NICORETTE FRUITFUSION 6 MG GUM - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Nicorette Fruitfusion 6 mg Gum

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Chewing Gum containing 6 mg nicotine, as nicotine resinate.

Excipients with known effect:

Butylated hydroxytoluene

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Medicated Chewing Gum

A square, coated and whitish coloured piece of gum.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Nicorette Fruitfusion 6mg Gum relieves and/or prevents craving and nicotine withdrawal symptoms associated with tobacco dependence in highly dependent smokers (> 20 cigarettes per day). 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 Fruitfusion 6mg Gum is indicated in pregnant and lactating women making a quit attempt.

4.2 Posology and method of administration

Highly dependent smokers (> 20 cigarettes per day), adults and children over 12 years of age.

Nicorette Fruitfusion 6mg Gum should be chewed slowly according to the instructions.

In general, if the patient smokes 20 or fewer cigarettes a day, 2mg nicotine gum is indicated. If more than 20 cigarettes per day are smoked, 4mg or 6mg nicotine gum will be needed to meet the withdrawal of the high serum nicotine levels from heavy smoking. The 6 mg gum can be recommended particularly to those requiring enhanced craving relief compared to 4mg gum (See section 5.1).

The duration and frequency of nicotine dosing may be adapted to individual needs:

Treatment with Nicorette Fruitfusion 6 mg Gum for highly dependent children and adolescent smokers should be discussed with a healthcare professional (e.g. a doctor, pharmacist or nurse).

Nicorette Fruitfusion 6 mg Gum 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 gum and as soon as they are able, reduce the number of gums used until they have stopped completely.

Smokers aiming to reduce cigarettes should use Nicorette Fruitfusion 6 mg Gum, 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.

Maximum daily dose: 15 pieces per day.

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 Nicorette Fruitfusion 6 mg Gum are recommended to contact their pharmacist or doctor for advice.

For those using the 6 mg Gum, switching to the 2 or 4 mg Gums may be helpful when stopping treatment or reducing the number of gums used each day.

The chewing gums 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.

4.3 Contraindications

Hypersensitivity to nicotine or any component of the chewing gum.

Nicorette Fruitfusion 6 mg Gum is contraindicated in children under the age of 12 years.

4.4 Special warnings and precautions for use

Any risks that may be associated with NRT are substantially outweighed 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 Nicorette Fruitfusion 6 mg Gum 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 CVA 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, Nicorette Fruitfusion 6 mg Gum 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.

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

Renal or hepatic impairment: Nicorette Fruitfusion 6 mg Gum should be used 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.

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.

Phaeochromocytoma and uncontrolled hyperthyroidism: As nicotine causes release of catecholamines, Nicorette Fruitfusion 6 mg Gum should be used with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma.

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, tacrine clozapine and ropinirole.

Excipients: Nicorette Fruitfusion 6 mg Gum also contains butylated hydroxy toluene (E321); this may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

This medicine contains less than 1 mmol sodium (23 mg) in each chewing gum, that is to say essentially ‘sodium- free’.

Denture warning: Smokers who wear dentures may experience difficulty in chewing Nicorette Fruitfusion 6 mg Gum. The chewing gum may stick to, and may in rare cases damage dentures.

Those who experience excessive side effects with the 6mg gum, should discard the gum and increase the period of time taken between each gum. If side effects are not resolved by these measures, individuals should switch to the 4mg gum.

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

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 fetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but if this is not achievable Nicorette Fruitfusion 6mg Gum 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 fetus 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.

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 Fruitfusion 6mg gum has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effectsEffects of smoking Cessation

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

This product may cause adverse reactions similar to those associated with nicotine given by other means, including smoking, and these are mainly dosedependent. At recommended doses this product has not been found to cause any serious adverse effects. Most of the undesirable effects reported by the patients occur during the early phase after start of treatment.

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. Excessive swallowing of dissolved nicotine may, at first, cause hiccupping.

Nicotine from the gum may sometimes cause a slight irritation of the throat at the start of treatment and may also cause increased salivation. Most patients will adapt to this sensation after the first few days.

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

Those who are prone to indigestion may suffer initially from minor degrees of indigestion or heartburn if the 6 mg nicotine gum is used; slower chewing and the use of the 2 or 4 mg nicotine gum (if necessary more frequently) will usually overcome this problem.

The chewing gum may stick to, and may in rare cases damage dentures.

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), including isolated reports Not known – cannot be estimated from the available data.

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

Table 1. ADRs Identified During Post-Marketing Experience and Clinical

Trials with Nicotine Oral Formulations with Frequency Category Estimated from Clinical Trials

AAt the application site,

* tightness of jaw and pain in jaw with nicotine gum formulation;

systemic effects,

* ** Higher frequency observed in clinical studies with inhaler formulation, ****Higher frequency observed in clinical studies with mouth spray formulation

# reported the same or less frequently than placebo.

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.

4.9 Overdose

Toxicity

Nicotine is highly toxic by ingestion, inhalation and skin contact. 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 fatal dose has been estimated to be as little as 40 mg of nicotine in an adult and just a few milligrams of nicotine have caused severe symptoms. It can be very rapidly absorbed with CNS, neuromuscular and autonomic features. Symptoms may persist for up to 72 hours in severe cases of poisoning.

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.

All patients who have taken a deliberate overdose should be referred for assessment.

Children and adults who have ingested 0.2 mg/kg or more nicotine, or those who are symptomatic, should be referred for medical assessment.

Children or adults who have accidentally ingested less than 0.2 mg/kg nicotine and who have no new symptoms since the time of ingestion do not need to be referred for medical assessment. Patients should be advised to seek medical attention if symptoms develop.

All symptomatic children and adults following accidental transdermal patch application should be referred for medical assessment.

Features

Early features of ingestion include burning in the mouth and throat, nausea, vomiting, confusion, dizziness, weakness, hypersalivation, sweating and increased bronchial secretions. There may be sympathetic features including tachycardia, tachypnoea, hypertension and agitation followed by bradycardia, systemic hypotension and respiratory depression.

More severe poisoning leads to arrhythmias including atrial fibrillation, coma, convulsions and respiratory and cardiac arrest. Due to the short half life of nicotine recovery is likely if survival exceeds 2–3 hours.

Skin contact may lead to irritation followed by variable absorption depending on the length of exposure and concentration. Systemic features may follow.

Eye contact with liquid may lead to irritation and lacrimation.

Management

General measures

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.

Maintain a clear airway/ensure adequate ventilation. Monitor pulse and BP. Perform 12 lead ECG and measure QRS duration and QT interval and repeat especially if the patient is symptomatic or has taken slow release preparations.

Good neurological outcome after cardiac arrest (due to nicotine poisoning) may occur after prolonged resuscitation. Cardiac arrest in hospital or witnessed out of hospital, with bystander CPR, should be continued for at least 1 hour (discuss with local poisons centre).

The benefits of gastric decontamination are uncertain. Consider activated charcoal (50g adults: 1g/kg children) provided airway can be protected in those presenting within 1 hour of ingestion of more than 0.2mg/kg of nicotine.

Asymptomatic patients who have ingested more than 0.2mg/kg of nicotine should be observed for at least 4 hours. However, if other cardiac/ cardiotoxic agents have been taken monitor for the longest period recommended for these.

In symptomatic patients check U&Es, creatinine kinase and arterial blood gases.

Contact the local poisons information centre (UK – NPIS: Ireland – NPIC) for specific advice.

Bradycardia

If symptomatic give IV atropine.

If associated with hypotension, dobutamine or isoprenaline may be considered

Temporary pacemaker or external pacing may be required.

Agitation

Agitated adults can be sedated (IV diazepam: if ineffective oral or parenteral haloperidol)

Agitated children are better managed without sedation. Exclude other causes (eg hypoxia: infection: hypoglycaemia: raised ICP). Seek expert paediatric advice.

Hypertension

Adults: in agitated patient hypertension may settle with sedation. If hypertension persists give IV nitrates until blood pressure controlled. Calcium antagonists are an alternative as second line therapy. Phentolamine or sodium nitroprusside are options if there is hypertension without evidence of cardiac ischaemia (but may cause a rapid fall in blood pressure) or alternatively IV labetalol.

Children (under 5 years): Seek expert paediatric advice.

Convulsions

Give oxygen, check blood sugar, U&Es and arterial blood gases. Correct acidbase balance and metabolic disturbances as necessary

A single brief convulsion does not require treatment. Otherwise control with IV diazepam or lorazepam. If unresponsive seek advice from NPIS/NPIC or appropriate specialist.

Other points to note

A high percentage of urine screens will be positive for nicotine in both smokers and non-smokers

Quantitative blood concentrations are not readily available. Appropriate history and recognition of clinical finding are important

Other treatments/measures indicated by patient’s clinical condition

On discharge patients should be advised to seek medical attention if symptoms develop.

Skin exposure

Remove soiled clothes, nicotine patches or contaminating fluid

Wash skin with soap and water

Treat symptoms of systemic toxicity as above.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in nicotine dependence

ATC code: N07B A01

The pharmacological effects of nicotine are well documented. Those resulting from chewing Nicorette Fruitfusion 6mg Gum are comparatively small. The response at any one time represents a summation of stimulant 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.

Abrupt cessation of the established, regular use of tobacco-containing products results in the characteristic syndrome, with withdrawal symptoms including cravings (urges to smoke) as described in section 4.8.

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

Compared with nicotine 4 mg gum, the amount of nicotine absorbed from the nicotine 6 mg gum is greater (section 5.2). Based on results from clinical smoking cessation studies, high-dose NRT products result in better craving control than lower dosetreatments. A single-dose study in 250 healthy smokers demonstrated that the 6 mg gum reduced urges to smoke from a baseline level of on average 73 mm on a 100 mm visual analogue scale with on average 44 mm over the first 60 minutes and 39 mm over the first 3 hours after administration. These reductions were significantly greater than with the 4 mg gum. A statistically significant increase in craving relief with the 6 mg gum as compared with the 4 mg gum was found from earliest time points (i.e. from 0 to 3 min, to 5 and to 10 minutes) continuously up to the following 2, 4 and 5 hours after start of administration.

Post-hoc analyses showed that a 50% reduction in perceived cravings was reached in 9.4 minutes (median estimated time) for the 6 mg gum, significantly (p=0.001) faster than with the 4 mg gum (16.3 min). The median duration with 50% reduction, or more, of perceived cravings was 111 min with the 6 mg gum and this was statistically significantly longer than with the 4 mg gum (74 min).

Weight Gain Control

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.

5.2 Pharmacokinetic properties

The pharmacokinetics of nicotine have been extensively studied. The pharmacokinetic studies of the 6mg gum have been performed in 3 studies. The studies included 118 subjects.

Absorption

Nicotine administered in chewing gums is readily absorbed through the oral mucosa membranes. Demonstrable blood levels are obtained within 4 minutes after starting of chewing and reach a maximum at the end of chewing (i.e. after 30 minutes of chewing, using a metronome to control the chewing rate) or shortly thereafter. Blood levels are almost proportional to the amount of nicotine released by chewing 2, 4 and 6 mg gums.

The amount of nicotine extracted from one chewing gum depends on how vigorously and for how long it is chewed. After 30 minutes of chewing (at a rate of one chew every two seconds), the amount of nicotine extracted from the 6 mg gum in one study was on average 4.9 mg (SD 0.69 , n=37).

The amount of nicotine absorbed depends on the amount extracted and the loss from the oral cavity due to swallowing or expectoration. Systemic bioavailability of swallowed nicotine is lowered due to first-pass hepatic metabolism.

The average maximum nicotine plasma concentration was 13.8 ng/mL (SD=5.4, n=38) after a single-dose of the 6 mg gum. Total nicotine exposure, as measured by AUC’,– after a single-dose was 46.2 ng/mLxh on average (SD=19.2, n=38) with the 6 mg gum. This corresponds to a bioavailability of approximately 54% of labeled amount. Upon usage of the maximum proposed daily dosage i.e. one gum per hour, an average steady-state concentration of 37.4 ng/mL (SD=14.4, n=35) was measured.

Distribution

The volume of distribution following intravenous administration of nicotine is about 2.2 to 3.3 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 significant effects on the nicotine pharmacokinetics.

Biotransformation

Results of pharmacokinetic studies suggest that nicotine metabolism and elimination are independent of the choice of nicotine formulation, and thus results from studies with intravenous administration of nicotine are used to describe distribution, biotransformation, metabolism and excretion.

The major nicotine-eliminating organ is the liver, although the kidneys and lungs also metabolise nicotine. More than 17 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 14 to 20 hours and concentrations that exceed nicotine by 10-fold.

Elimination

The average plasma clearance of nicotine is between 66.6and 90.0 l/h and the half-life is 2–3 hours.

The primary urinary metabolites are cotinine (10–12% of the dose) and trans-3-hydroxy-cotinine (28–37% of the dose). About 10–15% of nicotine is excreted unchanged in the urine. As much as 23% of the nicotine may be excreted unchanged in the urine with high flow rates and acidification of the urine below pH 5.

Linearity/non-linearity

The maximum concentration of nicotine in plasma increases with gum dose, with averages of 5.9, 10.1 and 13.8 ng/mL for the 2, 4 and 6 mg dose.

AUCt seems to increase proportionally with dose (15.1, 28.2 and 43.0 ng/mLxh for the 2,4 and 6 mg dose) whereas the increase in AUG,,– is slightly lower than expected at higher doses with averages of 17.1, 30.7 and 46.2 ng/mLxh for the 2, 4 and 6 mg dose.

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 50% on average 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 patients with mild liver impairment (Child-Pugh score 5) and deceased by 40–50% in patients with moderate liver impairment (Child-Pugh score 7).There is no information available in subjects with a Child-Pugh score > 7.

Geriatric

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

Nicotine was positive in some in vitro genotoxicity tests but there are also negative results with the same test systems. Nicotine was negative in in vivo tests.

Animal experiments have shown that nicotine exposure results in decreased birthweight decreased litter size and decreased survival of offspring.

The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core Gum

Chewing gum base, containing butylated hydroxy toluene (E321)

Xylitol (E967)

Peppermint oil

Sodium carbonate, anhydrous (E500)

Acesulfame Potassium (E950)

Levomenthol

Magnesium oxide, light (E530)

Sub-coating

Tuttifrutti flavour

Hypromellose (E464)

Sucralose (E955)

Polysorbate 80 (E433)

Coating

Xylitol (E967)

Acacia

Titanium dioxide (E171)

Tuttifrutti flavour

Carnauba wax (E903)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister: 3 Years

Box: 3 Years. Shelf life after opening 3 months.

6.4 Special precautions for storage

Blister: This medicinal product does not require any special temperature storage conditions. Store in original container to protect from light.

Box: This medicinal product does not require any special temperature storage conditions. Store in original container to protect from light. Use within 3 months after opening of box.

6.5 Nature and contents of container

PVC/PVDC/Al Blister packed strips each containing 15 pieces supplied in packs of 105 and 210 pieces.

and

Laminated cardboard box (PET/Cardboar­d/PET), wrapped in a transparent plastic film, containing 25 pieces, supplied in packs of 25, 100 (4 × 25) and 200 (8 × 25).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Dispose of Nicorette Gum sensibly.

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

7 MARKETING AUTHORISATION HOLDER

McNeil Products Limited

50 – 100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0381

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

16/10/2013