Document: spc-doc_PL 00079-0627 change

• spc-doc_PL 00079-0627
• spc-doc_PL 02855-0292

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nicabate A 2 mg Mint Lozenges

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each lozenge contains 2 mg nicotine (as 11.1 mg nicotine polacrilex) as the active ingredient.

Each lozenge includes the excipients aspartame (E951), sodium alginate and sodium carbonate anhydrous.

For full list of excipients see Section 6.1.

3 PHARMACEUTICAL FORM

Lozenge

White, round lozenge with convex surfaces, debossed NL2S on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nicabate A Mint Lozenges are indicated for the relief of nicotine withdrawal symptoms including cravings. Permanent cessation of tobacco use is the eventual objective. Nicabate A Mint Lozenges can be used:

•    for smoking cessation (abrupt and gradual)

•    as an aid for smokers during temporary abstinence.

Nicabate A Mint Lozenges should preferably be used in conjunction with a behavioural support programme.

4.2 Posology and method of administration

Directions for use:

Nicabate A 2 mg Mint 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 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 the success rate.

Adults (18 years and over):

Abrupt cessation of smoking:

Users should make every effort to stop Nicabate A Mint 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

Those who use the lozenges beyond 9 months 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 consumption has not been achieved after 6 weeks of treatment, a healthcare professional should be consulted.

Reduced tobacco consumption 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 to consult 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, but as data are limited, duration of NRT in this age group is restricted to 12 weeks. If longer treatment is required, or where adolescents are unwilling or unable to quit smoking abruptly, advice from a healthcare professional should be sought.

Nicabate A Mint Lozenges are not recommended for use in children under 12 years of age.

4.3 Contraindications

Nicabate A Mint Lozenges are contraindicated in:

• those with hypersensitivity to nicotine or any of the excipients;

•    those allergic to soya;

•    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 hospitalised 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, Nicabate A Mint 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. If there is a clinically significant increase in cardiovascular or other effects attributable to nicotine, the lozenge dose should be reduced or discontinued.

Diabetes: Blood glucose levels may be more variable when stopping smoking, with or without NRT as catecholamines released by nicotine can affect carbohydrate metabolism, so it is important for diabetics to closely monitor their blood glucose levels more closely than usual while using this product.

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 effects.

•    Phaeochromocytoma and uncontrolled hyperthyroidism: Use with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

•    GI disease: Swallowing of nicotine may exacerbate symptoms in persons suffering from active oesophagitis, oral or pharyngeal inflammation, gastritis, gastric ulcer or peptic ulcer 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.

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: Nicabate A Mint Lozenges contain a source of phenylalanine equivalent to 3mg/dose. May be harmful for people with phenylketonuria.

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interactions with other Medicaments 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. Smoking cessation itself may require the adjustment of some drug therapy.

4.6 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 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. If patches are used they should be removed before going to bed.

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.

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 more easily prolonged.

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 ways including smoking. These may be attributed to the pharmacological effects of nicotine, some of which are dose dependent. At recommended doses Nicabate A Mint Lozenges have not been found to cause any serious adverse effects. Excessive consumption of Nicabate A Mint 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

The minimum lethal dose of nicotine in a non tolerant man has been estimated to be 40 to 60 mg. Even small quantities of nicotine may be dangerous in children and may prove fatal. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately.

Symptoms

Signs and symptoms of an overdose from nicotine lozenges would be expected to be the same as those of acute nicotine poisoning, including pallor, cold sweat, salivation, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, disturbed hearing and vision, tremor, mental confusion and weakness. Prostration, hypotension, respiratory failure, rapid or weak or irregular pulse, circulatory collapse and convulsions (including terminal convulsions) may ensue with large overdoses.

Management

In the event of an overdose (e.g. too many lozenges ingested) the user should seek medical attention immediately. All nicotine intake should cease immediately and the patient be treated symptomatically. Artificial respiration with oxygen should be instituted if necessary. Activated charcoal reduces the gastrointestinal absorption of nicotine.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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. 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

Nicabate A Mint 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 Nicabate A Mint Lozenge 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 Nicabate A Mint 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 Nicabate A Mint 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 Nicabate A Mint Lozenges indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, Nicabate A Mint 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 (E421)

Sodium alginate Xanthan gum Potassium bicarbonate Calcium polycarbophil Sodium carbonate anhydrous Aspartame (E951)

Magnesium stearate

Mint flavour powder 57581 (contains lactose and soya protein)

6.2 Incompatibilities

None known.

DATE OF REVISION OF THE TEXT

17/01/2014