1    NAME OF THE MEDICINAL PRODUCT

NiQuitin Mint 4mg Lozenges

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each compressed lozenge contains 4mg Nicotine (as 26.66mg Nicotine Resinate)

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Compressed Lozenge

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nicotine Perrigo 4mg Lozenges are indicated for the treatment of tobacco dependence by relieving

nicotine withdrawal symptoms including cravings, associated with smoking cessation. Permanent

cessation of tobacco use is the eventual objective.

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

4.2    Posology and method of administration

Posology

Adults (18 years and over):

Users should make every effort to stop smoking completely during treatment with Nicotine Perrigo 4mg Lozenges.

Recommended treatment schedule:

Step 1 Weeks 1 to 6	Step 2 Weeks 7 to 9	Step 3 Weeks 10 to 12
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.

To help stay smoke free beyond 12 weeks, users may take 1-2 lozenges per day only on occasions when they are strongly tempted to smoke.

Lozenges should not be used for more than 6 months. If users still feel the need for treatment, a healthcare professional should be consulted.

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

Paediatric population

Nicotine Perrigo 4mg Lozenges should only be used in adolescents (12-17 years) with the advice of a healthcare professional.

Nicotine Perrigo 4mg Lozenges are contraindicated in children under the age of 12 years in the indication of treatment of nicotine dependence (see section 4.3).

Method of Administration

Nicotine Perrigo 4mg Lozenges are suitable for smokers who have their first cigarette of the day less than 30 minutes after 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. Liquids which lower the pH in the mouth such as coffee, juices and soft drinks, can decrease the absorption of nicotine in the mouth. To obtain maximum absorption of nicotine these liquids should be avoided for up to 15 minutes before the lozenge is used.

4.3 Contraindications

Nicotine Perrigo 4mg Lozenges are contraindicated in:

•    hypersensitivity to the active substance (nicotine) or to any of the excipients

•    children under the age of 12 years and

•    non smokers

•    those with phenylketonuria

•    those with unstable or worsening angina pectoris, Prinzmetals angina or severe cardiac arrhythmias

•    those who have recently suffered myocardial infarction or cerebrovascular accident.

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.

The following patients should be treated only after advice from a doctor: those with cardiovascular disease (also not hospitalized), with uncontrolled hypertension, with insulin dependent diabetes.

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.

Gastrointestinal 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 Perrigo 4mg Lozenges are sugar free, but do contain aspartame which metabolises to phenylalanine, which is of relevance for those with phenylketonuria.

Sodium content: Each 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 have definitely been established, however nicotine may possibly enhance the haemodynamic effects of adenosine.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Smoking during pregnancy is associated with risks such as intra-uterine growth retardation, premature birth or stillbirth. Stopping smoking is the single most effective intervention for improving the health of both pregnant smoker and her baby. The earlier abstinence is achieved the better. Ideally smoking cessation during pregnancy should be achieved without NRT. However for women unable to quit on their own, NRT may be recommended by a healthcare professional to assist a quit attempt. The risk of using NRT to the fetus is lower than that expected with tobacco smoking, due to lower maximal plasma nicotine concentration and no additional exposure to polycyclic hydrocarbons and carbon monoxide.

However, as nicotine passes to the fetus affecting breathing movements and has a dose dependent effect on placental/fetal circulation, the decision to use NRT should be made as early on in the pregnancy as possible. The aim should be to use NRT for only 2-3 months.

Intermittent dosing products may be preferable as these usually provide a lower daily dose of nicotine than patches. However patches may be preferred if the woman is suffering from nausea during pregnancy.

Lactation

Nicotine from smoking and NRT is found in breast milk. However the amount of nicotine the infant is exposed to from NRT is relatively small and less hazardous than the second-hand smoke they would otherwise be exposed to. Ideally smoking cessation during pregnancy should be achieved without NRT. However for women unable to quit on their own, NRT may be recommended by a healthcare professional to assist a quit attempt. Using intermittent dose NRT preparations, compared with patches, may minimize the amount of nicotine in the breast milk as the time between administrations of NRT and feeding can be made as long as possible. Women should try to breastfeed just before they take the product.

4.7 Effects on ability to drive and use machines

Nicotine Perrigo 4mg Lozenges has no influence on the ability to drive and use machines.

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 Perrigo 4mg Lozenges have not been found to cause any serious adverse effects. Excessive consumption of Nicotine Perrigo 4mg 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.

Immune system disorders

Very rare <1/10000: anaphylactic reactions Platelet bleeding and clotting disorders

Uncommon >1/1000; <1/100: gingival bleeding; nosebleed Psychiatric disorders

Common >1/100; <1/10: insomnia; anxiety; irritability; increased appetite

Uncommon >1/1000; <1/100: anger; aggravated anxiety; abnormal dreaming; abnormal hunger; mood swings; wakefulness

Central and peripheral nervous system disorders

Common >1/100; <1/10: headache

Uncommon >1/1000; <1/100: lightheaded feeling; localised numbness Heart rate and rhythm disorders

Uncommon >1/1000; <1/100: aggravated palpitations; palpitations; tachycardia Vascular (extracardiac) disorders

Uncommon >1/1000; <1/100: vascular disorder; flushing; skin flushed Respiratory system disorders

Common >1/100; <1/10: pharyngitis

Uncommon >1/1000; <1/100: laryngismus; aggravated asthma; lower respiratory tract infection; coughing; nasal irritation; throat irritation; nasal congestion

Gastrointestinal system disorders

Very common >1/10: nausea

Common >1/100; <1/10: vomiting; dyspepsia, heartburn, indigestion; hiccup; mouth irritation, mouth ulceration; tongue ulceration; diarrhoea; belching; flatulence

Uncommon >1/1000; <1/100: peptic ucler; dysphagia; aggravated dyspepsia;

gastroesophageal reflux; hiatus hernia; oesophagitis; eructation; buccal mucosa ulceration; borborygmus; dry lips; dry throat; tongue disorder; tooth ache

Special senses other, disorders

Uncommon >1/1000; <1/100: parageusia, metallic taste; taste perversion Skin and appendages disorders

Uncommon >1/1000; <1/100: erythema; itching; rash; skin reaction localised; increased sweating

Musculoskeletal system disorders

Uncommon >1/1000; <1/100: jaw pain

Urinary system disorders

Uncommon >1/1000; <1/100: nocturia

Body as a whole - general disorders

Uncommon >1/1000; <1/100: overdose effect; pain; leg pain; oedema legs

4.9 Overdose

Symptoms: The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60mg. Symptoms of acute nicotine poisoning include nausea, 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

ATC Code NO 7B A01: Drug in nicotine dependence.

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 Perrigo 4mg 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 Perrigo 4mg Lozenges is typically achieved in 20-30 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 12.7 and 9.4 ng/ml respectively. Ingestion of Nicotine Perrigo 4mg 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 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 excess of those which will result from recommended use of Nicotine Perrigo 4mg 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 Perrigo 4mg Lozenges indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, Nicotine Perrigo 4mg Lozenges should only be used by pregnant women on medical advice if other forms of treatment have failed.

Environmental Risk Assessment (ERA)

It is not the intention of the applicant to increase the overall usage of this drug substance as a result of this application, since the product is not being brought to market to address a new indication.

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

6.4    Special precautions for storage

Do not store above 25°C. Store in the original packaging in order to protect from light.

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.

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

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Wrafton Laboratories Limited

Trading as Perrigo

Wrafton

Braunton

Devon

EX33 2DL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 12063/0114

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 15/02/2013

10 DATE OF REVISION OF THE TEXT

02/11/2016