempt should be made as soon as the number of cigarettes has been reduced to a level whereby the smoker feels ready to quit completely, then start as outlined for “smoking cessation” as given above.

If the attempt to stop smoking completely has not been started within 6 months after the beginning of treatment, it is recommended to consult a healthcare professional.

Combination Therapy

It may sometimes be beneficial to utilize more than one form of NRT concurrently. For example, combination therapy could be used by smokers who have relapsed with NRT monotherapy in the past, who experience breakthrough acute cravings or have difficulty controlling cravings for cigarettes using monotherapy. Hence, if required, the Nicorette Invisi Patch and Nicorette Icy White 2mg medicated chewing gum may be combined.

Step 1: The Nicorette Invisi 15mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 8 weeks. The Nicorette Icy White 2mg medicated chewing gum would be used ad libitum when the smoker felt an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces per day.

Step 2: After the initial 8 weeks the lower dose Nicorette Invisi 10mg Patch should be used. The Nicorette Invisi 10mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 4 weeks. The Nicorette Icy White 2mg medicated chewing gum would be used ad libitum when the smoker felt an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces per day.

Step 3: Use of the Nicorette Invisi Patch should be stopped after the 12 week treatment program. The Nicorette Icy White 2 mg medicated chewing gum can continue to be used for a further 3 months during which time the habits associated with smoking will be lost.

Recommended dosage

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

Children and Adolescents

Nicorette Icy White 2mg Gum should not be administered to persons under 18 years of age without recommendation from a health care professional.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use in non-smokers

4.4 Special Warnings and Precautions for use

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

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, Nicorette Gum may be considered but as data on safety in this patient group are limited, initiation should only be under close medical supervision.

• 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

• 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

• Seizures: Use with caution in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine (see section 4.8).

• Phaeochromocytoma and uncontrolled hyperthyroidism. Nicotine, both from NRT and smoking, causes the release of catecholamines from the adrenal medulla. Therefore, Nicorette should be used with caution in patients with uncontrolled hyperthyroidism or pheochromocytoma.

• 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 reductions in nicotine-induced catecholamine release can affect carbohydrate metabolism. Patients with diabetes mellitus may require lower doses of insulin as a result of smoking cessation.

• Smokers who wear dentures may experience difficulties in chewing Nicorette Gum. The chewing gum may stick to, and may in rare cases damage dentures.

Transferred dependence: Nicotine in any dose form is capable of inducing a dependence syndrome after chronic use and is highly toxic after acute use. However, dependence with Nicorette Icy White 2mg Gum is a rare side-effect and is both less harmful and easier to break than smoking dependence.

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

4.5 Interactions with other medicinal products and other forms of interaction

Smoking (but not nicotine) is associated with an increase in CYP1A2 activity. After cessation of smoking, reduced clearance of substrates for this enzyme may occur. This may lead to an increase in plasma levels for some medicinal products of potential clinical importance and for products with a narrow therapeutic window, e.g. theophylline, tacrine, ropinirole and clozapine.

The plasma concentration of other drugs 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 is unknown.

Limited data indicate the metabolism of flecainide and pentazocine may also be induced by smoking

Nicotine may possibly enhance the haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increased pain response (angina-pectoris type chest pain) provoked by adenosine administration.

4.6 Fertility, 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 freely 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 the use of nicotine replacement therapy. The risk of continued smoking may pose a greater hazard to the foetus as compared with the use of nicotine replacement therapy products in a supervised cessation programme. Use of Nicorette Icy White 2mg Gum should only be initiated after advice from a physician.

Lactation:

Nicotine passes freely into breast milk in quantities that may affect the child even in therapeutic dose. Nicorette Icy White 2mg Gum should therefore be avoided during breast-feeding. Should smoking cessation not be achieved, use of the Nicorette Gum by breast feeding smokers should only be initiated after advice from a health care professional. Women should take Nicorette Gum just after having breastfed.

Fertility

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

Adverse Drug Reactions (ADRs)

Nicorette Icy White 2mg Gum may cause adverse reactions similar to those associated with nicotine administered by other means and are dose dependent.

Most of the undesirable effects reported by the patient occur during the early phase of treatment and are mainly dose dependent. Irritation in the mouth and throat may be experienced, however most patients adapt to this with ongoing use.

Allergic reactions (including symptoms of anaphylaxis) can occur during the use of this product.

Adverse reactions observed in patients treated with oral nicotine formulations during clinical trials and post-marketing experience are listed below by system organ class (SOC). Frequencies are defined in accordance with current guidance, as: Very common

(>1/10); common (>1/100, <1/10); uncommon (>1/1 000, <1/100); rare (>1/10 000, <1/1 000); very rare (<1/10 000), Not known - cannot be estimated from the available data.

^a Systemic effects; ^b Tightness of jaw and pain in jaw with nicotine gum formulation ^c At the application site

*Identified only for formulations applied during the night

**Higher frequency observed in clinical studies with inhaler formulation.

***Reported the same or less frequently than placebo

**** Higher frequency observed in clinical studies with mouth spray formulation # 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.

**** Cases of seizures have been reported in subjects taking anti-convulsant therapy or with a history of epilepsy.

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 HPRA Pharmacovigilance, website: www.hpra.ie.

4.9 Overdose

Excessive use of nicotine from either NRT and/or smoking might cause symptoms of an overdose. Symptoms of an overdose are those of acute nicotine poisoning and include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. At high doses, these symptoms may be followed by hypotension, weak and irregular pulse, breathing difficulties, prostration, circulatory collapse and general convulsions.

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Management of overdose:

The administration of nicotine must be stopped immediately and the patient should be treated symptomatically. If excessive amount of nicotine is swallowed, activated charcoal reduces the gastrointestinal absorption of nicotine. Tachycardia causing circulatory impairment may require treatment with a β-blocker. Excitation and convulsions may be treated with diazepam. Mechanically assisted ventilation should be instituted if necessary.

The risk of poisoning as a result of swallowing the gum is very small, as absorption in the absence of chewing is slow and incomplete.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Drug for treatment of addictionATC Code: NO7B A01The pharmacological effects of nicotine are well documented. Those resulting from chewing Nicorette Icy White 2mg Gum are comparatively small. The response at any one time represents a summation of stimulation and depressant actions from direct, reflex and chemical mediator influences on several organs. The main pharmacological actions are central stimulation and/or depression; transient hyperpnoea; peripheral vasoconstriction (usually associated with a rise in systolic pressure); suppression of appetite and stimulation of peristalsis.The gum contains a number of ingredients that are recognized as having properties for removal of dental staining. Clinical studies have shown that the gum helps to improve tooth whiteness.

5.2 Pharmacokinetic Properties

Nicotine administered in chewing gums is readily absorbed from the buccal mucous membranes. Demonstrable blood levels are obtained within 5 – 7 minutes and reach a maximum about 30 minutes after the start of chewing.Blood levels are roughly proportioned to the amount of nicotine chewed and are unlikely to exceed those obtained from smoking cigarettes.

5.3 Preclinical Safety Data

There are no findings derived from preclinical testing of relevance to the prescriber in determining the safety of the product which have not been considered in other relevant sections of this Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Core Gum

Chewing gum base (contains Butylated hydroxytoluene (E321)) Xylitol (E967)

Peppermint oil

Sodium carbonate, anhydrous

Sodium hydrogen carbonate

Acesulfame Potassium

Levomenthol

Magnesium oxide, light

Talc

Sub coating

Winterfresh

Hypromellose

Sucralose

Polysorbate 80

Purified water

Hard Coating

Xylitol (E967)

Pre-gelatinised starch

Titanium dioxide (E171)

Winterfresh

Carnauba wax

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions for Storage.

Do not store above 25°C.

6.5 Nature and Contents of Container

PVC/PVDC/Al Blister packed strips each containing 6, 10 or 15 pieces supplied in packs of 10, 12, 15, 30, 105 and 210 pieces.Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No Special Requirements

7 Marketing Authorisation Holder

JNTL Consumer Health I (Ireland) Ltd.Block 5High StreetTallaght,Dublin 24Ireland

8. Marketing Authorisation Number

PA 23490/019/008

9. Date of first authorisation/Renewal of authorisation

Date of first authorisation: 6^th August 2010

10. Date of revision of text

December 2023

NAME OF THE MEDICINAL PRODUCT

Nicorette Cools 2 mg Lozenge

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each lozenge contains 2 mg nicotine (as nicotine resinate).

For the full list of excipients, see section 6.1

PHARMACEUTICAL FORM

Compressed lozenge (lozenge)

An oval, white to off-white tablet imprinted with an “n” on one side and “2” on the other side. The size of the lozenge is about 14 x 9 x 7 mm

CLINICAL PARTICULARS

Therapeutic indications

Nicorette Cools 2 mg Lozenges are to be used for the treatment of tobacco dependence by relief of nicotine withdrawal symptoms and cravings in smokers 18 years and above. Permanent cessation of tobacco use is the eventual objective.

Nicorette Cools 2 mg Lozenges should preferably be used in conjunction with a behavioural support programme.

Posology and method of administration

Posology

Selecting the strength of lozenge to be used will depend on the smoking habits of the individual.

Adults

Nicorette Cools 2 mg Lozenges are suitable for smokers with low nicotine dependency e.g. those smoking their first cigarette of the day more than 30 minutes after waking up or those who smoke 20 cigarettes or less per day.

Lozenges should not be used for more than 9 months. If users still feel the need for treatment, a healthcare professional should be consulted.

Behavioural therapy advice and support will normally improve the success rate.

Abrupt cessation of smoking:

The patient should make every effort to stop smoking completely during treatment with Nicorette Cools Lozenges.

The lozenges should be used whenever there is an urge to smoke.

Sufficient lozenges should be used each day and most smokers usually require 8 to 12, not to exceed 15 lozenges.

The duration of treatment is individual, but up to six weeks treatment is recommended to break the habit of smoking. The nicotine dose should then be gradually reduced, by decreasing the total number of lozenges used per day. The treatment should be stopped, when the daily consumption is down to 1-2 lozenges.

Use a lozenge whenever there is an urge to smoke to maintain complete abstinence from smoking. In the event of sudden cravings any spare lozenges should be retained and used whenever there is a craving or an urge to smoke.

Gradual cessation through progressive reduction in smoking:

For smokers who are unwilling or unable to quit abruptly.

Use a lozenge between smoking episodes to manage the urge to smoke, to prolong smoke-free intervals and with the intention to reduce smoking as much possible.

The number of lozenges a day is variable and depends on the patients needs. Nonetheless it should not exceed 15 lozenges per day.

If a reduction in number of cigarettes per day has not been achieved after 6 weeks, professional advice should be sought.

Reduced tobacco consumption should lead to complete cessation of smoking. A quit attempt should be made as soon as the smoker feels ready, but not later than 6 months after start of treatment. When the number of cigarettes has been reduced to a level from which the user feels able to quit completely, then the schedule for “abrupt cessation” as given above should be started.

If the attempt to stop smoking completely has not been started within 6 months after the beginning of treatment, it is recommended to consult a healthcare professional.

Paediatric population

Nicorette Cools 2 mg Lozenges should only be used by adolescents (12-17 years inclusive) with advice from a healthcare professional. Nicorette Cools Lozenges are not to be used by children below the age of 12.

The safety and efficacy of Nicorette Cools 2 mg Lozenges in children and adolescents has not been investigated.

Method of administration

Oromucosal use.

One lozenge should be placed in the mouth and allowed to dissolve. Periodically, the lozenge should be moved from one side of the mouth to the other, and repeated, until the lozenge is completely dissolved (approximately 16-19 minutes). The lozenge should not be chewed or swallowed whole.

Users should not eat or drink while a lozenge is in the mouth.

Contraindications

• Hypersensitivity to nicotine or to any of the excipients listed in section 6.1.

• Children under the age of 12 years.

• Those who have never smoked.

Special warnings and precautions for use

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

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, Nicorette Cools 2 mg Lozenge 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 released can affect carbohydrate metabolism.

• Allergic reactions: Susceptibility to angioedema and urticaria.

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

• Seizures: Use with caution in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine (see section 4.8).

Lozenges can represent a choking hazard. Use with caution in individuals with aspiration and swallowing problems

Paediatric population

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

Stopping Smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs metabolized by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops smoking, this may result in a 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.

Transferred dependence: Transferred dependence is unusual and is both less harmful and easier to break than smoking dependence.

Excipients:

This medicine contains less than 1 mmol sodium (23 mg) per lozenge, that is to say essentially ‘sodium-free’.

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 haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increased pain response (angina-pectoris type chest pain) provoked by adenosine administration. See section 4.4 for more information on altered metabolism of certain drugs when stopping smoking.

Fertility, 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 this medicine by the pregnant smoker should only be initiated after advice from a healthcare professional.

Breast-feeding

Nicotine passes freely into breast milk in quantities which may affect the child, even at therapeutic doses. The Nicorette Cools Lozenges should therefore be avoided during breastfeeding.

Should smoking cessation not be achieved, use of the Nicorette Cools Lozenges by breast feeding smokers, should only be initiated after advice from a healthcare professional. Where nicotine replacement therapy is used whilst breast-feeding, the Nicorette Cools Lozenges should be taken just after breast-feeding and not during the two hours before breast-feeding.

Fertility

Smoking increases the risk for infertility in women and men. In vitro studies have shown that nicotine can adversely affect human sperm quality. In rats, impaired sperm quality and reduced fertility have been shown (see section 5.3).

Effects on ability to drive and use machines

Nicorette Cools 2 mg Lozenge has no or negligible influence on the ability to drive and use machines. However, nicotine replacement users should be aware that cessation of smoking may cause changes in behaviour.

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.

The Nicorette Cools Lozenge may cause adverse reactions similar to those associated with nicotine given by other means.

Most of the undesirable effects reported by the subjects occur during the early phase of treatment and are mainly dose dependent.

Irritation in the mouth and throat may be experienced, however most subjects adapt to this with ongoing use.

Allergic reactions (including symptoms of anaphylaxis) occur rarely during use of Nicorette Cools Lozenge.

Adverse reactions with oromucosal nicotine formulations identified from clinical trials and during post-marketing experience are presented below. The frequency category has been estimated from clinical trials for the adverse reactions identified during post-marketing experience.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000),not known (cannot be estimated from the available data).

* Cases of seizures have been reported in subjects taking anti-convulsant therapy or with a history of epilepsy

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 HPRA Pharmacovigilance, Website: www.hpra.ie.

Overdose

The acute minimum lethal oral dose of nicotine in man is believed to be 40 to 60 mg. When used as directed symptoms of overdose with nicotine may occur in patients with low pre-treatment nicotine intake or if other sources of nicotine are used concomitantly.

Paediatric population

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Symptoms

Symptoms of overdose are those of acute nicotine poisoning and include nausea, vomiting, increased salivation, abdominal pain, diarrhea, sweating, headache, dizziness, disturbed hearing and marked weakness. At high doses, these symptoms may be followed by hypotension, weak and irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of overdose:

Administration of nicotine must be stopped immediately and the patient should be treated symptomatically. If excessive amount of nicotine is swallowed, activated charcoal reduces the gastrointestinal absorption of nicotine.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic Properties

Pharmacotherapeutic group: Drug used in nicotine dependence.

ATC Code: N07B A01

(Smoking cessation: N07BA, nicotine 01.)

Nicotine, the main alkaloid in tobacco products and a naturally occurring autonomic substance, is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects. When consumed in tobacco products, it has been shown to be addictive and upon cessation craving and withdrawal symptoms occur. These craving and withdrawal symptoms include urge to smoke, depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty in concentrating, restlessness and increased appetite or weight gain. The lozenges replace some of the nicotine provided by tobacco and help reduce the severity of craving and withdrawal symptoms.

Cessation rates for reference Nicotine Lozenges from clinical studies have been reported as follows:

After administration of Nicorette Cools 2 mg Lozenges the majority of subjects in a bioequivalence study experienced craving relief (i.e. relief in urges to smoke) from 5 minutes onwards.

Pharmacokinetic Properties

Absorption

Nicorette Cools 2 mg Lozenges completely dissolve in the oral cavity, and the entire amount of nicotine contained in the lozenge becomes available for buccal absorption or ingestion (swallowing). Complete dissolution of Nicorette Cools 2 mg Lozenge is typically achieved in 16-19 minutes. The peak plasma concentration of nicotine achieved after a single dose is approximately 5 ng/ml for a Nicorette Cools 2 mg Lozenge. Ingestion of Nicorette Cools 2 mg Lozenges not following dosing instructions (chewed, retained in the mouth and swallowed; chewed and immediately swallowed) gives a slower and a somewhat reduced absorption of nicotine.

Distribution

As the plasma protein binding of nicotine is low (4.9% - 20%), the volume of distribution of nicotine is large (2.5 l/kg). The distribution of nicotine to tissue is pH dependent, with the highest concentrations of nicotine found in the brain, stomach, kidney and liver.

Biotransformation

Nicotine is extensively metabolized to a number of metabolites, all of which are less active than the parent compound. The metabolism of nicotine primarily occurs in the liver, but also in the lung and kidney. Nicotine is metabolized primarily to cotinine but is also metabolized to nicotine N-oxide. Cotinine has a half-life of 15-20 hours and its blood levels are 10 times higher than for nicotine. Cotinine is further oxidized to trans-3-hydroxycotinine, which is the most abundant metabolite of nicotine in the urine. Both nicotine and cotinine undergo glucuronidation.

Elimination

The elimination half-life of nicotine is approximately 2 hours (range 1 - 4 hours). Total clearance for nicotine ranges from approximately 62 to 89 l/hr. Non-renal clearance for nicotine is estimated to be about 75% of total clearance. Nicotine and its metabolites are excreted almost exclusively in the urine. The renal excretion of unchanged nicotine is highly dependent on urinary pH, with greater excretion occurring at acidic pH.

Preclinical Safety Data

The general toxicity of nicotine is well known and taken into account in the recommended posology. Nicotine was not mutagenic in appropriate assays. The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine. In studies in pregnant animals, nicotine showed maternal toxicity, and consequential mild fetal toxicity. Additional effects included pre- and postnatal growth retardation and delays and changes in postnatal CNS development.

Studies in female rodents have shown that nicotine can decrease the number of oocytes in the fallopian tubes, decrease the concentration of serum estradiol, and result in a number of changes to the ovary and uterus. Studies in male rats have shown that nicotine can decrease testis weight, cause a reversible decrease in Sertoli cell numbers with impairment of spermatogenesis, and result in a variety of changes in the epididymis and vas deferens.

Effects were only noted following exposure to nicotine at levels in excess of those which will result from recommended use of Nicorette Lozenges.

PHARMACEUTICAL PARTICULARS

List of Excipients

Lozenge core:

Mannitol (E421)

Xanthan gum

Winterfresh RDE4-149 Spray dried (Gum arabic (E414), Peppermint, Menthol and Eucalyptol flavourings)

Sodium carbonate, anhydrous (E500)(i)

Sucralose (E955)

Acesulfame potassium (E950) Magnesium stearate (E470b) Coating:

Hypromellose (E464)

Winterfresh RDE4-149 (Peppermint, Menthol and Eucalyptol flavourings)

Titanium dioxide (E171)

Sucralose (E955)

Microcrystalline cellulose (E460)

Potassium aluminium silicate (E555)

Acesulfame potassium (E950)

Polysorbate 80 (E433)

Incompatibilities

Not Applicable.

Shelf Life

Polypropylene container: 3 years.

Special Precautions for Storage

Polypropylene container: Store the lozenges in the original container in order to protect from moisture

Nature and Contents of Container

Polypropylene container with silica gel desiccant (“Flip pack”) containing 20 lozenges. Pack Sizes: 20 (1x20) or 80 (4x20) or 160 (8x20) lozenges.

Not all pack sizes may be marketed.

Instructions for Use and Handling and Disposal

Remaining unused medicinal product may have harmful effects if reaching the aquatic environment. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORIZATION HOLDER

JNTL Consumer Health I (Ireland) Ltd.

Block 5

High Street

Tallaght, Dublin 24

Ireland

MARKETING AUTHORISATION NUMBER(S)

PA 23490/019/011

DATE OF FIRST AUTHORISATION RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 16^th December 2011

DATE OF REVISION OF THE TEXT

December 2023

1. NAME OF THE MEDICINAL PRODUCT

Nicorette Quickmist 1mg/spray, oromucosal spray, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One spray delivers 1 mg nicotine in 0.07 ml solution. 1 ml solution contains 13.6 mg nicotine.Excipient with known effect:Ethanol 7.1 mg/sprayPropylene glycol 11 mg/sprayButylated hydroxytoluene 363 ng/sprayFor the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oromucosal spray, solutionA clear to weakly opalescent, colourless to light yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Nicorette QuickMist is to be used for the treatment of tobacco dependence in adults by relief of nicotine withdrawal symptoms, including cravings, during a quit attempt or to cut down smoking before stopping completely. Permanent cessation of tobacco use is the final objective. Nicorette QuickMist should preferably be used in conjunction with a behavioral support program.

4.2 Posology and method of administration

Posology

Behavioural therapy advice and support will normally improve the success rate.

Adults and Elderly

Up to 4 sprays per hour may be used. Do not exceed 2 sprays per dosing episode and do not exceed 64 sprays (4 sprays per hour, over 16 hours) in any 24-hour period.

Abrupt Smoking Cessation

For Smokers willing and ready to stop smoking immediately.

Subjects should stop smoking completely during the course of treatment with Nicorette QuickMist.

The following chart lists the recommended usage schedule for the oromucosal spray during full treatment (Step I) and during tapering (Step II and Step III).

Step I: Weeks 1-6

Use 1 or 2 sprays when cigarettes normally would have been smoked or if cravings emerge. If after a single spray cravings are not controlled within a few minutes, a second spray should be used. If 2 sprays are required, future doses may be delivered as 2 consecutive sprays.

Most smokers will require 1-2 sprays every 30 minutes to 1 hour.

Step II: Weeks 7-9

Start reducing the number of sprays per day. By the end of week 9 subjects should be using HALF the average number of sprays per day that was used in Step I.

Step III: Weeks 10-12

Continue reducing the number of sprays per day so that subjects are not using more than 4 sprays per day during week 12. When subjects have reduced to 2-4 sprays per day, oromucosal spray use should be discontinued.

Example: If an average of 15 cigarettes per day are usually smoked, 1-2 sprays should be used at least 15 times during the day.

To help stay smoke free after Step III, subjects may continue to use the oromucosal spray in situations when they are strongly tempted to smoke. One spray may be used in situations where there is an urge to smoke, with a second spray if one spray does not help within a few minutes. No more than four sprays per day should be used during this period.

Gradual cessation through progressive reduction in smoking

For smokers who are not willing or ready to quit abruptly.

The oromucosal spray is used between periods of smoking in order to prolong the smoke-free intervals and with the intention to reduce smoking as much as possible. The patient should be aware that an incorrect use of the spray may enhance adverse effects.

A cigarette is replaced with one dose (1-2 sprays) and a quit attempt should be made as soon as the smoker feels ready and no later than 12 weeks after start of treatment. If a reduction in cigarette consumption has not been achieved after 6 weeks of treatment, a healthcare professional should be consulted. After quitting smoking, gradually reduce the number of sprays per day. When subjects have reduced to 2-4 sprays per day, oromucosal spray should be discontinued.

Regular use of the oromucosal spray beyond 6 months is not recommended. Some ex-smokers may need treatment with the oromucosal spray longer to avoid returning to smoking. Any remaining oromucosal spray should be retained to be used in the event of sudden cravings.

Paediatric population

Do not administer Nicorette QuickMist to persons under 18 years of age. There is no experience of treating adolescents under the age of 18 with Nicorette QuickMist.

Method of administration

After priming, point the spray nozzle as close to the open mouth as possible. Press firmly the top of the dispenser and release one spray into the mouth, avoiding the lips. Subjects should not inhale while spraying to avoid getting spray into the respiratory tract. For best results, do not swallow for a few seconds after spraying.

Subjects should not eat or drink when administering the oromucosal spray.

4.3 Contraindications

• Hypersensitivity to nicotine 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 QuickMist should not be used by non-smokers.

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

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 oromucosal spray 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.

• Allergic reactions: Susceptibility to angioedema and urticaria.

• 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.

• Seizures: Use with caution in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine (see section 4.8).

Paediatric population

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

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.

Excipients: This medicine contains about 7 mg of alcohol (ethanol) in each spray which is equivalent to 97 mg/ml. The amount in one spray of this medicine is equivalent to less than 2 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

This medicinal product contains less than 1 mmol sodium (23 mg) per spray, i.e. essentially ‘sodium- free’. This medicine contains 11 mg propylene glycol in each spray which is equivalent to 150 mg/mL. Due to the presence of butylated hydroxytoluene, Nicorette QuickMist may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Care should be taken not to spray the eyes whilst administering the oromucosal spray.

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 increased pain response (angina-pectoris type chest pain) provoked by adenosine administration, (see section 4.4, Stopping smoking).

4.6 Fertility, 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 QuickMist by the pregnant smoker should only be initiated after advice from a healthcare professional.

Lactation

Nicotine passes freely into breast milk in quantities that may affect the child even with therapeutic doses. Nicorette Pepparmint should therefore be avoided during breastfeeding. Should smoking cessation not be achieved, use of Nicorette Pepparmint by breast feeding smokers should only be initiated after advice from a healthcare professional. Women should take the product just after having breastfed and leave as long a time as is possible (2 hours is suggested) between taking the mouth spray and the next feed.

Fertility

Smoking increases the risk for infertility in women and men. In vitro studies have shown that nicotine can adversely affect human sperm quality. In rats, impaired sperm quality and reduced fertility has been shown.

4.7 Effects on ability to drive and use machines

Nicorette Pepparmint 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 apthous ulceration, or nasopharyngitis. In addition, and of clinical significance, nicotine cravings may result in profound urges to smoke.

Nicorette QuickMist may cause adverse reactions similar to those associated with nicotine given by other means and these are mainly dose-dependent. Allergic reactions such as angioedema, urticaria or anaphylaxis may occur in susceptible individuals.

Local adverse effects of administration are similar to those seen with other orally delivered forms. During the first few days of treatment irritation in the mouth and throat may be experienced, and hiccups are particularly common. Tolerance is normal with continued use.

Daily collection of data from trial subjects demonstrated that very commonly occurring adverse events were reported with onset in the first 2-3 weeks of use of the oromucosal spray, and declined thereafter.

Adverse reactions with oromucosal nicotine formulations identified from clinical trials and during post-marketing experience are presented below. The frequency category has been estimated from clinical trials for the adverse reactions identified during post-marketing experience.

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 (cannot be estimated from the available data).

*Cases of seizures have been reported in subjects taking anti-convulsant therapy or with a history of epilepsy.

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 HPRA Pharmacovigilance, Website: www.hpra.ie

4.9 Overdose

When used as directed symptoms of overdose with nicotine may occur in patients with low pre-treatment nicotine intake or if other sources of nicotine are used concomitantly.

Symptoms of overdose are those of acute nicotine poisoning and include nausea, vomiting, increased salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. At high doses, these symptoms may be followed by hypotension, weak and irregular pulse, breathing difficulties, prostration, circulatory collapse and general convulsions.

Paediatric population

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Management of overdose: Administration of nicotine must be stopped immediately and the patient should be treated symptomatically. If excessive amount of nicotine is swallowed, activated charcoal reduces the gastrointestinal absorption of nicotine.

The acute minimum lethal oral dose of nicotine in man is believed to be 40 to 60 mg.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drug used in nicotine dependence.

ATC code: N07B A01

Nicotine is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects.

Abrupt cessation of the established, regular use of tobacco-containing products results in the characteristic syndrome, with withdrawal symptoms including cravings (urges to smoke).

Clinical studies have shown that nicotine replacement products can help smokers abstain from smoking by raising blood nicotine levels and relieving these withdrawal symptoms.

Craving Relief

Compared with nicotine gum or nicotine lozenge, the absorption of nicotine from the oromucosal spray is more rapid (section 5.2).

In an open-label, single-dose, crossover craving study in 200 healthy smokers it was observed that two sprays of 1 mg reduced the urges to smoke significantly more than nicotine lozenge 4 mg, starting at 60 seconds after administration, and a difference between the formulations was observed for 10 minutes.

In another open-label, single-dose, crossover craving study in 61 healthy smokers it was observed that 2 sprays of 1 mg reduced the urge to smoke significantly more than the reference product, starting 30 seconds after administration in the study population, including the subset of subjects rating their baseline urges to smoke as severe. In addition, 53/58 (91%) and 45/58 (78%) of subjects reached 25% and 50% reduction in urges to smoke over the study period (i.e.

2h), respectively.

Smoking cessation

Two placebo-controlled efficacy studies have been performed. In the first study, 83/318 (26.1%) of participants using oromucosal spray managed to quit smoking at week 6 compared to 26/161 (16.1%) in the placebo group. At weeks 24 and 52 50/318 (15.7%) and 44/318 (13.8%), respectively in the oromucosal spray group and 11/161 (6.8%) and 9/161 (5.6%), respectively in the placebo group managed to quit smoking. In the second study, 30/597 (5.0%) of participants in the oromucosal spray group were smoke free at week 6 compared to 15/601 (2.5%) in the placebo group.

5.2 Pharmacokinetic properties

Variations in delivery format have been found to have significant effects on rate and extent of absorption.

The pharmacokinetics of the oromucosal spray has been studied in 4 studies. The studies included 141 subjects.

Absorption

A maximum concentration of 5.3 ng/mL is reached within 13 minutes after administration of a 2 mg dose. Comparing the AUC over the first 10 minutes after administration the estimates of the oromucosal spray at a dose of 1 and 2 mg exceeds those of nicotine gum as well as nicotine lozenge at doses of 4 mg (0.48 and 0.64 h*ng/mL vs. 0.33 and 0.33 h*ng/mL).

AUC_∞ estimates show the bioavailability of nicotine administered by oromucosal spray is similar to that of nicotine gum or lozenge. The AUC_∞ of the oromucosal spray 2 mg measured 14.0 h*ng/mL in comparison with 23.0 h*ng/mL and 26.7 h*ng/mL for nicotine gum 4 mg and nicotine lozenge 4 mg, respectively.

Steady-state average nicotine plasma concentrations achieved after administration of the maximum dose (i.e. 2 sprays of the oromucosal spray 1 mg every 30 minutes) are in the order of magnitude approximately 28.8 ng/mL as compared with 23.3 ng/mL for nicotine gum 4 mg (1 gum, hourly) and 25.5 ng/mL for nicotine lozenge 4 mg (1 lozenge, hourly).

Distribution

The volume of distribution following intravenous administration of nicotine is about 2 to 3 l/kg.

Plasma protein binding of nicotine is less than 5%. Therefore, changes in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states would not be expected to have any significant effects on the nicotine pharmacokinetics.

Biotransformation

The major nicotine-eliminating organ is the liver, although the kidney and lung also metabolise nicotine. 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-fold.

Elimination

The average plasma clearance of nicotine is 70 l/hour and the half-life is 2-3 hours.

The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxy-cotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine. As much as 30% of nicotine may be excreted unchanged in the urine with high flow rates and acidification of the urine below pH 5.

Linearity/non-linearity

There is only a small deviation from dose-linearity of AUC_∞ and C_max as shown when single doses of 1, 2, 3 and 4 sprays of the 1 mg oromucosal spray are given.

Renal Impairment

Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Nicotine clearance was on average decreased by 50% in subjects with severe renal impairment. Raised nicotine levels have been seen in smokers undergoing hemodialysis.

Hepatic Impairment

The pharmacokinetics of nicotine are unaffected in patients with mild liver impairment (ChildPugh score 5) and decreased by 40-50% in patients with moderate liver impairment (ChildPugh score 7). There is no information available in subjects with a Child-Pugh score > 7.

Elderly

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

5.3. Preclinical safety data

In vitro genotoxicity testing of nicotine has yielded predominantly negative results. There are some equivocal results when testing at high nicotine concentrations.

In vivo tests of genotoxicity have been negative.

Animal experiments have shown that nicotine exposure results in decreased birth-weight, decreased litter size and decreased survival of offspring.

Results of carcinogenicity assays do not provide any clear evidence of a tumorigenic effect of nicotine.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene glycol (E1520)

Anhydrous ethanol

Trometamol

Poloxamer 407

Glycerol (E422)

Sodium hydrogen carbonate

Levomenthol

Mint flavour

Cooling flavour

Sucralose

Acesulfame potassium

Butylated hydroxytoluene (E321)

Hydrochloric acid (for pH adjustment)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2.5 years.

6.4 Special precautions for storage

Do not store above 30°C

6.5 Nature and contents of container

13.2 ml solution is filled in a PET bottle. One bottle contains 150 sprays of 1 mg. The bottle is placed in a dispenser with a mechanical spray pump with an actuator. The dispenser has a child resistant feature.

Pack sizes

1x1 dispenser, 2x1 dispensers

1x1 dispenser + Near Field Communication (NFC), 2x1 dispensers + NFC: Includes an NFC chip underneath the back label of the dispenser to allow connectivity with a smartphone app.

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.

7. MARKETING AUTHORISATION HOLDER

JNTL Consumer Health I (Ireland) Ltd.

Block 5

High Street

Tallaght

Dublin 24

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

PA23490/019/013

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 3^rd August 2012 Date of last renewal: 6^th October 2015

10. DATE OF REVISION OF THE TEXT

December 2023

1. Name Of The Medicinal Product

Nicorette Invisi 10mg/16 hours Transdermal Patch

2. Qualitative And Quantitative Composition

Nicotine, 10mg released over 16 hours use. Each patch is 9.0cm², containing 1.75mg nicotine/cm³For the full list of excipients, see section 6.1

3. Pharmaceutical Form

Transdermal Patch

Beige semi-transparent patch consisting of pre coated backing layer, nicotine source layer, a skin contact adhesive layer on a pre-coated, aluminized and siliconised release layer with “nicorette” printed on the top face of the patch. The patch is approximately 3 x 3cm (with rounded corners)

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of tobacco dependence by relieving nicotine craving and withdrawal symptoms, thereby facilitating smoking cessation in smokers motivated to quit.In certain circumstances, Nicorette Invisi 10mg Patch may be used in combination with Nicorette 2mg Gum or Nicorette 15mg Inhaler for the treatment of tobacco dependence as part of a stop smoking programme.

4.2 Posology and Method of Administration

Smoking Cessation

Adults and the Elderly

The strength of patch to be used will depend on the smoking habit of the individual. In general, if the patient smokes fewer than 20 cigarettes a day it is recommended that they start on the 15mg Invisi Patch and then step down to the Nicorette 10mg Invisi Patch. If more than 20 cigarettes per day are smoked it is recommended that they start on the 25mg Invisi Patch and then step down to the Nicorette 15mg and 10mg Invisi Patch.

Experience with the treatment of nicotine dependence shows that success rates are improved if patients also receive support therapy and counselling.

The patch should be applied to an intact area of the skin upon waking up in the morning and removed at bedtime. Patch treatment mimics the fluctuations of nicotine over the day in smokers, with no nicotine administration during sleep. Daytime nicotine patch treatment does not give the nicotine induced sleep disturbances seen with nicotine administration during sleep.

Heavy smokers are recommended to start at Step 1 with the 25 mg/ 16 hours patch and use one patch daily for 8 weeks.

Gradual weaning from the patch should then be initiated. One 15 mg/16 hours patch should be used daily for 2 weeks followed by one 10 mg/16 hours patch daily for 2 weeks.

Light smokers are recommended to start at Step 2 (15 mg) for 8 weeks and decrease the dose to Step 3 (10 mg) for the final 4 weeks.

Table 1 Heavy Smokers Light Smokers

Combination Therapy

It may sometimes be beneficial to utilize more than one form of NRT concurrently. For example, combination therapy could be used by heavy smokers (more than 20 cigarettes a day) or smokers who have relapsed with NRT monotherapy in the past, who experience breakthrough acute cravings or have difficulty controlling cravings for cigarettes using monotherapy. Hence, if required, the Nicorette Invisi Patch may be combined with Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler..

Step 1: The Nicorette Invisi 15mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 8 weeks. The Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler would be used ad libitum when the smoker feels an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces of gum or 6 inhaler cartridges per day.

Step 2: After the initial 8 weeks the lower dose Nicorette Invisi 10mg Patch should be used. The Nicorette Invisi 10mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 4 weeks. The Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler would be used ad libitum when the smoker feels an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces of gum or 6 inhaler cartridges per day.

Step 3: Use of the Nicorette Invisi Patch should be stopped after the 12 week treatment program. The Nicorette 2 mg medicated chewing gum or Nicorette 15mg Inhaler can continue to be used for a further 3 months during which time the habits associated with smoking will be lost.

Recommended dosage

Children and Adolescents

Nicorette Invisi Patch should not be administered to persons under 18 years of age without recommendation from a health care professional. There is limited experience of treating this age group with Nicorette Invisi Patch.

Use of the patch beyond 6 months is generally not recommended. Some ex-smokers may need longer treatment to avoid returning to smoking.

How to apply the patches

Nicorette Invisi Patch should be applied to clean, dry intact areas of hairless skin, for example on the hip, upper arm, 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 the patch.

2. Cut open the pouch with scissors along the side, as indicated. Select a clean, dry, hairless intact area of skin, such as the hip, upper arm or chest.

3. Peel one part of the silvery aluminum backing away as far as possible. Avoid touching the sticky surface of the patch with your fingers, as far as possible

4. Apply the sticky part of the patch carefully onto the skin and peel off the remaining half of the silvery aluminum backing.

5. Press the patch firmly onto the skin with your palm or finger-tips.

6. Rub your fingers firmly round the edge to ensure that the patch sticks firmly.

After removal, used patches should be disposed of carefully.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use in non-smokers.

4.4 Special Warnings and Precautions for Use

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

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, Nicorette Invisi 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 reductions 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.

• Seizures: Use with caution in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine (see section 4.8)

Patients with chronic dermatological disorders such as psoriasis, chronic dermatitis or urticaria should not apply Nicorette Invisi Patch to the affected areas. Erythema may occur. If it is severe or persistent, treatment should be discontinued.

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

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

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

4.5 Interactions with other medicinal products and other forms of interaction

Smoking (but not nicotine) is associated with an increase in CYP1A2 activity. After cessation of smoking, reduced clearance of substrates for this enzyme may occur. This may lead to an increase in plasma levels for some medicinal products of potential clinical importance and for products with a narrow therapeutic window, e.g. theophylline, tacrine, clozapine and ropinirole

The plasma concentration of other drugs metabolised in part by CYP1A2 e.g. imipramine, olanzapine, clonipramine and fluvoxamine may also increase on cessation of smoking, although data to support this are lacking and the possible clinical significance of this effect is unknown.

Limited data indicate the metabolism of flecainide and pentazocine may also be induced by smoking.

Nicotine may possibly enhance the haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increased pain response (angina-pectoris type chest pain) provoked by adenosine administration.

4.6 Fertility, 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 freely 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 the use of nicotine replacement therapy. The risk of continued smoking may pose a greater hazard to the foetus as compared with the use of nicotine replacement therapy products in a supervised cessation programme. Use of Nicorette Invisi Patch should only be initiated after advice from a physician.

Lactation:

Nicotine passes freely into breast milk in quantities that may affect the child even in therapeutic dose. Nicorette Invisi Patch should therefore be avoided during breastfeeding.

Should smoking cessation not be achieved, use of the Nicorette Invisi Patch by breast feeding smokers should only be initiated after advice from a health care professional.

Fertility

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

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 Invisi Patch 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.

Adverse drug reactions

Nicorette Invisi Patch may cause adverse reactions similar to those associated with nicotine administered by other means and are mainly dose dependent.

About 20% of users experienced mild local skin reactions, during the first weeks of treatment. Allergic reactions (including symptoms of anaphylaxis) occur rarely during use of Nicorette Invisi Patch.

Most of the undesirable effects reported by the subjects occur during the early phase of treatment and are mainly dose dependent.

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

Frequencies are provided according to the following convention:

Very common (>1/10); common (> 1/100, <1/10); uncommon (>1/1 000, < 1/100); rare (>1/10 000, < 1/1 000); very rare (<1/10 000), Not known (cannot be estimated from the available data). ** Frequency category estimated using the “Rule of 3”

^a systemic effects; ^b In vicinity/region of patch

# 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.

Cases of seizures have been reported in subjects taking anti-convulsant therapy or with a history of epilepsy.

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 HPRA Pharmacovigilance, website: www.hpra.ie.

4.9 Overdose

Excessive use of nicotine from either NRT and/or smoking might cause symptoms of an overdose. Symptoms of overdose are those of acute nicotine poisoning and include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. At high doses, these symptoms may be followed by hypotension, weak and irregular pulse, breathing difficulties, prostration, circulatory collapse and general convulsions.

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Management of overdose

The administration of nicotine must be stopped immediately and the patient should be treated symptomatically. Remove patch and rinse application site with water. Oral activated charcoal reduces gastrointestinal absorption of nicotine. Tachycardia causing circulatory impairment may require treatment with a β blocker. Excitation and convulsions may be treated with diazepam. Mechanically assisted ventilation should be instituted if necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drug for treatment of addiction.

ATC code: N07B A01

Abrupt cessation of the use of tobacco-containing products following a prolonged period of daily use results in a characteristic withdrawal syndrome that includes four or more of the following: dysphoria or depressed mood; insomnia; irritability, frustration or anger; anxiety; difficulty concentrating, restlessness or impatience; decreased heart rate; and increased appetite or weight gain. Nicotine craving, which is recognised as a clinically relevant symptom, is also an important element in nicotine withdrawal.

Clinical studies have shown that nicotine replacement products can help smokers abstain from smoking.

5.2 Pharmacokinetic Properties

The patches are labeled by the average amount of nicotine released over 16 hours.

A linear relationship exists between released amount of nicotine (dose) and plasma levels of nicotine over the therapeutic dose range, 10-25 mg/16 hours. The mean peak plasma levels of nicotine (C_max ) achieved are calculated to:

The calculated peak plasma levels are in the same range as true measured peak plasma concentrations: 11 ng/mL for the 10 mg patch and 25 ng/mL for the 25 mg patch. Interpolation yields a peak plasma concentration of 16 ng/mL for the 15 mg patch.

The maximum level of plasma concentration after administration is reached after approximately 9 hours (t_max). The plasma peak is in the afternoon/ evening when the risk of relapse is highest.

The volume of distribution of nicotine is about 2 to 3 L/kg and the half-life approximately 3 hours. The major eliminating organ is the liver, and average plasma clearance is about 70 L/hour. The kidney and lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound.

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

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

The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxycotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine.

Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Raised nicotine levels have been seen in smoking patients undergoing hemodialysis.

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

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

Plasma nicotine concentrations show dose proportionality for the three patch doses.

5.3 Preclinical safety data

Non-clinical studies with Nicorette Invisi Patch support the well established safety of nicotine use in NRT and documented safety profile for the excipients.

There is no clear evidence of nicotine being genotoxic or mutagenic. The well established carcinogenicity of tobacco smoke is mainly related to substances formed by the pyrolysis of tobacco. None of these occur in nicotine patch.

6. Pharmaceutical Particulars

List of Excipients

Backing Layer polyethylenterephthalate film (PET)

Nicotine Matrix

triglycerides, medium-chain

basic butylated methacrylate copolymer

Acrylate Matrix Acrylic adhesive solution potassium hydroxide croscarmellose sodium aluminium acetylacetonate Release Liner polyethylenterephthalate (PET) film single side aluminised, both sides siliconised

Printing Ink Solution blending varnish, printing ink beige, printing ink brown

Incompatibilities

Not applicable

Shelf Life

3 years

Special Precautions for Storage.

Do not store above 25ºC.

Nature and Contents of Container

Heat-sealed multilaminate pouch containing one patch. The pouch material consists of paper, adhesive, polyethyelene terephthalate film, aluminium, and either polyacrylinitrile copolymer or cyclo olefine copolymer coextrudate.

Cartons of 1,2,3,5,7 and 14 patches

Not all pack sizes may be marketed.

Special precautions for disposal

Nicotine residues in the used patches may present a hazard to children and pets, thus used patches should be folded, sticky sides together, put back in an empty pouch and placed in household rubbish.

7. Marketing Authorisation Holder

JNTL Consumer Health I (Ireland) Ltd.

Block 5

High Street

Tallaght

Dublin 24

Ireland

8. Marketing Authorisation Number

PA23490/019/005

9. Date of First Authorisation/Renewal of Authorisation

Date of first authorisation: 5^th September 2008Date of last renewal: 5^th September 2013

10. Date of (Partial) Revision of the Text

December 2023

1. Name Of The Medicinal Product

Nicorette Invisi 15mg/16 hours Transdermal Patch

2. Qualitative And Quantitative Composition

Nicotine, 15mg released over 16 hours use. Each patch is 13.5cm², containing 1.75mg nicotine/cm³

For the full list of excipients, see section 6.1

3. Pharmaceutical Form

Transdermal Patch

Beige semi-transparent patch consisting of pre coated backing layer, nicotine source layer, a skin contact adhesive layer on a pre-coated, aluminized and siliconised release layer with “nicorette” printed on the top face of the patch. The patch is approximately 3 x 4cm (with rounded corners)

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of tobacco dependence by relieving nicotine craving and withdrawal symptoms, thereby facilitating smoking cessation in smokers motivated to quit.In certain circumstances, Nicorette Invisi 15mg Patch may be used in combination with Nicorette 2mg Gum or Nicorette 15mg Inhaler for the treatment of tobacco dependence as part of a stop smoking programme.

4.2 Posology and Method of Administration

Smoking Cessation

Adults and the Elderly

The strength of patch to be used will depend on the smoking habit of the individual. In general, if the patient smokes fewer than 20 cigarettes a day it is recommended that they start on the 15mg Invisi Patch and then step down to the Nicorette 10mg Invisi Patch. If more than 20 cigarettes per day are smoked it is recommended that they start on the 25mg Invisi Patch and then step down to the Nicorette 15mg and 10mg Invisi Patch.

Experience with the treatment of nicotine dependence shows that success rates are improved if patients also receive support therapy and counselling.

The patch should be applied to an intact area of the skin upon waking up in the morning and removed at bedtime. Patch treatment mimics the fluctuations of nicotine over the day in smokers, with no nicotine administration during sleep. Daytime nicotine patch treatment does not give the nicotine induced sleep disturbances seen with nicotine administration during sleep.

Heavy smokers are recommended to start at Step 1 with the 25 mg/ 16 hours patch and use one patch daily for 8 weeks.

Gradual weaning from the patch should then be initiated. One 15 mg/16 hours patch should be used daily for 2 weeks followed by one 10 mg/16 hours patch daily for 2 weeks.

Light smokers are recommended to start at Step 2 (15 mg) for 8 weeks and decrease the dose to Step 3 (10 mg) for the final 4 weeks.

Table 1 Heavy Smokers Light Smokers

Combination Therapy

It may sometimes be beneficial to utilize more than one form of NRT concurrently. For example, combination therapy could be used by heavy smokers (more than 20 cigarettes a day) or smokers who have relapsed with NRT monotherapy in the past, who experience breakthrough acute cravings or have difficulty controlling cravings for cigarettes using monotherapy. Hence, if required, the Nicorette Invisi Patch may be combined with Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler.

Step 1: The Nicorette Invisi 15mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 8 weeks. The Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler would be used ad libitum when the smoker feels an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces of gum or 6 inhaler cartridges per day.

Step 2: After the initial 8 weeks the lower dose Nicorette Invisi 10mg Patch should be used. The Nicorette Invisi 10mg Patch would be applied daily on waking for 16 hours and removed just before bedtime for a total of 4 weeks. The Nicorette 2mg medicated chewing gum or Nicorette 15mg Inhaler would be used ad libitum when the smoker feels an urge to smoke or in situations where he/she feels that breakthrough cravings may occur, up to a maximum of 15 pieces of gum or 6 inhaler cartridges per day.

Step 3: Use of the Nicorette Invisi Patch should be stopped after the 12 week treatment program. The Nicorette 2 mg medicated chewing gum or Nicorette 15mg Inhaler can continue to be used for a further 3 months during which time the habits associated with smoking will be lost.

Recommended dosage

Children and Adolescents

Nicorette Invisi Patch should not be administered to persons under 18 years of age without recommendation from a health care professional. There is limited experience of treating this age group with Nicorette Invisi Patch.

Use of the patch beyond 6 months is generally not recommended. Some ex-smokers may need longer treatment to avoid returning to smoking.

How to apply the patches

Nicorette Invisi Patch should be applied to clean, dry intact areas of hairless skin, for example on the hip, upper arm, or chest. These areas should be varied each day and the same site should not be used on consecutive days.

7. Wash your hands before applying the patch.

8. Cut open the pouch with scissors along the side, as indicated. Select a clean, dry, hairless intact area of skin, such as the hip, upper arm or chest.

9. Peel one part of the silvery aluminum backing away as far as possible. Avoid touching the sticky surface of the patch with your fingers, as far as possible

10. Apply the sticky part of the patch carefully onto the skin and peel off the remaining half of the silvery aluminum backing.

11. Press the patch firmly onto the skin with your palm or finger-tips.

12. Rub your fingers firmly round the edge to ensure that the patch sticks firmly.

After removal, used patches should be disposed of carefully.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Use in non-smokers.

a. Special Warnings and Precautions for Use

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

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, Nicorette Invisi 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 reductions 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.

• Seizures: Use with caution in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine (see section 4.8).

Patients with chronic dermatological disorders such as psoriasis, chronic dermatitis or urticaria should not apply Nicorette Invisi Patch to the affected areas. Erythema may occur. If it is severe or persistent, treatment should be discontinued.

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

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

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

b. Interactions with other medicinal products and other forms of interaction

Smoking (but not nicotine) is associated with an increase in CYP1A2 activity. After cessation of smoking, reduced clearance of substrates for this enzyme may occur. This may lead to an increase in plasma levels for some medicinal products of potential clinical importance and for products with a narrow therapeutic window, e.g. theophylline, tacrine, clozapine and ropinirole

The plasma concentration of other drugs metabolised in part by CYP1A2 e.g. imipramine, olanzapine, clonipramine and fluvoxamine may also increase on cessation of smoking, although data to support this are lacking and the possible clinical significance of this effect is unknown.

Limited data indicate the metabolism of flecainide and pentazocine may also be induced by smoking.

Nicotine may possibly enhance the haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increased pain response (angina-pectoris type chest pain) provoked by adenosine administration.

4.6 Fertility, 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 freely 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 the use of nicotine replacement therapy. The risk of continued smoking may pose a greater hazard to the foetus as compared with the use of nicotine replacement therapy products in a supervised cessation programme. Use of Nicorette Invisi Patch should only be initiated after advice from a physician.

Lactation

Nicotine passes freely into breast milk in quantities that may affect the child even in therapeutic dose. Nicorette Invisi Patch should therefore be avoided during breastfeeding.

Should smoking cessation not be achieved, use of the Nicorette Invisi Patch by breastfeeding smokers should only be initiated after advice from a health care professional.

Fertility

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

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 Invisi Patch 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.

Adverse drug reactions

Nicorette Invisi Patch may cause adverse reactions similar to those associated with nicotine administered by other means and are mainly dose dependent.

About 20% of users experienced mild local skin reactions, during the first weeks of treatment. Allergic reactions (including symptoms of anaphylaxis) occur rarely during use of Nicorette Invisi Patch.

Most of the undesirable effects reported by the subjects occur during the early phase of treatment and are mainly dose dependent.

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

Frequencies are provided according to the following convention:

Very common (>1/10); common (> 1/100, <1/10); uncommon (>1/1 000, < 1/100); rare (>1/10 000, < 1/1 000); very rare (<1/10 000), Not known (cannot be estimated from the available data). ** Frequency category estimated using the “Rule of 3”

^a systemic effects; ^b In vicinity/region of patch

# 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.

• Cases of seizures have been reported in subjects taking anti-convulsant therapy or with a history of epilepsy.

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 HPRA Pharmacovigilance, website: www.hpra.ie.

4.9 Overdose

Excessive use of nicotine from either NRT and/or smoking might cause symptoms of an overdose. Symptoms of overdose are those of acute nicotine poisoning and include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. At high doses, these symptoms may be followed by hypotension, weak and irregular pulse, breathing difficulties, prostration, circulatory collapse and general convulsions.

Doses of nicotine that are tolerated by adult smokers during treatment may produce severe symptoms of poisoning in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Management of overdose

The administration of nicotine must be stopped immediately and the patient should be treated symptomatically. Remove patch and rinse application site with water. Oral activated charcoal reduces gastrointestinal absorption of nicotine. Tachycardia causing circulatory impairment may require treatment with a β blocker. Excitation and convulsions may be treated with diazepam. Mechanically assisted ventilation should be instituted if necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drug for treatment of addiction.

ATC code: N07B A01

Abrupt cessation of the use of tobacco-containing products following a prolonged period of daily use results in a characteristic withdrawal syndrome that includes four or more of the following: dysphoria or depressed mood; insomnia; irritability, frustration or anger; anxiety; difficulty concentrating, restlessness or impatience; decreased heart rate; and increased appetite or weight gain. Nicotine craving, which is recognised as a clinically relevant symptom, is also an important element in nicotine withdrawal.

Clinical studies have shown that nicotine replacement products can help smokers abstain from smoking.

5.2 Pharmacokinetic Properties

The patches are labeled by the average amount of nicotine released over 16 hours.

A linear relationship exists between released amount of nicotine (dose) and plasma levels of nicotine over the therapeutic dose range, 10-25 mg/16 hours. The mean peak plasma levels of nicotine (C_max) achieved are calculated to:

The calculated peak plasma levels are in the same range as true measured peak plasma concentrations: 11 ng/mL for the 10 mg patch and 25 ng/mL for the 25 mg patch. Interpolation yields a peak plasma concentration of 16 ng/mL for the 15 mg patch.

The maximum level of plasma concentration after administration is reached after approximately 9 hours (t_max). The plasma peak is in the afternoon/ evening when the risk of relapse is highest.

The volume of distribution of nicotine is about 2 to 3 L/kg and the half-life approximately 3 hours. The major eliminating organ is the liver, and average plasma clearance is about 70 L/hour. The kidney and lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound.

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

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

The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxycotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine.

Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Raised nicotine levels have been seen in smoking patients undergoing hemodialysis.

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

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

Plasma nicotine concentrations show dose proportionality for the three patch doses.

5.3 Preclinical Safety Data

Non-clinical studies with Nicorette Invisi Patch support the well established safety of nicotine use in NRT and documented safety profile for the excipients.

There is no clear evidence of nicotine being genotoxic or mutagenic. The well established carcinogenicity of tobacco smoke is mainly related to substances formed by the pyrolysis of tobacco. None of these occur in nicotine patch.

6. Pharmaceutical Particulars

List of Excipients

Backing Layer polyethylenterephthalate film (PET)

Nicotine Matrix

triglycerides, medium-chain

basic butylated methacrylate copolymer

Acrylate Matrix Acrylic adhesive solution potassium hydroxide croscarmellose sodium aluminium acetylacetonate Release Liner polyethylenterephthalate (PET) film single side aluminised, both sides siliconised

Printing Ink Solution blending varnish, printing ink beige, printing ink brown

Incompatibilities

Not applicable

Shelf Life

3 years

Special Precautions for Storage.

Do not store above 25ºC.

Nature and Contents of Container

Heat-sealed multilaminate pouch containing one patch. The pouch material consists of paper, adhesive, polyethyelene terephthalate film, aluminium, and either polyacrylinitrile-copolymer or cyclo olefine copolymer coextrudate.

Cartons of 1,2,3,5,7 and 14 patches.

Not all pack sizes may be marketed.

Special precautions for disposal

Nicotine residues in the used patches may present a hazard to children and pets, thus used patches should be folded, sticky sides together, put back in an empty pouch and placed in household rubbish.

7. Marketing Authorisation Holder

JNTL Consumer Health I (Ireland) Ltd.Block 5High StreetTallaghtDublin 24Ireland

8. Marketing Authorisation Number

PA23490/019/006

9. Date of First Authorisation/Renewal of Authorisation

Date of first authorisation: 5^th September 2008Date of last renewal: 5^th September 2013

10. Date of (Partial) Revision of the Text

December 2023