SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nicorette Cools 4 mg Lozenge

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each lozenge contains 4 mg nicotine (as nicotine resinate).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Compressed lozenge.

An oval, white to off-white lozenge imprinted with a “n” on one side and “4” on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2 Posology and method of administration

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.

4.3 Contraindications

Hypersensitivity to any of components of the lozenge.

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

4.4 Special warnings and precautions for use

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.

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 hypertension 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 NRT is initiated as catecholamines released by nicotine 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: 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. Ulcerative stomatitis has been reported.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6    Fertility pregnancy and lactation

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. 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.

Lactation

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.

4.7    Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 and decreased heart rate.

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.

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). Fequencies 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).

Body System	Incidence	Reported adverse event (Preferred Term)
Immune system disorders	Common	Hypersensitivity a
	Not known	Anaphylactic reaction a
Psychiatric disorders	Uncommon	Abnormal dreams*
Nervous system disorders	Very common	Headache a#
	Common	Burning sensation c
	Common	Dizziness
	Common	Dysgeusia
	Common	Paraesthesia a
Eye disorders	Not known	Blurred vision
	Not known	Lacrimation increased
Cardiac disorders	Uncommon	Palpitations a
	Uncommon	Tachycardia a
	Very rare	Reversible atrial fibrillation
Vascular disorders	Uncommon	Flushing a
	Uncommon	Hypertension a
Respiratory, thoracic and mediastinal disorders	Very common	Cough**
	Very common	Sore mouth or throat
	Very common	Throat irritation
	Uncommon	Bronchospasm
	Uncommon	Dysphonia
	Uncommon	Dyspnoea a
	Uncommon	Nasal congestion
	Uncommon	Sneezing
	Uncommon	Throat tightness
Gastrointestinal disorders	Very Common	Hiccups
	Very common	Nausea a
	Common	Abdominal pain
	Common	Diarrhoea***
	Common	Dry mouth
	Common	Dyspepsia

Body System	Incidence	Reported adverse event (Preferred Term)
	Common	Flatulence
	Common	Salivary hypersecretion
	Common	Stomatitis
	Common	Vomiting a
	Uncommon	Eructation
	Uncommon	Glossitis
	Uncommon	Oral mucosal blistering and exfoliation
	Uncommon	Paraesthesia oral***
	Rare	Dysphagia
	Rare	Hypoaesthesia oral***
	Rare	Retching
	Not known	Dry throat
	Not known	Gastrointestinal discomforta
	Not known	Lip pain
Musculoskeletal and connective tissue disorders	Uncommon	Pain in Jaw b
	Not known	Muscle tightness b
Skin and Subcutaneous Tissue Disorders	Uncommon	Hyperhidrosis a
	Uncommon	Pruritus a
	Uncommon	Rash a
	Uncommon	Urticaria**
	Not known	Erythemaa
General disorders and administration site conditions	Common	Fatigue a
	Uncommon	Asthenia a
	Uncommon	Chest discomfort and pain a
	Uncommon	Malaise a
	Rare	Allergic reactions including angioedema

^a Systemic effects; ^b Tightness ofjaw 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

# 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.

4.9 Overdose

Symptoms: 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.

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 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)

How strong was your urge to smoke?	Before start of administration of study treatment	After 2 minutes	After 5 minutes	After 10 minutes
Category 1 (No or very light urge to smoke)	0 (0%)	20 (23.5%)	43 (50.5%)	57 (68%)
Category 2 -Category 4	80 (100%)	65 (76.5%)	42 (49.5%)	28 (32%)

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

and percent)

Any relief in urges to smoke?	Before start of administration of study treatment	After 2 minutes	After 5 minutes	After 10 minutesa
Yes	0 (0%)	40 (47%)	70 (85%)	78 (93%)
No	90 (100%)	45 (53%)	15 (15%)	6 (7%)

one observation missing

5.2 Pharmacokinetic properties

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 singledose 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 safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

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

OPA/Al/PVC blisters: 24 months.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

OPA/Al/PVC blisters Pack Size: 24 (2x12) lozenges.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0375

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/02/2012

10    DATE OF REVISION OF THE TEXT

18/05/2016