1. NAME OF THE MEDICINAL PRODUCT

Paramed Nicotine 4 mg Lozenges

Wilko Nicotine 4 mg Lozenges

NicAid 4 mg Lozenges

Superdrug Nicotine 4 mg Lozenges

ASDA Nicotine 4 mg Lozenges

Morrison’s Nicotine 4 mg Lozenges

Galpharm Nicotine Replace 4 mg Lozenges

Sainsbury’s Healthcare 4 mg Nicotine Lozenges

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each lozenge contains 4 mg nicotine (as 26.660 mg nicotine resinate)

For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Compressed lozenge

Cream/white, biconvex round lozenge, embossed with ‘L873’

4.1    Therapeutic indications

Nicotine 4 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 4 mg Lozenges are indicated in pregnant and lactating women making a quit attempt.

Nicotine 4 mg Lozenges should preferably be used in conjunction with a behavioural support programme.

4.2    Posology and method of administration Directions for use

Nicotine 4 mg Lozenges are suitable for smokers who have their first cigarette of the day within 30 minutes of waking up.

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 20 - 30 minutes). 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 4 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 have quit smoking but are having difficulty discontinuing using the lozenges are recommended to seek additional help and advice from a healthcare 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 effectiveness in children and adolescents who smoke have not been evaluated. Nicotine 4 mg Lozenges are not recommended for use in children under the age of 12.

4.3 Contraindications

Nicotine 4 mg Lozenges are contraindicated in:

• hypersensitivity to nicotine or any of the excipients

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 considered to be haemodynamically unstable should be encouraged to stop smoking with non-pharmacological interventions. If this fails,Nicotine 4 mg Lozenges may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision. Once patients are discharged from hospital they can use NRT as normal.

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.

Allergic reactions: Susceptibility to angioedema and urticaria

A risk benefit assessment should be made 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 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.

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs catalysed by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops this may result in a slower metabolism and a consequent rise 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:Nicotine 4 mg Lozenges are sugar free, but do contain aspartame which metabolises to phenylalanine, which is of relevance for those with phenylketonuria.

Sodium content: EachNicotine 4 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 clinically relevant interactions between nicotine replacement therapy and other drugs has definitely been established. However nicotine may possibly enhance the haemodynamic effects of adenosine.

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. 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 NRT 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 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 4 mg

Lozenges have not been found to cause any serious adverse effects. Excessive consumption of Nicotine 4 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 disorders Common >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 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 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 concentrating, restlessness and increased appetite or weight gain. The lozenges replace some of the nicotine provided by tobacco and help reduce the severity of these nicotine craving and withdrawal symptoms.

5.2 Pharmacokinetic properties

Nicotine 4 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). The complete dissolution of Nicotine 4mg Lozenge is typically achieved in 2030 minutes. The peak plasma concentrations of nicotine achieved after a single dose are approximately 4.4 ng/ml. When dosed every 1.5 hours, the steady state peak and trough concentrations are 26.0 and 19.7 ng/ml respectively. Ingestion of Nicotine 4 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 (80-93%) is still absorbed.

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.

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 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.

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.

5.3 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.

Effects were only noted following exposure to nicotine at levels in excess of those which will result from recommended use of Nicotine 4 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 Nicotine 4 mg Lozenges indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, Nicotine 4 mg Lozenges should only be used by pregnant 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, Colourless Laminate comprising: 76 micron UltRx3000 ACLAR / Adhesive / 254 micron PVC blister pack comprising of 20 micron Aluminium Foil with heat seal lacquer.

Clear, Colourless Laminate comprising: 60 micron PVC/240 micron COC (Cyclic Olefin Copolymer) / 90gsm PVdC blister pack comprising of 20 micron Aluminium Foil with heat seal lacquer.

Clear, Colourless Triplex Laminate comprising: 250 ±5% pm Clear UPVC/25 - 35 pm Low density Polyethylene/90 ±5% gm^-2 PVdC Coating blister pack comprising of 20 micron Aluminium Foil with heat seal lacquer.

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