Nicotine

Swallowed nicotine may exacerbate symptoms in subjects suffering from active oesophagitis, oral and pharyngeal inflammation, gastritis or peptic ulcer.

Nicotine should be used with caution in patients with hypertension, stable angina pectoris, cerebrovascular disease, occlusive peripheral arterial disease, heart failure.

Nicotine should be used with caution in patients with diabetes mellitus, hyperthyroidism or pheochromocytoma and with moderate to severe hepatic and/or severe renal impairment.

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 foetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but if this is not achievable this product 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.

Use of nicotine by the pregnant smoker should only be initiated after advice from a health care professional.

In the case of failure in highly dependent pregnant smokers, tobacco withdrawal via nicotine replacement therapy may be recommended. Indeed, foetal risk is probably lower than that expected with tobacco smoking, due to:

• lower maximal plasma nicotine concentration than with inhaled nicotine
• no additional exposure to polycyclic hydrocarbons and carbon monoxide
• improved chances of quitting smoking by the third trimester.

Smoking continued during the third trimester may lead to intra-uterine growth retardation or even premature birth or stillbirth, depending on the daily amount of tobacco.

Tobacco withdrawal with or without nicotine replacement therapy should not be undertaken alone but as part of a medically supervised smoking cessation program.

In the third trimester nicotine has haemodynamic effects (e.g. changes in foetal heart rate) which could affect the foetus close to delivery. Therefore, after the sixth month of pregnancy, the lozenge should only be used under medical supervision in pregnant smokers who have failed to stop smoking by the third trimester.

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.

There is no evidence of any risks associated with driving or operating machinery when the lozenge is used following the recommended dose. Nevertheless one should take into consideration that smoking cessation can cause behavioural changes.

Nicotine transdermal patch / inhalator has no or negligible influence on the ability to drive and use machines.

Oral administration

Nicotine lozenge can cause adverse reactions similar to those associated with nicotine administered by smoking. These can be attributed to the pharmacological effects of nicotine, which are dose-dependent. Non dose-dependent adverse reactions are as follows: hypersensitivity, angioneurotic oedema and anaphylactic reactions.

Most of the adverse reactions which are reported by patients occur generally during the first 3-4 weeks after initiation of therapy.

Nicotine from lozenges may sometimes cause a slight irritation of the throat and increased salivation at the start of the treatment. Excessive swallowing of nicotine which is released in the saliva may, at first, cause hiccups. Those who are prone to indigestion may suffer initially from minor degrees of dyspepsia or heartburn; slower sucking will usually overcome this problem.

Excessive consumption of lozenges by subjects who have not been in the habit of inhaling tobacco smoke, could possibly lead to nausea, faintness and headache.

Increased frequency of aphthous ulcer may occur after abstinence from smoking.

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000, <1/1,000) or very rare (<1/10,000).

Nervous system disorders

Common: dizziness, headache

Gastrointestinal disorders

Common: nausea, flatulence, hiccups, gastritis, dry mouth, stomatitis and oesophagitis.

Cardiac disorders

Uncommon: Palpitations

Rare: atrial arrhythmia

Immune system disorders

Rare: hypersensitivity, angioneurotic oedema and anaphylactic reactions.

Certain symptoms which have been reported such as dizziness, headache and insomnia may be ascribed to withdrawal symptoms in connection with smoking cessation and may be due to insufficient administration of nicotine.

Cold sores may develop in connection with smoking cessation, but any relation with the nicotine treatment is unclear.

The patient may still experience nicotine dependence after smoking cessation.

Transdermal use

Effect of Smoking Cessation

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

Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.

Adverse Drug Reactions (ADRs)

Nicotine transdermal patch may cause adverse reactions similar to those associated with nicotine given by other means, including smoking, and these are mainly dose-dependent. At recommended doses this product has not been found to cause any serious adverse effects. Excessive use of this product by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Most of the undesirable effects reported by the subjects occur during the early phase of treatment and are mainly dose dependent.

About 20% of nicotine patch users experience mild local skin reactions, during the first weeks of treatment. In some patients the skin reactions may become more severe e.g. skin blistering or burning sensation or may be more generalized.

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

Adverse events observed in patients treated with nicotine patch formulations during clinical trials and post-marketing surveillance 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), Not known – cannot be estimated from the available data.

Immune system disorders

Uncommon: Hypersensitivity^a#

Rare**: Anaphylactic reaction^a

Nervous system disorders

Common: Dizziness, Headache^a§

Uncommon: Paraesthesia^a#

Cardiac disorders

Uncommon: Palpitations^a, Tachycardia^a

Very rare: Reversible atrial fibrillation

Vascular disorders

Uncommon: Flushing^a, Hypertension^a

Respiratory, Thoracic and Mediastinal Disorders

Uncommon: Dyspnoea^a

Gastrointestinal disorders

Common: Nausea^a§, Vomiting^a

Rare**: Gastrointestinal discomfort^a

Skin and subcutaneous tissue disorders

Very common: Pruritus

Common: Rash^a, Urticaria^a

Uncommon: Hyperhidrosis^a

Rare**: Angioedema^a, Erythema^a

Musculoskeletal and Connective Tissue Disorders

Uncommon: Myalgia^b

Rare**: Pain in extremity

General disorders and administration site conditions

Uncommon: Application site reactions, Asthenia^a, Chest discomfort and pain^a, Malaise^a, Fatigue^a#§

** Frequency category estimated using the "Rule of 3"
^a Systemic effects; b In vicinity/region of patch
^# Although the frequency is <1% the PT occurred at a frequency ≥1% in another formulation in which the PT was identified as a systemic ADR.
^§ Although the frequency in the active group is less than that of the placebo group, the frequency in the specific formulation in which the PT was identified as a systemic ADR was greater in the active group than the placebo group.

Oromucosal use

Effects of smoking Cessation

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

Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.

Adverse Drug Reactions

This product may cause adverse reactions similar to those associated with nicotine given by other means, including smoking, and these are mainly dose-dependent. At recommended doses this product has not been found to cause any serious adverse effects. Excessive use of nicotine inhalator by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Most of the undesirable effects reported by the patient occur during the first weeks after starting treatment. About 40% of users experience mild local reactions such as cough and irritation in the mouth and throat however most subjects adapt to this with ongoing use.

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

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

Immune System Disorders

Common: Hypersensitivity^a

Not known: Anaphylactic reaction^a

Psychiatric disorders

Uncommon: Abnormal dreams^c

Nervous System Disorders

Very Common: Headache^a#

Common: Burning sensation*, Dizziness, Dysgeusia, Paraesthesia^a

Eye Disorders

Not known: Blurred Vision, Lacrimation increased

Cardiac Disorders

Uncommon: Palpitations^a, Tachycardia^a

Very Rare: Reversible atrial fibrillation

Vascular Disorders

Uncommon: Flushing^a, Hypertension^a

Respiratory, Thoracic and Mediastinal Disorders

Very Common: Throat irritation**

Common: Cough**, Nasal Congestion

Uncommon: Bronchospasm, Dysphonia, Dyspnoea^a, Sneezing, Throat tightness

Gastrointestinal Disorders

Very Common: Nausea^a, Stomatitis, Hiccups****

Common: Abdominal pain, Diarrhoea***, Dry mouth, Dyspepsia, Flatulence, Salivary hypersecretion, Vomiting^a

Uncommon: Eructation, Glossitis, Oral mucosal blistering and exfoliation

Rare: Paraesthesia oral***, Dysphagia, Hypoaesthesia oral***

Not known: Retching, Dry throat, Gastrointestinal discomfort^a, Lip pain

Skin and Subcutaneous Tissue Disorders

Uncommon: Hyperhidrosis^a, Pruritus^a, Rash^a

Not known: Urticaria^a, Angioedema^a, Erythema^a

Musculoskeletal and Connective Tissue Disorders

Uncommon: Pain in Jaw^b

Not known: Muscle tightness^b

General Disorders and Administration Site Conditions

Common: Fatigue^a

Uncommon: Asthenia^a, Chest discomfort and pain^a, Malaise^a

^a Systemic effects.
^b Tightness of jaw and pain in jaw with nicotine gum formulation.
^c Identified only for formulations applied during the night.
* At the application site.
** Higher frequency observed in clinical studies with inhaler formulation.
*** Reported the same or less frequently than placebo.
**** Higher frequency observed in clinical studies with mouth spray formulation.
^# Although the frequency in the active group is less than that of the placebo group, the frequency in the specific formulation in which the PT was identified as a systemic ADR was greater in the active group than the placebo group.