Nicorette Cools 4 mg Lozenge relieves and/or prevents craving and nicotine withdrawal symptoms associated with tobacco dependence. It is indicated to aid smokers wishing to quit or reduce prior to quitting, to assist smokers who are unwilling or unable to smoke, and as a safer alternative to smoking for smokers and those around them.

Nicorette Cools 4 mg Lozenge is indicated in pregnant and lactating women making a quit attempt.

This product is suitable for smokers who smoke more than 20 cigarettes per day.

Adults and Children over 12 years of age

This product should be used whenever the urge to smoke is felt or to prevent cravings in situations where these are likely to occur.

Smokers willing or able to stop smoking immediately should initially replace all their cigarettes with the lozenge and as soon as they are able, reduce the number of lozenges used until they have stopped completely.

Smokers aiming to reduce cigarettes should take the lozenge, as needed, between smoking episodes to prolong smoke-free intervals and with the intention to reduce smoking as much as possible.

As soon as they are ready smokers should aim to quit smoking completely.

Most smokers require 8 to 12 lozenges per day, not to exceed 15 lozenges.

When making a quit attempt behavioural therapy, advice and support will normally improve the success rate. Those who have quit smoking,but are having difficulty discontinuing with the lozenge are recommended to contact their pharmacist or doctor for advice.

Method of administration

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. You should not chew or swallow the lozenge.

Hypersensitivity to any of components of the lozenge.

Nicorette Cools 4mg Lozenge is contraindicated in children under the age of 12 years.

Any risks which may be associated with the use of NRT are substantially outweighed in virtually all circumstances by the well-established dangers of continued smoking.

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

Underlying cardiovascular disease: In stable cardiovascular disease this product presents a lesser hazard than continuing to smoke. However dependent smokers currently hospitalised as a result of myocardial infarction, unstable or worsening angina including Prinzmetal's angina, severe dysrhythmia or cerebrovascular accident and who are considered to be haemodynamically unstable and/or who have uncontrolled hypertention should be encouraged to stop smoking with non-pharmacological interventions. If this fails, this product may be considered, but as data on safety in this patient group are limited, initiation should only be under 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. Ulcerative stomatitis has been reported.

Seizures: Potential risks and benefits of nicotine should be carefully evaluated before use in subjects with a history of epilepsy as cases of convulsions have been reported in association with nicotine.

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

Transferred dependence: Transferred dependence is rare and 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, clozapine and ropinirole.

Choking hazard: Lozenges can represent a choking hazard, therefore keep out of the reach of children. Use with caution in individuals with aspiration and swallowing problems.

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

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.

Pregnancy

Stopping smoking is the single most effective intervention for improving the health of both the pregnant smoker and her baby, and the earlier abstinence is achieved the better. Ideally smoking cessation during pregnancy should be achieved without NRT. Nicotine passes to the foetus and affects its breathing movements and circulation. The effect on the circulation is dose-dependent. However, if the mother cannot (or is considered unlikely to) quit without pharmacological support, NRT may be used as the risk to the foetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but if this is not achievable this product may be used in pregnancy as a safer alternative to smoking. Because of the potential for nicotine-free periods, intermittent dose forms are preferable, but patches may be necessary if there is significant nausea and/or vomiting. If patches are used they should, if possible, be removed at night when the foetus would not normally be exposed to nicotine.

Use of nicotine by the pregnant smoker should only be initiated after advice from a health care professional.

Lactation

Nicotine should be avoided during breast-feeding. The relatively small amounts of nicotine found in breast milk during NRT use are less hazardous to the infant than second-hand smoke. Intermittent dose forms would minimize the amount of nicotine in breast milk and permit feeding when levels were at their lowest.

Use of the nicotine by breast feeding smokers should only be initiated after advice from a health care professional. Women should take the product as soon as possible after breastfeeding.

This product has no or negligible influence on the ability to drive and use machines.

Effects of Smoking Cessation

Some symptoms may be related to nicotine withdrawal associated with stopping smoking. These can include: irritability/aggression, frustration/anger, dysphoria/depressed mood, anxiety, restlessness, poor concentration, increased appetite/weight gain, urges to smoke (cravings), night-time awakenings/sleep disturbance, decreased heart rate, dizziness, presyncopal symptoms, cough, constipation, gingival bleeding or nasopharyngitis.

Increased frequency of aphthous ulcer may occur after stopping smoking. The causality is unclear.

Adverse Drug Reactions

This product may cause adverse reactions similar to those associated with nicotine given by other means, including smoking, and these are mainly dose-dependent. At recommended doses this product has not been found to cause any serious adverse effects. Excessive consumption of this product by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Most of the undesirable effects reported by the patient occur during the first 3-4 weeks after start of treatment. During the first few days of treatment irritation in the mouth and throat may be experienced. Most patients will get used to this sensation after the first few days.

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

The 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.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms: Symptoms of overdose with nicotine from this product may occur in smokers who have previously had a low nicotine intake from cigarettes or if other sources of nicotine are used concomitantly with this product.

Acute or chronic toxicity of nicotine in man is highly dependent on mode and route of administration. Adaptation to nicotine (e.g. in smokers) is known to significantly increase tolerability compared with non-smokers. The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60 mg. Symptoms of acute nicotine poisoning include nausea, vomiting, increased salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of an overdose: All nicotine intake should stop immediately and the patient should be treated symptomatically. Artificial respiration should be instituted if necessary. Activated charcoal reduces the gastro-intestinal absorption of nicotine.

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.

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 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 is an important element in the withdrawal syndrome after smoking cessation.

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

Increased appetite is a recognised symptom of nicotine withdrawal and post-cessation weight gain is common. Clinical trials have demonstrated that Nicotine Replacement Therapy can help control weight following a quit attempt.

A bioequivalence study for Nicorette Cools 2mg and 4mg Lozenges measured relief in urges to smoke (i.e. craving relief) at specified intervals after the start of study drug administration.

Study subjects rated urges to smoke using a scale with 4 ordered categories:

1 No or very light urge to smoke (0-25% of maximum urge conceivable)

2 Noticeable urge to smoke (25%-50% of maximum urge conceivable)

3 Disturbing urge to smoke (50%-75% of maximum urge conceivable)

4 Very strong or extreme urge to smoke (75%-100% of maximum urge conceivable)

The data below presents urges to smoke data obtained for Nicorette Cools 4 mg Lozenge in 97 subjects, before and at 2, 5 and 10 minutes after start of treatment administration.

Table 1: Subjects who rated their urges to smoke either 'No or very light' or stronger (number and percent)

Table 2: Subjects who experienced any relief in urges to smoke (number and percent)

^a one observation missing

Absorption

A Nicorette Cools 4mg Lozenge dissolves completely, typically in 10-20 minutes. Assuming complete dissolution in the mouth, most of its nicotine is absorbed through the oral mucosa. This fraction is almost entirely delivered to the systemic circulation. The remaining nicotine released in the mouth is swallowed and undergoes considerable first-pass metabolism in the intestine and liver. As a consequence, only a small part of the total nicotine given with a lozenge reaches the circulation via the intestine.

A maximum nicotine plasma concentration of about 5 ng/mL is achieved after a single- dose of the Nicorette Cools 2mg Lozenge, and about 8 ng/mL after a single-dose of the Nicorette Cools 4mg Lozenge. Area under the time vs. plasma concentration curve extrapolated to infinity (AUC_∞ ) after a single-dose of a Nicorette Cools 2mg Lozengeis about 16 h*ng/mL, and about 31 h*ng/mL after a single-dose of a Nicorette Cools 4mg Lozenge.

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 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 terminal half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold.

Elimination

The average plasma clearance is about 70 l/h and the elimination half-life is approximately 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, but as much as 30% of nicotine may be excreted unchanged with high flow rates and acidification of the urine below pH 5.

Characteristics in specific groups of subjects

Renal Impairment

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

Hepatic Impairment

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

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

Preclinical data indicate that nicotine is neither mutagenic nor genotoxic.

There are no other 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.

Core

Mannitol (E421)

Xanthan gum (E415)

Winterfresh Flavour

Sodium carbonate anhydrous

Sucralose (E955)

Acesulfame potassium (E950)

Magnesium stearate (E470b)

Coating

Hypromellose (Methocel E3)

Winterfresh Flavour

Titanium dioxide (E171)

Sucralose (E955)

Sepifilm gloss

Acesulfame potassium (E950)

Polysorbate 80

Purified water

Not applicable.

Polypropylene container with silica gel desiccant (“ Flip pack” ): 36 months

Cardboard box: 36 months. Use within 3 months after removing the overwrap.

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

Cardboard box: Store in the original container in order to protect from moisture.

Polypropylene container with silica gel desiccant (“ Flip pack” )

Pack Sizes: 20 (1x20) and 80 (4x20) lozenges.

Cardboard box of 40 lozenges. Pack sizes: 40 (1x40) and 80 (2x40) lozenges.

Not all pack sizes may be marketed.

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