1. NAME OF THE MEDICINAL PRODUCT

Paramed Nicotine 2 mg Lozenges

Wilko Nicotine 2 mg Lozenges

NicAid 2 mg Lozenges

Superdrug Nicotine 2 mg Lozenges

ASDA Nicotine 2 mg Lozenges

Morrison’s Nicotine 2 mg Lozenges

Galpharm Nicotine Replace 2 mg Lozenges

Sainsbury’s Healthcare 2 mg Nicotine Lozenges

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each lozenge contains 2 mg nicotine (as 13.33 mg Nicotine Resinate)

For full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Compressed lozenge

Cream/white, biconvex round lozenge, embossed ‘L344’

4.1    Therapeutic indications

Nicotine 2 mg Lozenges relieve and/or prevent craving and nicotine withdrawal symptoms associated with tobacco dependence. They are 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.

Nicotine 2 mg Lozenges are indicated in pregnant and lactating women making a quit attempt.

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

4.2    Posology and method of administration Directions for use

Nicotine 2 mg Lozenges are suitable for smokers who have their first cigarette of the day more than 30 minutes after waking up.

One lozenge should be placed in the mouth a nd allowed to dissolve. Periodically, the lozenge should be moved from one side of th e mouth to the other, and repeated, until

the lozenge is c ompletely dissolved (approximately 20 - 30 minute s). The lozenge should not be chewed or swallowed whole.

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

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

Adults (18 years and over, including the elderly):

Abrupt cessation of smoking:

Users should make every effort to stop smoking completely during treatment with Nicotine 2 mg Lozenges.

The suggested treatment is:

Step 1 Weeks 1 to 6	Step 2 Weeks 7 to 9	Step 3 Weeks 10 to 12	To help stay smoke free over the next 12 weeks: use 1-2 lozenges per day only on occasions when strongly tempted to smoke
Initial treatment period	Step down treatment period	Step down treatment period
1 lozenge every 1 to 2 hours	1 lozenge every 2 to 4 hours	1 lozenge every 4 to 8 hours

During weeks 1 to 6 it is recommended that users take a minimum of 9 lozenges per day.

Users should not exceed 15 lozenges per day.

Those who h ave quit smoking but a re h aving dif ficulty discontinuing usin g th e lozenges ar e re commended t o seek addi tional hel p and advi ce from a heal thcare professional.

Gradual cessation of smoking:

For smokers who are unwilling or unable to quit abruptly.

Use a lozenge 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 lozenges a day is variable and depends on the patients needs. Nonetheless it should not exceed 15 lozenges per day.

If a reduction in cigarette usage has not been achieved after 6 weeks of treatment, a healthcare professional should be consulted.

Reduced tobacco usage should lead to complete cessation of smoking. This should be attempted as soon as possible.

When the number of cigarettes has been reduced to a level from which the user feels able to quit completely, then start on the schedule for “abrupt cessation” as given above.

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

Reduction in smoking:

For smokers who wish to cut down with no immediate plans to quit.

Use a lozenge 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. Users should be encouraged to stop smoking completely as soon as 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 users are still feeling the need to use the lozenges on a regular basis 6 months after the start of treatment and have still been unable to undertake a permanent quit attempt, then it is recommended to seek additional help and advice from a healthcare professional.

Temporary abstinence:

Use a lozenge every 1-2 hours to control troublesome withdrawal symptoms including cravings. Users should not take more than 15 lozenges per day.

Users should be encouraged to stop smoking completely as soon as possible.

If users are still feeling the need to use lozenges on a regular basis 6 months after the start of treatment and have still been unable to undertake a permanent quit attempt, then it is recommended to seek additional help and advice from a healthcare professional.

Adolescents and children

Adolescents (12-17 years) should follow the schedule of treatment for abrupt cessation of smoking as given above. Where adolescents are unwilling or unable to quit smoking abruptly, advice from a healthcare professional should be sought.

Safety and ef fectiveness i n chi ldren and adolescents who sm oke h ave not be en evaluated. Nicotine 2 mg Lozenges are not recommended for use in children under the age of 12.

4.3 Contraindications

Nicotine 2 mg Lozenges are contraindicated in:

•    hypersensitivity to nicotine or any of the excipients

•    children under the age of 12 years and non smokers

4.4 Special warnings and precautions for use

The risks associated with the use of NRT are substantially outweighed in virtually all circumstances by the well established dangers of continued smoking.

Patients hospitalized for MI, severe dysrhythmia or CVA who are consi dered to be haemodynamically unst able should be encouraged to stop smoking with nonpharmacological inte rventions. If this fa ils, Nic otine 2 mg Lozenges may be considered, but as data on safety in this patient group are limited, initiation should only be under m edical supervision. Once patients are disch arged from h ospital they can use NRT as normal.

Diabetes Mellitus: Patients with diabetes mellitu s should be advis ed to m onitor their blood sugar lev els more closely than usual when NRT is initiated as catecholamines released by nicotine can affect carbohydrate metabolism.

Allergic reactions: Susceptibility to angioedema and urticaria

A risk ben efit assessment should be mad e by an appropriate healthcare professional for patients with the following conditions: •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 events •Phaeochromocytoma and uncontrolled hyperthyroidism: Use with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

•GI disease: Swallowed nicotine may exacerbate symptoms in patients suffering from oesophagitis, gastric or peptic ulcers and oral NRT should be used with caution in these conditions. Ulcerative stomatitis has been reported.

Danger in small children: Doses o f nic otine tolerated by a dult and adolescent smokers can produ ce se vere tox icity in sm all c hildren that ma y be fata l. Products containing nicotine should not be left where they may be misused, handled or ingested by children.

Stopping smoking: Polycyclic aromatic h ydrocarbons in tobacco smoke induce the metabolism of drug s catalysed by CYP 1A 2 (and possibly by CYP 1A1 ). When a smoker stops this may result in a slower metabolism and a consequ ent ri se in blood levels of such drugs.

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

Phenylketonuria: Ni cotine 2 mg Lozenges are s ugar fre e, but do contain aspartame which me tabolises to phe nylalanine, whic h is of re levance fo r those with phenylketonuria.

Sodium content: Each Nicotine 2 mg Lozenge contains 15 mg of sodium. People on a low sodium diet should take this into account.

4.5 Interaction with other medicinal products and other forms of interaction

No c linically re levant inte ractions be tween ni cotine repl acement t herapy and ot her drugs h as definitel y be en established. However nicotine ma y possibl y e nhance the haemodynamic effects of adenosine.

4.6 Fertility, pregnancy and lactation Pregnancy

Stopping smoking is the sing le most effe ctive intervention for improving the health of both t he pre gnant sm oker and her b aby, and t he ea rlier abstinence i s achieved t he better. Howeve r, if the mother cannot (o r is considered unlikel y to) quit withou t pharmacological support, NRT may be used as the risk to the fo etus is lower than th at expected with smoking tobacco. Stopping completely is by far the best option but NRT may be used in pregnancy as a safer alternative to smoking.

Because of the pote ntial for nic otine-free periods, inte rmittent 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 f ound in breast milk during NRT use are les s hazardous to the in fant than second-ha nd smoke. Intermittent dose f orms would minimise 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

Not applicable.

4.8 Undesirable effects

NRT can cause adverse reactions similar to those associated with nicotine administered in other way, including smoking. These may be attributed to the pharmacological effects of nicotine, which are dose dependent. At recommended doses Nicotine 2 mg Lozenges have not been found to cause any serious adverse effects. Excessive consumption of Nicotine 2 mg Lozenges by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Certain symptoms which have been reported such as depression, irritability, anxiety and insomnia may be related to withdrawal symptoms associated with smoking cessation. Subjects quitting smoking by any means could expect to suffer from headache, dizziness, sleep disturbance, increased coughing or a cold.

Related adverse events with excess in active compared to placebo group in a controlled study.

Probability of an adverse reaction:

Very common

Gastrointestinal system disorders Very common >1/10: nausea; hiccup, flatulence. Common

Psychiatric disordersCommon >1/100; <1/10: insomnia.

Central and peripheral nervous system disorders Common >1/100; <1/10: dizziness; headache.

Respiratory system disorders Common >1/100; <1/10: coughing; pharyngitis; sore throat.

Common >1/100; <1/10: vomiting; constipation, diarrheoa; dysphagia; dyspepsia; heartburn; indigestion; belching; mouth irritation, mouth ulceration; tongue ulceration; dry mouth; bloating.

Uncommon

Platelet, bleeding and clotting disorders Uncommon >1/1000; <1/100: gingival bleeding

Metabolic and nutritional disorders.

Uncommon >1/1000; <1/100: thirst; excessive thirst.

Uncommon >1/1000; <1/100: anxiety; anxiety attack; anxiety reaction; nightmares; marked restlessness; decreased appetite; lost appetite; lethargy.

Uncommon >1/1000; <1/100; migraine; mucosal burning; burning sensation; paraesthesia mouth; sensory disturbance; hyperalertness.

Uncommon >1/1000; <1/100: dyspnoea; shortness of breath; aggravated cough; lower respiratory tract infection; respiratory disorder; excessive sneezing.

Uncommon >1/1000; <1/100: gastroesophageal reflux; oesophageal reflux aggravated; retching; eructation; gagging; catarrh; increased saliva; lip ulceration; GI disorder; abdominal griping; sore lips; dry throat.

Special senses other, disorders: Uncommon >1/1000; <1/100: taste perversion.

Skin and appendages disorders: Uncommon >1/1000; <1/100: itching; rash Body as a whole: general disorders.

Uncommon >1/1000; <1/100: throat swelling; chest pain; tightness of chest; overdose effect; withdrawal syndrome; malaise; hot flushes; halitosis.

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

Nicotine is highly toxic by ingestion, inhalation and skin contact. 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. The half-life of nicotine ranges from 24 minutes to 2 hours, but symptoms may persist for up to 72 hours in severe cases of poisoning.

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. 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

•    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 acid-base 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

ATC Code NO 7B A01

Nicotine is an agonist at ni cotine r eceptors in the periph eral and central nervous system and has pronou nced CNS and cardiova scular ef fects. W hen co nsumed in tobacco p roducts, it h as been shown to b e addictive and abstinence is linked to craving and withdrawal symptoms. These craving and withdrawal symptoms include urge to smoke, depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty in c oncentrating, re stlessness a nd inc reased a ppetite or we ight g ain. The lozenges r eplace som e of t he ni cotine provided b y toba cco and h elp reduce th e severity of these nicotine craving and withdrawal symptoms.

5.2 Pharmacokinetic properties

Nicotine 2 mg Lozenges completely dissolve in the oral cavity, and the entire amount of ni cotine cont ained in t he l ozenge b ecomes avai lable fo r buc cal a bsorption or ingestion (s wallowing). The complete dissolution of Nic otine 2 mg Lozenge is typically achi eved in 20-30 minutes. The p eak pl asma concent rations of ni cotine achieved after a sin gle dose are approximately 4.4 ng/ml. When dosed every 1. 5 hours, the stead y state peak and trou gh concentrations ar e 12.7 and 9.4 n g/ml respectively. Ingestion of Nicotine 2 mg Lozenges not following dosing instructions (chewed, retained in the mouth, and swallowed; chewed and immediately swallowed) does not result in faster or higher absorption, but a substantial amount of nicotine (8093%) is still absorbed.

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

Nicotine is extensively metabolized to a number of metabolites, all of which are less active than the par ent compound. The metabolism of nicotine primaril y occurs in the liver, but a lso in th e lung and kidney. Nicotine i s metabolized primarily to cotinine but is a lso metabolized to nic otine N'-oxide. Cotinine has a half-life of 1 5-20 hours and its blood levels are 10 times higher than nicotine. Cotinine is further oxidized to trans-3'-hydroxycotinine, which is th e most a bundant metabolite of nicotine in the urine. Both nicotine and cotinine undergo glucuronidation.

The elimination half-lif e of nicotine is approximately 2 hours (range 1 - 4 hours). Total clearance for nicotine ranges from approximately 62 to 89 l/hr. Non-re nal clearance for nicotine is estimated to be about 75% of total clearance. Nicotine and its metabolites a re e xcreted a lmost e xclusively in the urine . The re nal ex cretion of unchanged nicotine is highly d ependent on urinar y pH, with greater ex cretion occurring at acidic pH.

5.3 Preclinical safety data

The g eneral tox icity of nicotine is well known and taken into account in the recommended posolo gy. Nicotine w as not mu tagenic in approp riate assays. The results of carcinogenicity assays did not pr ovide any clear evidence of a tumorigenic effect of ni cotine. In studies in pregnant animals, nicotine showed m aternal toxicity, and consequential mild foetal toxicity. Additional effects included pre- and postnatal growth retardation and delays and changes in postnatal CNS development.

Effects were only noted following exposure to nicotine at levels in e xcess of those which will re sult from recommended use of Ni cotine 2 mg Lozenges. Effects on fertility have not been established.

Comparison of the systemic exposure necessary to elicit these adverse responses from preclinical test systems with that associated with the recommended use of Ni cotine 2 mg Lozenges indica te tha t the pot ential risk is low a nd outwe ighed b y the demonstrable benefit of nicotine therapy in smoking cessation. However, Nicotine 2

mg Lozenges should on ly be used by pr egnant women on medical advice if other forms of treatment have failed.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Mannitol

Magnesium stearate Sodium alginate Xanthan gum Potassium bicarbonate Sodium carbonate anhydrous Aspartame Peppermint flavour

6.2 Incompatibilities

Not applicable

6.3    Shelf life

24 months in ACLAR/PVC/AL blisters 21 months in COC/PVdC/AL blisters 18 months in uPVC/PVdC/AL blisters

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Clear, Col ourless Lam inate com prising: 76 m icron UltRx3000 ACLAR / Ad hesive / 25 4 micron PVC blister pack comprising of 20 micron Aluminium Foil with heat seal lacquer.

Clear, Colo urless Lam inate com prising: 60 micron PVC/240 m icron COC (C yclic Ol efin Copolymer) / 90g sm PV dC blister pack comprising of 20 m icron Aluminium F oil with heat seal lacquer.

Clear, Colourless Triplex Laminate comprising: 250 ±5% ^m Clear UPVC/25 - 35 ^m Low density P olyethylene/90 ± 5% gm ^-2 PV dC Coati ng bli ster pa ck com prising of 20 m icron Aluminium Foil with heat seal lacquer.

Each pack contains 12, 36 or 72 lozenges in a cardboard carton.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Wrafton Laboratories Limited

Wrafton

Braunton

Devon

EX33 2DL

8    MARKETING AUTHORISATION NUMBER(S)

PL 12063/0068

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/02/2007

10 DATE OF REVISION OF THE TEXT

14/11/2014