Nicomild

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 in-take 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

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 a nicotine patch 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

Overdose from Topical Exposure

The nicotine patch(es) should be removed immediately in the event of an overdose or if the patient shows signs of overdosage. The user should seek medical attention immediately. The skin surface may be flushed with water and dried. No soap should be used since it may increase nicotine absorption. Nicotine will continue to be delivered into the bloodstream for several hours after removal of the system because of a depot of nicotine in the skin.

Overdose from Ingestion

All nicotine intake should stop immediately. The patient should seek medical attention immediately and be treated symptomatically.

Artificial respiration with oxygen should be instituted if necessary. Activated charcoal reduces the gastrointestinal absorption of nicotine.

The toxicity of nicotine cannot be directly compared with that of smoking, because tobacco smoke contains additional toxic substances (e.g. carbon monoxide, and tar).

Chronic smokers can tolerate doses of nicotine that, in a non-smoker, would be more toxic, because of the development of tolerance.

The acute lethal dose of nicotine in a non-tolerant man has been estimated to be 0.5 - 0.75mg per kg body weight, corresponding in an adult to 40 to 60mg. Even small quantities of nicotine are dangerous in children, and may result in severe symptoms of poisoning which may prove fatal. If poisoning is suspected in a child, a doctor must be consulted immediately.

Overdose with Nicomild TTS may occur when many pieces are applied simultaneously on the skin.

Symptoms

Symptoms of acute nicotine poisoning include nausea, vomiting, salivation, abdominal pain, diarrhoea, sweating, headache, tachycardia, dizziness, disturbed hearing and vision and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse, coma and terminal convulsions.

Management of overdose

If the patient shows signs of overdose, the patch should be removed immediately. The skin surface may be washed with water and dried (no soap should be used). The skin will continue to deliver nicotine into the blood stream for several hours after removal of the system, possibly because of a depot of nicotine in the skin. The patient should then be treated symptomatically. Artificial respiration with oxygen should be instituted if necessary.

Signs and symptoms of an overdose of the Nicomild (nicotine inhalation system) Inhaler would be expected to be the same as those of acute nicotine poisoning including: pallor, cold sweat, nausea, salivation, vomiting, abdominal pain, diarrhea, headache, dizziness, disturbed hearing and vision, tremor, mental confusion, and weakness. Prostration, hypotension, and respiratory failure may ensue with large overdoses. Lethal doses produce convulsions quickly and death follows as a result of peripheral or central respiratory paralysis or, less frequently, cardiac failure.

The oral LD50 for nicotine is > 5 mg/kg in dogs and > 24 mg/kg in rodents. Death is due to respiratory paralysis. The oral minimum acute lethal dose for nicotine in adult humans is reported to be 40 to 60 mg ( < 1 mg/kg). The effects of using several cartridges in rapid succession are unknown (See WARNINGS, Safety Note Concerning Children).

One cartridge of Nicomild Inhaler contains 10 mg nicotine, of which, approximately 4 mg is delivered nicotine. It is unlikely that an excessive nicotine overdose will occur via inhalation. Should such an overdose occur, however, with signs of nicotine poisoning, the patient should be instructed to contact his/her physician immediately. For additional emergency information, call your regional poison center or call the National Capital Poison Center toll free (1-800-222-1222).

Persons ingesting Nicomild (nicotine inhalation system) Inhaler cartridges should be referred to a health care facility for management. In unconscious patients with a secure airway, instill activated charcoal via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Repeated doses of activated charcoal should be administered as long as the cartridge remains in the gastrointestinal tract since it will continue to release nicotine for many hours. The Nicomild (nicotine inhalation system) Inhaler cartridges can be identified with a radiogram.

Other supportive measures include diazepam or barbiturates for seizures, atropine for excessive bronchial secretions or diarrhea, respiratory support for respiratory failure, and vigorous fluid support for hypotension and cardiovascular collapse.

Contraindications

Hypersensitivity to any component of the inhalator.

Nicomild Inhalator is contraindicated in children under the age of 12 years.

Nicomild is contraindicated in patients with hypersensitivity to the system, the active substance, or any of the excipients.

Nicomild patches should not be used by non-smokers, occasional smokers or children under 12 years.

Nicomild TTS should not be administered to non-smokers or occasional smokers. The system is contraindicated in diseases of the skin which may complicate patch therapy, and known hypersensitivity to nicotine or any of the components of the patch.

Use of Nicomild (nicotine inhalation system) Inhaler therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to menthol.

Incompatibilities

Not applicable

Not applicable.

None known.

Undesirable effects

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 and decreased heart rate.

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 Nicomild 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.

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

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

# 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.

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.

Subjects quitting smoking by any means could expect to suffer from asthenia, headache, dizziness, sleep disturbance, coughing or influenza-like illness. Certain symptoms which have been reported such as depression, irritability, nervousness, restlessness, mood lability, anxiety, drowsiness, impaired concentration and insomnia may be related to withdrawal symptoms associated with smoking cessation.

Application site reactions are the most frequent adverse reaction associated with Nicomild. Nicomild can cause other adverse reactions related to the pharmacological effect of nicotine or withdrawal effects related to smoking.

The following undesirable effects have been reported in clinical trials or spontaneously post-marketing.

Certain symptoms which have been reported such as depression, irritability, nervousness, restlessness, mood lability, anxiety, drowsiness, impaired concentration, insomnia and sleep disturbances may be related to withdrawal symptoms associated with smoking cessation. Subjects quitting smoking by any means could expect to suffer from asthenia, headache, dizziness, coughing or influenza-like illness.

Immune System Disorders

Uncommon>1/1000; <1/100: hypersensitivity NOS*

Very rare <1/10000: anaphylactic reactions

Psychiatric

Very common >1/10: sleep disorders including abnormal dreams and insomnia

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

Nervous system disorders

Very Common >1/10: headache, dizziness

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

Not known: seizures

Cardiac disorders

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

Uncommon >1/1000; <1/100: tachycardia NOS

Respiratory, Thoracic and Mediastinal Disorders

Common >1/100; <1/10: dyspnoea, pharyngitis, cough

Gastrointestinal Disorders

Very Common >1/10: nausea, vomiting

Common >1/100; <1/10: dyspepsia, abdominal pain upper, diarrhea NOS, dry mouth, constipation

Skin and Subcutaneous Tissue Disorders

Common >1/100; <1/10: sweating increased

Very rare > 1/100000; <1/10000: dermatitis allergic*, dermatitis contact*, photosensitivity

Musculoskeletal and Connective Tissue Disorders

Common >1/100; <1/10: arthralgia, myalgia

General Disorders and Administration Site Conditions

Very Common >1/10: application site reactions NOS*

Common >1/100; <1/10: chest pain, pain in limb, pain NOS, asthenia, fatigue

Uncommon >1/1000; <1/100 malaise, influenza-like illness

* see below

Application site reactions, including transient rash, itching, burning, tingling, numbness, swelling, pain and urticaria are the most frequent undesirable effects of Nicomild patch. The majority of these topical reactions are minor and resolve quickly following removal of the patch. Pain or sensation of heaviness in the limb or area around which the patch is applied (e.g. chest) may be reported.

Hypersensitivity reactions, including contact dermatitis and allergic dermatitis have also been reported. In the case of severe or persistent local reactions at the application site (e.g. severe erythema, pruritus or oedema) or a generalized skin reaction (e.g. urticaria, hives or generalised skin rashes) users should be instructed to discontinue use of Nicomild and contact their physician.

If there is a clinically significant increase in cardiovascular or other effects attributable to nicotine, the Nicomild dose should be reduced or discontinued.

In principle, the Nicomild TTS can cause adverse reactions similar to those associated with nicotine administered by other means (including smoking) and these are mainly dose dependent. Since the maximum plasma concentrations of nicotine that are produced by the patch are lower than those produced by smoking and fluctuate less, nicotine-related adverse reactions occurring during treatment with the patch can be expected to be less marked than during smoking.

Clinical trial experience has shown that skin reactions at the application sites are the most frequent adverse reactions. This led to the premature discontinuation of Nicomild transdermal patch in approximately 6% of clinical trial participants. These reactions include application site burning, oedema, erythema, irritation, pruritus, rash, urticaria and vesicles. The majority of these reactions were mild. Most of the skin reactions resolved within 48 hours, but in more severe cases the erythema and infiltration lasted from 1 to 3 weeks. The time of onset of significant skin reactions was between 3 and 8 weeks from the start of therapy. In isolated cases the skin reactions extended beyond the application sites. Isolated cases of urticaria, angioneurotic oedema and dyspnoea were reported.

Upper respiratory tract infection and cough reported as adverse reactions may be linked to a chronic bronchitis induced by long term smoking in the past.

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

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 to <1/1,000); very rare (<1/10,000), or not known (can not to be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

*Symptoms may be ascribed also to withdrawal symptoms in connection with smoking cessation and may be due to insufficient replacement of nicotine

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

Assessment of adverse events in the 1,439 patients (730 on active drug) who participated in controlled clinical trials (including three dose finding studies) is complicated by the occurrence of signs and symptoms of nicotine withdrawal in some patients and nicotine excess in others. The incidence of adverse events is confounded by: (1) the many minor complaints that smokers commonly have, (2) continued smoking by many patients and (3) the local irritation from both the active drug and the placebo.

Nicomild (nicotine inhalation system) Inhaler and the placebo were both associated with local irritant side effects. Local irritation in mouth and throat was reported by 40% of patients on active drug as compared to 18% of patients on placebo. Irritant effects were higher in the two pivotal trials with higher doses being 66% on active drug and 42% on placebo. Coughing (32% active versus 12% placebo) and rhinitis (23% active versus 16% placebo) were also higher on active drug. The majority of patients rated these symptoms as mild. The frequency of cough, and mouth and throat irritation declined with continued use of Nicomild (nicotine inhalation system) Inhaler. Other adverse events that occurred in over 3% of patients on active drug in placebo controlled pivotal trials considered possibly related to the local irritant effects of the Nicomild (nicotine inhalation system) Inhaler are taste comments, pain in jaw and neck, tooth disorders and sinusitis.

Symptoms of withdrawal were common in both active and placebo groups. Common withdrawal symptoms seen in over 3% of patients on active drug included: dizziness, anxiety, sleep disorder, depression, withdrawal syndrome, drug dependence, fatigue and myalgia.

The most common nicotine-related adverse event was dyspepsia. This was present in 18% of patients in the active group compared to 9% of patients in the placebo group. Other nicotine related events present in greater than 3% of patients on active drug include nausea, diarrhea, and hiccup.

Smoking related adverse events present in greater than 3% of patients on active drug include chest discomfort, bronchitis, and hypertension.

Adverse events of unknown relationship to nicotine occurring in greater than 3% of patients on active drug include headache (26% of patients on active and 15% of patients on placebo), influenza-like symptoms, pain, back-pain, allergy, paresthesias, flatulence and fever.

Nicomild (nicotine inhalation system) Inhaler is likely to have a low abuse potential based on differences between the product and cigarettes in three characteristics commonly considered important in contributing to abuse: slower absorption, smaller fluctuations in blood levels and lower blood levels of nicotine. Nicomild Inhaler, like many other nicotine-based smoking cessation therapies, does not produce arterial concentrations similar to cigarettes. However, nicotine withdrawal symptoms were noted in clinical trials at the time of Nicomild (nicotine inhalation system) Inhaler tapering and after Nicomild (nicotine inhalation system) Inhaler discontinuation.

Dependence might occur from transference of tobacco-related nicotine dependence to the Nicomild (nicotine inhalation system) Inhaler. The use of the inhaler beyond 6 months has not been evaluated in clinical trials and is not recommended. To minimize the risk of dependence, patients should be encouraged to withdraw gradually from Nicomild (nicotine inhalation system) Inhaler therapy after 3 months of usage (See DOSAGE AND ADMINISTRATION). If necessary, dose reduction can be achieved by gradual reduction of the dose over a 6 to 12 week period.

Preclinical safety data

None stated.

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 Nicomild. 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 Nicomild indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, Nicomild should only be used by pregnant women on medical advice if other forms of treatment have failed.

No additional data

Therapeutic indications

Nicomild Inhalator relieves and/or prevents craving and nicotine withdrawal symptoms associated with tobacco dependence. It is 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.

Nicomild Inhalator is indicated in pregnant and lactating women making a quit attempt.

Nicomild patches 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.

Nicomild patches are indicated in pregnant and lactating women making a quit attempt.

If possible, when stopping smoking, Nicomild patches should be used in conjunction with a behavioural support programme.

Nicomild patches relieve and/or prevent cravings 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.

Nicomild patches are indicated in pregnant and lactating women making a quit attempt.

Nicomild patches should preferably be used in conjunction with a behavioural support programme.

Nicomild (nicotine inhalation system) Inhaler is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms. Nicomild (nicotine inhalation system) Inhaler therapy is recommended for use as part of a comprehensive behavioral smoking cessation program.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic Group: Drug for treatment of addiction.

ATC Code: N07B A01

Nicomild Inhalator facilitates uptake of nicotine through the buccal mucosa into the venous circulation. The amount taken up alleviates the craving symptoms caused by the absence of nicotine from smoking.

Increased appetite is a recognised symptom of nicotine withdrawal and post-cessation weight gain is common. Clinical trials have demonstrated that Nicotine Replacement Therapy can help control weight following a quit attempt.

Pharmacotherapeutic classification: N07B A01

(Anti-smoking agents: N07BA, Nicotine 01)

Nicotine, the chief alkaloid in tobacco products and a naturally occurring autonomic drug, is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects.

Withdrawal from nicotine in addicted individuals is characterised by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue) and weight gain.

Withdrawal symptoms, such as cigarette craving, may be controlled in some individuals by steady-state plasma levels lower than those for smoking.

In clinically controlled trials, Nicomild was shown to alleviate nicotine withdrawal symptoms as well as craving. Nicomild reduced the severity of cravings by at least 35% at all times of day during the first two weeks of abstinence, compared to placebo (p<0.05).

Pharmacotherapeutic group: drugs used in nicotine dependence, ATC code: N07BA01

S(-)-nicotine is the most pharmacologically active form of nicotine, the major alkaloid of tobacco. S(-)-nicotine acts primarily on cholinergic receptors of the nicotinic type in the peripheral and central nervous system. For many effects, low doses of S(-)-nicotine have a stimulant action, and high doses a depressant effect. Intermittent administration of S(-)-nicotine affects neurohormonal pathways, and results in the release of acetylcholine, noradrenaline, dopamine, serotinin, vasopressin, beta-endorphin, growth hormone, cortisol and ACTH. These neuroregulators may be involved in the reported behavioural and subjective effects of smoking.

Quitting smoking abruptly after prolonged, daily consumption induces a withdrawal syndrome consisting of at least four of the following symptoms: dysphoria or depressive mood, insomnia, irritability, feelings of frustration or anger, anxiety, difficulty concentrating, agitation or impatience, slowed cardiac rhythm, increased appetite and weight gain. The craving for nicotine is considered as a recognized clinical symptom of the withdrawal syndrome.

Nicotine replacement therapy is an established therapy as an aid to smoking cessation. Nicomild TTS provides for a convenient once daily administration by exploiting the fact that S(-)-nicotine is readily absorbed through the skin into the systemic circulation. Placebo-controlled, double-blind studies have shown that nicotine replacement therapy with the patch produces smoking abstinence rates statistically significantly better than placebo, with or without group support. There was also a strong trend towards reduction of withdrawal symptoms.

Application of Nicomild TTS to smokers abstinent overnight resulted in small increases in mean heart rate and systolic blood pressure and a decrease in stroke volume. The effects were smaller in magnitude than those produced by cigarette smoking.

The cardiovascular effects of nicotine include peripheral vasoconstriction, tachycardia, and elevated blood pressure. Acute and chronic tolerance to nicotine develops from smoking tobacco or ingesting nicotine preparations. Acute tolerance (a reduction in response for a given dose) develops rapidly (less than 1 hour), but not at the same rate for different physiologic effects (skin temperature, heart rate, subjective effects). Withdrawal symptoms such as cigarette craving can be reduced in most individuals by plasma nicotine levels lower than those from smoking.

Withdrawal from nicotine in addicted individuals can be characterized by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue), and weight gain. Nicotine toxicity is characterized by nausea, abdominal pain, vomiting, diarrhea, diaphoresis, flushing, dizziness, disturbed hearing and vision, confusion, weakness, palpitations, altered respiration and hypotension. Both smoking and nicotine can increase circulating cortisol and catecholamines, and tolerance does not develop to the catecholaminereleasing effects of nicotine. Changes in the response to a concomitantly administered adrenergic agonist or antagonist should be watched for when nicotine intake is altered during Nicomild (nicotine inhalation system) Inhaler therapy and/or smoking cessation (See PRECAUTIONS: DRUG INTERACTIONS).

Pharmacokinetic properties

The following information is based on data derived from Nicomild 10mg Inhalator:

Nicotine given i.v. has a volume of the distribution of 2 or 3 l/kg with a half life of 1-2 hours. Average plasma clearance is about 1-2 l/min mainly in the liver. More than 20 metabolites are known, all less active than nicotine: cotinine, with a half life of 15-20 hours and concentrations ten times that of nicotine is the main one.

Plasma binding of nicotine below 5% means significant displacement of drugs or nicotine is unlikely. Nicotine is excreted in the urine principally as cotinine (15%), 3-hydroxycotinine (45%), nicotine (10%).

Most inhaled nicotine is absorbed via the buccal mucosa. Forced rapid inhalation over 20 minutes, results in a wide range of nicotine doses (1.3-6.2 mg). On average 2 mg of nicotine is released during 20 minutes of intensive use. Uptake is slow and free of the peaks resultant from cigarette smoking. In normal use, plasma levels of 6-8ng/ml nicotine are obtained - about one third that from smoking, which is equivalent to an hourly 2mg nicotine chewing gum.

When used like a cigarette the inhalator on average delivers 1mg in 80 puffs (e.g. 8 puffs per minute for 10 minutes). When used in this way this results in, a degree of nicotine substitution of about 50% compared to hourly smoking. Peak plasma levels occur within 15 minutes after the end of inhalation. Forced rapid inhalation for 20 minutes per hour for 12 hours achieved steady state plasma levels of 20-25ng/ml.

Ambient temperature affects volatilisation of nicotine, the biologically available dose rising by 35% for each 10°C above 20°C. Use below 15°C is not recommended.

Because the pattern of use if decided by the patient up to a limit of 6 cartridges per day to relieve craving, therapeutic levels of nicotine are individual, dictated by the level of dependence.

Absorption

Following transdermal application, the skin rapidly absorbs nicotine released initially from the patch adhesive. The plasma concentrations of nicotine reach a plateau within 2-4 hours after initial application of Nicomild with relatively constant plasma concentrations persisting for 24 hours or until the patch is removed. Approximately 68% of the nicotine released from the patch enters systemic circulation and the remainder of the released nicotine is lost via vaporisation from the edge of the patch.

With continuous daily application of Nicomild (worn for 24 hours), dose- dependent steady state plasma nicotine concentrations are achieved following the second Nicomild application and are maintained throughout the day. These steady state maximum concentrations are approximately 30% higher than those following a single application of Nicomild.

Plasma concentrations of nicotine are proportional to dose for the three dosage forms of Nicomild. The mean plasma steady state concentrations of nicotine are approximately 17 ng/ml for the 21 mg/day patch, 12 ng/ml for the 14 mg/day patch and 6 ng/ml for the 7 mg/day patch. For comparison, half-hourly smoking of cigarettes produces average plasma concentrations of approximately 44 ng/ml.

The pronounced early peak in nicotine blood levels seen with inhalation of cigarette smoke is not observed with Nicomild.

Distribution

Following removal of Nicomild, plasma nicotine concentrations decline with an apparent mean half-life of 3 hours, compared with 2 hours for IV administration due to continued absorption of nicotine from the skin depot. If Nicomild is removed most non-smoking patients will have non-detectable nicotine concentrations in 10 to 12 hours.

A dose of radiolabelled nicotine given intravenously showed a distribution of radioactivity corresponding to the blood supply with no organ selectively taking up nicotine. The volume of distribution of nicotine is approximately 2.5 l/kg.

Metabolism

The major elimination organ is the liver and average plasma clearance is about 1.2 l/min; the kidney and the lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be pharmacologically inactive. The principal metabolites are cotinine and trans- 3-hydroxycotinine. Steady state plasma cotinine concentrations exceed nicotine by 10-fold. The half-life of nicotine ranges from 1 to 2 hours and cotinine's between 15 and 20 hours.

Excretion

Both nicotine and its metabolites are excreted through the kidneys and about 10% of nicotine is excreted unchanged in the urine. As much as 30% may be excreted in the urine with maximum flow rates and extreme urine acidification (pH≤5).

There were no differences in nicotine kinetics between men and women using Nicomild. Obese men using Nicomild had significantly lower AUC and Cmax values compared with normal weight men. Linear regression of AUC vs total body weight showed the expected inverse relationship (AUC decreases as weight increases). Nicotine kinetics were similar for all sites of application on the upper body and upper outer arm.

Absorption

Nicotine is directly absorbed through the skin and enters the systemic circulation.

Following a single application of the Nicomild TTS to the skin of healthy abstinent smokers, there is an initial 1-2 hours delay followed by a progressive rise in nicotine plasma concentrations, with a plateau attained at about 8-10 hours after application.

Following withdrawal of the patch, plasma nicotine levels fall more slowly than would be expected given the plasma elimination half-life of nicotine (after intravenous administration: 2 hours).

The probable existence of a cutaneous deposit explains why about 10 % of the nicotine reaching the blood derives from the skin after patch withdrawal. The absolute bioavailability of the patch, compared to intravenous nicotine perfusion, is about 77 %.

In the majority of subjects, the area under the plasma concentration curve (0-24 hours) increases in proportion to the dose of nicotine delivered by the patch.The patch is designed to deliver approximately 0.7mg/cm2/24 hours.

Steady state plasma concentrations after repeated daily administration are within the range observed during moderate cigarette smoking.

Absorption of nicotine over 24 hours varies by a factor of two between different individuals; however within-individual variability is small indicating consistent performance of the transdermal system.

Distribution

S(-)-nicotine is distributed widely in the body with a volume of distribution of approximately 180 litres. Nicotine crosses the blood-brain barrier, placenta, and is detectable in breast milk. The plasma protein binding of nicotine is negligible (< 5%).

Elimination

Total plasma clearance of nicotine ranges from 0.92 to 2.43 litres/min. It is eliminated mainly via hepatic metabolism and the main metabolites are cotinine and nicotine 1'-N-oxide. The renal elimination of unchanged nicotine is pH-dependent and minimal in the event of an alkaline urinary pH.

Nicotine is excreted in breast milk.

Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in patients with hyperthyroidism, pheochromocytoma or insulin-dependent diabetes, since nicotine causes the release of catecholamines by the adrenal medulla.

Nicotine delays healing in peptic ulcer disease; therefore, Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in patients with active peptic ulcers and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

Nicotine therapy constitutes a risk factor for development of malignant hypertension in patients with accelerated hypertension; therefore, Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in these patients and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

A PATIENT INFORMATION sheet is included in the package of Nicomild (nicotine inhalation system) Inhaler cartridges dispensed to the patient. Patients should be encouraged to read the information sheet carefully and to ask their physician and pharmacist about the proper use of the product (See DOSAGE AND ADMINISTRATION). Patients must be advised to keep both used and unused cartridges out of the reach of children and pets.

Nicotine itself does not appear to be a carcinogen in laboratory animals. However, nicotine and its metabolites increased the incidences of tumors in the cheek pouches of hamsters and forestomach of F344 rats, respectively when given in combination with tumor-initiators. One study, which could not be replicated, suggested that cotinine, the primary metabolite of nicotine, may cause lymphoreticular sarcoma in the large intestine of rats. Neither nicotine nor cotinine was mutagenic in the Ames salmonella test. Nicotine induced reparable DNA damage in an E. coli test system. Nicotine was shown to be genotoxic in a test system using Chinese hamster ovary cells. In rats and rabbits, implantation can be delayed or inhibited by a reduction in DNA synthesis that appears to be caused by nicotine. Studies have shown a decrease in litter size in rats treated with nicotine during gestation.

(See WARNINGS sections). The harmful effects of cigarette smoking on maternal and fetal health are clearly established. These include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. The specific effects of Nicomild (nicotine inhalation system) Inhaler therapy on fetal development are unknown. Therefore pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before using pharmacological approaches.

Spontaneous abortion during nicotine replacement therapy has been reported; as with smoking, nicotine as a contributing factor cannot be excluded.

Nicomild (nicotine inhalation system) Inhaler therapy should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of using it by the pregnant patient, who might continue to smoke.

Nicotine was shown to produce skeletal abnormalities in the offspring of mice when toxic doses were given to the dams (25 mg/kg IP or SC).

Nicotine teratogenicity has not been studied in humans except as a component of cigarette smoke (each cigarette smoked delivers about 1 mg of nicotine). It has not been possible to conclude whether cigarette smoking is teratogenic to humans.

A nicotine bolus (up to 2 mg/kg) to pregnant rhesus monkeys caused acidosis, hypercarbia, and hypotension (fetal and maternal concentrations were about 20 times those achieved after smoking one cigarette in 5 minutes). Fetal breathing movements were reduced in the fetal lamb after intravenous injection of 0.25 mg/kg nicotine to the ewe (equivalent to smoking 1 cigarette every 20 seconds for 5 minutes). Uterine blood flow was reduced about 30% after infusion of 0.1 μg/kg/min nicotine to pregnant rhesus monkeys (equivalent to smoking about six cigarettes every minute for 20 minutes).

Cigarette smoking during pregnancy is associated with an increased risk of spontaneous abortion, low birth weight infants and perinatal mortality. Nicotine and carbon monoxide are considered the most likely mediators of these outcomes. The effects of cigarette smoking on fetal cardiovascular parameters have been studied near term. Cigarettes increased fetal aortic blood flow and heart rate and decreased uterine blood flow and fetal breathing movements. Nicomild (nicotine inhalation system) Inhaler therapy has not been studied in pregnant women.

Nicomild (nicotine inhalation system) Inhaler is not recommended for use during labor and delivery. The effect of nicotine on a mother or the fetus during labor is unknown.

Caution should be exercised when the Nicomild (nicotine inhalation system) Inhaler is administered to nursing mothers. The safety of Nicomild Inhaler therapy in nursing infants has not been examined. Nicotine passes freely into breast milk; the milk to plasma ratio averages 2.9. Nicotine is absorbed orally. An infant has the ability to clear nicotine by hepatic first-pass clearance; however, the efficiency of removal is probably lowest at birth. Nicotine concentrations in milk can be expected to be lower with Nicomild (nicotine inhalation system) Inhaler when used as recommended than with cigarette smoking, as maternal plasma nicotine concentrations are generally reduced with nicotine replacement. The risk of exposure of the infant to nicotine from Nicomild (nicotine inhalation system) Inhaler therapy should be weighed against the risks associated with the infant's exposure to nicotine from continued smoking by the mother (passive smoke exposure and contamination of breast milk with other components of tobacco smoke) and from the Nicomild (nicotine inhalation system) Inhaler alone, or in combination with continued smoking.

Safety and effectiveness in pediatric and adolescent patients below the age of 18 years have not been established for any nicotine replacement product. However, no specific medical risk is known or expected in nicotine dependent adolescents. Nicomild (nicotine inhalation system) Inhaler should be used for the treatment of tobacco dependence in the older adolescent only if the potential benefit justifies the potential risk.

Clinical studies of Nicomild (nicotine inhalation system) Inhaler did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reports on clinical experience have not identified differences between older and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosage range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease.

Signs and symptoms of an overdose of the Nicomild (nicotine inhalation system) Inhaler would be expected to be the same as those of acute nicotine poisoning including: pallor, cold sweat, nausea, salivation, vomiting, abdominal pain, diarrhea, headache, dizziness, disturbed hearing and vision, tremor, mental confusion, and weakness. Prostration, hypotension, and respiratory failure may ensue with large overdoses. Lethal doses produce convulsions quickly and death follows as a result of peripheral or central respiratory paralysis or, less frequently, cardiac failure.

The oral LD50 for nicotine is > 5 mg/kg in dogs and > 24 mg/kg in rodents. Death is due to respiratory paralysis. The oral minimum acute lethal dose for nicotine in adult humans is reported to be 40 to 60 mg ( < 1 mg/kg). The effects of using several cartridges in rapid succession are unknown (See WARNINGS, Safety Note Concerning Children).

One cartridge of Nicomild Inhaler contains 10 mg nicotine, of which, approximately 4 mg is delivered nicotine. It is unlikely that an excessive nicotine overdose will occur via inhalation. Should such an overdose occur, however, with signs of nicotine poisoning, the patient should be instructed to contact his/her physician immediately. For additional emergency information, call your regional poison center or call the National Capital Poison Center toll free (1-800-222-1222).

Persons ingesting Nicomild (nicotine inhalation system) Inhaler cartridges should be referred to a health care facility for management. In unconscious patients with a secure airway, instill activated charcoal via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Repeated doses of activated charcoal should be administered as long as the cartridge remains in the gastrointestinal tract since it will continue to release nicotine for many hours. The Nicomild (nicotine inhalation system) Inhaler cartridges can be identified with a radiogram.

Other supportive measures include diazepam or barbiturates for seizures, atropine for excessive bronchial secretions or diarrhea, respiratory support for respiratory failure, and vigorous fluid support for hypotension and cardiovascular collapse.

Use of Nicomild (nicotine inhalation system) Inhaler therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to menthol.

Nicotine, the chief alkaloid in tobacco products, binds stereo-selectively to nicotinic-cholinergic receptors at the autonomic ganglia, in the adrenal medulla, at neuromuscular junctions, and in the brain. Two types of central nervous system effects are believed to be the basis of nicotine's positively reinforcing properties. A stimulating effect is exerted mainly in the cortex via the locus ceruleus and a reward effect is exerted in the limbic system. At low doses the stimulant effects predominate while at high doses the reward effects predominate. Intermittent intravenous administration of nicotine activates neurohormonal pathways, releasing acetylcholine, norepinephrine, dopamine, serotonin, vasopressin, beta-endorphin, growth hormone, and ACTH.

The cardiovascular effects of nicotine include peripheral vasoconstriction, tachycardia, and elevated blood pressure. Acute and chronic tolerance to nicotine develops from smoking tobacco or ingesting nicotine preparations. Acute tolerance (a reduction in response for a given dose) develops rapidly (less than 1 hour), but not at the same rate for different physiologic effects (skin temperature, heart rate, subjective effects). Withdrawal symptoms such as cigarette craving can be reduced in most individuals by plasma nicotine levels lower than those from smoking.

Withdrawal from nicotine in addicted individuals can be characterized by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue), and weight gain. Nicotine toxicity is characterized by nausea, abdominal pain, vomiting, diarrhea, diaphoresis, flushing, dizziness, disturbed hearing and vision, confusion, weakness, palpitations, altered respiration and hypotension. Both smoking and nicotine can increase circulating cortisol and catecholamines, and tolerance does not develop to the catecholaminereleasing effects of nicotine. Changes in the response to a concomitantly administered adrenergic agonist or antagonist should be watched for when nicotine intake is altered during Nicomild (nicotine inhalation system) Inhaler therapy and/or smoking cessation (See PRECAUTIONS: DRUG INTERACTIONS).

Most of the nicotine released from the Nicomild (nicotine inhalation system) Inhaler is deposited in the mouth. Only a fraction of the dose released, less than 5%, reaches the lower respiratory tract. An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases on the average 4 mg of the nicotine content of each cartridge of which about 2 mg is systemically absorbed. Peak plasma concentrations are typically reached within 15 minutes of the end of inhalation.

Absorption of nicotine through the buccal mucosa is relatively slow and the high and rapid rise followed by the decline in nicotine arterial plasma concentrations seen with cigarette smoking are not achieved with the inhaler. After use of the single inhaler the arterial nicotine concentrations rise slowly to an average of 6 ng/mL in contrast to those of a cigarette, which increase rapidly and reach a mean Cmax of approximately 49 ng/mL within 5 minutes.

The temperature dependency of nicotine release from the Nicomild (nicotine inhalation system) Inhaler was studied between 68°F and 104°F in eighteen patients. Average achievable steady state plasma levels after 20 minutes of an intensive inhalation regimen each hour at ambient room temperature are on the order of 23 ng/mL. The corresponding nicotine plasma levels achievable at 86°F and 104°F are on the order of 30 and 34 ng/mL. Nicotine peak plasma concentration (Cmax) at steady-state, after 20 minutes of an intensive inhalation regimen per hour, for 10 hours.

Ad libitum use of the Nicomild Inhaler typically produces nicotine plasma levels of 6–8 ng/mL, corresponding to about 1/3 of those achieved with cigarette smoking.

The volume of distribution following IV administration of nicotine is approximately 2 to 3 L/kg. Plasma protein binding of nicotine is < 5%. Therefore, changes in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states would not be expected to have significant effects on nicotine kinetics.

More than 20 metabolites of nicotine have been identified, all of which are less active than the parent compound. The primary urinary metabolites are cotinine (15% of the dose) and trans-3-hydroxycotinine (45% of the dose). Cotinine has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold. The major site for the metabolism of nicotine is the liver. The kidney and lung are also sites of nicotine metabolism.

About 10% of the nicotine absorbed is excreted unchanged in the urine. This may be increased to up to 30% with high urine flow rates and urinary acidification below pH 5. The average plasma clearance is about 1.2 L/min in a healthy adult smoker. The apparent elimination half-life of nicotine is 1 to 2 hours.

Intersubject variability coefficients of variation (C.V.) for the pharmacokinetic parameters (AUC and Cmax) were approximately 40% and 30% respectively, for males and females. There were no medically significant differences between females and males in the kinetics of Nicomild (nicotine inhalation system) Inhaler.

The efficacy of Nicomild (nicotine inhalation system) Inhaler therapy as an aid to smoking cessation was demonstrated in two single-center, placebo-controlled, double-blind trials with a total of 445 healthy patients. The number of Nicomild (nicotine inhalation system) Inhaler cartridges used was a minimum dose of 4 cartridges/day and a maximum dose of 20 cartridges/day. In both studies, the recommended duration of treatment was 3 months; however, the patients were permitted to continue to use the product for up to 6 months, if they wished. The quit rates are the percentage of all persons initially enrolled who continuously abstained after week 2. Nicomild (nicotine inhalation system) Inhaler was more effective than placebo at 6 weeks, 3 months and 6 months. The efficacy is shown in the following table.

Quit Rates by Treatment (N= 445 Patients in 2 Studies)

Patients who used Nicomild (nicotine inhalation system) Inhaler had a significant reduction in the “urge to smoke”, a major nicotine withdrawal symptom, compared with placebo-treated patients throughout the first week, (see Figure 1).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Any risks that may be associated with NRT are substantially outweighed by the well established dangers of continued smoking.

Underlying cardiovascular disease: In stable cardiovascular disease this product presents a lesser hazard than continuing to smoke. However dependent smokers currently hospitalised as a result of myocardial infarction, unstable or worsening angina including Prinzmetal's angina, severe dysrhythmia or CVA and who are considered to be haemodynamically unstable and/or who have uncontrolled hypertension should be encouraged to stop smoking with non-pharmacological interventions. If this fails, this product may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision.

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.

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

Renal or hepatic impairment: This product should be used 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.

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. If a child swallows, chews or sucks on the nicotine cartridge (used as well as unused) there is a risk of poisoning in the child.

Phaeochromocytoma and uncontrolled hyperthyroidism: As nicotine causes release of catecholamines, this product should be used with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma.

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

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs metabolised by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops smoking, this may result in slower metabolism and a consequent rise in blood levels of such drugs. This is of potential clinical importance for products with a narrow therapeutic window, e.g. theophylline, clozapine and ropinirole.

Lung Disease: Patients with obstructive lung disease may find use of the Inhalator difficult. Nicotine Gum, Patch, Nasal Spray or Sublingual tablet may be preferred in such cases. This product should be used with caution in patients with chronic throat disease and bronchospastic disease.

Allergic reactions: Susceptibility to angioedema and urticaria.

Potential choking hazard: This product contains some small parts. Any unused cartridges should remain in the cartridge tray to minimise the risk of swallowing.

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, Nicomild patches 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 nicotine patch 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 monitor their blood glucose levels more closely than usual while using this product.

Allergic reactions: Susceptibility to angioedema and urticaria.

Atopic or eczematous dermatitis (due to localised patch sensitivity): In the case of severe or persistent local reactions at the site of application (e.g. severe erythema, pruritus or oedema) or a generalised skin reaction (e.g. urticaria, hives or generalised skin rashes), users should be instructed to discontinue use of Nicomild and contact their physician.

Contact sensitisation: Patients with contact sensitisation should be cautioned that a serious reaction could occur from exposure to other nicotine-containing products or smoking.

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.

- Seizures: Potential risks and benefits of nicotine should be carefully evaluated before use in subjects taking anti-convulsant therapy or with a history of epilepsy as cases of convulsions have been reported in association with nicotine.

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. The patches should be folded in half with the adhesive side innermost and disposed of with care.

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.

Safety on handling: Nicomild is potentially a dermal irritant and can cause contact sensitisation. Care should be taken during handling and in particular contact with the eyes and nose avoided. After handling, wash hands with water alone as soap may increase nicotine absorption.

Any risks that may be associated with nicotine replacement therapy are substantially outweighed by the well established dangers of continued smoking.

Precautions:

Users should be informed that if they continue to smoke while using the patches, they may experience increased adverse effects due to the hazards of smoking, including cardiovascular effects.

Nicomild TTS should be used with caution on diseased skin. In the event of a severe or persistent skin reaction, discontinue treatment and use another pharmaceutical form of nicotine replacement therapy.

Underlying cardiovascular disease

In stable cardiovascular disease Nicomild TTS presents a lesser hazard than continuing to smoke. However dependent smokers currently hospitalized as a result of a recent myocardial infarction, unstable or worsening angina pectoris including Prinzmetal's angina, severe cardiac arrhythmias, uncontrolled hypertension, or recent cerebrovascular accident and who are considered to be haemodynamically unstable should be encouraged to stop smoking with non-pharmacological interventions (such as counselling). If this fails, Nicomild TTS may be considered but as data on safety in this patient group are limited, initiation should only be under medical supervision.

Diabetes mellitus

Patients with diabetes mellitus should be advised to monitor their blood sugar levels more closely than usual when nicotine replacement therapy is initiated as catecholamines released by nicotine can affect carbohydrate metabolism.

Allergic reactions

Discontinuation of treatment may be advisable in cases of severe or persistent allergic reactions.

Angioedema and urticaria have been reported. Contact sensitisation was reported in a few patients using transdermal nicotine in clinical trials. Patients who develop contact sensitisation to nicotine should be cautioned that a severe reaction could occur from smoking or exposure to other nicotine containing products.

Renal and or hepatic impairment

Should be used in caution in patients with moderate to severe hepatic impairment and/or severe impairment as the clearance of nicotine or its metabolites may be decreased with the potential for increased adverse effects.

Gastro-Intestinal disease

Nicomild TTS should be used with caution in patients with peptic ulcers.

Phaeochromocytoma and uncontrolled hyperthyroidism

Nicomild TTS should be used with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

Transferred dependence

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

Danger in small children

Nicotine is a toxic substance. Doses of nicotine that are tolerated by adult and adolescent smokers can produce severe toxicity in small children that may be fatal. Both before and after use, the patch contains a significant amount of nicotine. Subjects must be cautioned that the patches must not be handled casually or left where they might be inadvertently misused or consumed by children. Used patches must be disposed of with care by folding them in half with the adhesive sides inwards, and ensuring that they do not fall into the hands of children under any circumstances.

Nicomild TTS contains aluminium. The patch should therefore be removed prior to undergoing any MRI (Magnetic Resonance Imaging), defibrillation or cardioversion procedures.

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 slower metabolism and a consequent rise in blood levels of such drugs.

Nicotine from any source can be toxic and addictive. Smoking causes lung disease, cancer and heart disease, and may adversely affect pregnant women or the fetus. For any smoker, with or without concomitant disease or pregnancy, the risk of nicotine replacement in a smoking cessation program should be weighed against the hazard of continued smoking, and the likelihood of achieving cessation of smoking without nicotine replacement.

Tobacco smoke, which has been shown to be harmful to the fetus, contains nicotine, hydrogen cyanide, and carbon monoxide. The Nicomild (nicotine inhalation system) Inhaler does not deliver hydrogen cyanide and carbon monoxide. However, nicotine has been shown in animal studies to cause fetal harm. It is therefore presumed that Nicomild (nicotine inhalation system) Inhaler can cause fetal harm when administered to a pregnant woman. The effect of nicotine delivery by Nicomild (nicotine inhalation system) Inhaler has not been examined in pregnancy (See PRECAUTIONS). Therefore, pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before using pharmacological approaches. If Nicomild (nicotine inhalation system) Inhaler is used during pregnancy, or if the patient becomes pregnant while using it, the patient should be apprised of the potential hazard to the fetus.

This product contains nicotine and should be kept out of the reach of children and pets. The amounts of nicotine that are tolerated by adult smokers can produce symptoms of poisoning and could prove fatal if the nicotine from the Nicomild (nicotine inhalation system) Inhaler is inhaled, ingested, or buccally absorbed by children or pets. A cartridge contains about 60% of its initial drug content when it is discarded, which is about 6 mg. Patients should be cautioned to keep both the used and unused cartridges of Nicomild (nicotine inhalation system) Inhaler out of the reach of children and pets.

All components of the Nicomild (nicotine inhalation system) Inhaler system should also be kept out of the reach of children and pets to avoid accidental swallowing and choking.

The patient should be urged to stop smoking completely when initiating Nicomild (nicotine inhalation system) Inhaler therapy (See DOSAGE AND ADMINISTRATION). Patients should be informed that if they continue to smoke while using the product, they may experience adverse effects due to peak nicotine levels higher than those experienced from smoking alone. If there is a clinically significant increase in cardiovascular or other effects attributable to nicotine, the treatment should be discontinued (See WARNINGS). Physicians should anticipate that concomitant medications may need dosage adjustment (See DRUG INTERACTIONS). Sustained use (beyond 6 months) of Nicomild (nicotine inhalation system) Inhaler by patients who stop smoking has not been studied and is not recommended. (See Drug Abuse And Dependence).

Nicomild (nicotine inhalation system) Inhaler has not been specifically studied in asthma or chronic pulmonary disease. Nicotine is an airway irritant and might cause bronchospasm. Nicomild (nicotine inhalation system) Inhaler should be used with caution in patients with bronchospastic disease. Other forms of nicotine replacement might be preferable in patients with severe bronchospastic airway disease.

The risks of nicotine replacement in patients with cardiovascular and peripheral vascular diseases should be weighed against the benefits of including nicotine replacement in a smoking cessation program for them. Specifically, patients with coronary heart disease (history of myocardial infarction and/or angina pectoris), serious cardiac arrhythmias, or vasospastic diseases (Buerger's disease, Prinzmetal's variant angina and Raynaud's phenomena) should be evaluated carefully before nicotine replacement is prescribed. Tachycardia and palpitations have been reported occasionally with the use of Nicomild Inhaler as well as with other nicotine replacement therapies. No serious cardiovascular events were reported in clinical studies with Nicomild (nicotine inhalation system) Inhaler, but if such symptoms occur, its use should be discontinued.

Nicomild (nicotine inhalation system) Inhaler generally should not be used in patients during the immediate post-myocardial infarction period, nor in patients with serious arrhythmias, or with severe or worsening angina.

The pharmacokinetics of nicotine have not been studied in the elderly or in patients with renal or hepatic impairment. However, given that nicotine is extensively metabolized and that its total system clearance is dependent on liver blood flow, some influence of hepatic impairment on drug kinetics (reduced clearance) should be anticipated. Only severe renal impairment would be expected to affect the clearance of nicotine or its metabolites from the circulation (See Pharmacokinetics).

Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in patients with hyperthyroidism, pheochromocytoma or insulin-dependent diabetes, since nicotine causes the release of catecholamines by the adrenal medulla.

Nicotine delays healing in peptic ulcer disease; therefore, Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in patients with active peptic ulcers and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

Nicotine therapy constitutes a risk factor for development of malignant hypertension in patients with accelerated hypertension; therefore, Nicomild (nicotine inhalation system) Inhaler therapy should be used with caution in these patients and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

A PATIENT INFORMATION sheet is included in the package of Nicomild (nicotine inhalation system) Inhaler cartridges dispensed to the patient. Patients should be encouraged to read the information sheet carefully and to ask their physician and pharmacist about the proper use of the product (See DOSAGE AND ADMINISTRATION). Patients must be advised to keep both used and unused cartridges out of the reach of children and pets.

Nicotine itself does not appear to be a carcinogen in laboratory animals. However, nicotine and its metabolites increased the incidences of tumors in the cheek pouches of hamsters and forestomach of F344 rats, respectively when given in combination with tumor-initiators. One study, which could not be replicated, suggested that cotinine, the primary metabolite of nicotine, may cause lymphoreticular sarcoma in the large intestine of rats. Neither nicotine nor cotinine was mutagenic in the Ames salmonella test. Nicotine induced reparable DNA damage in an E. coli test system. Nicotine was shown to be genotoxic in a test system using Chinese hamster ovary cells. In rats and rabbits, implantation can be delayed or inhibited by a reduction in DNA synthesis that appears to be caused by nicotine. Studies have shown a decrease in litter size in rats treated with nicotine during gestation.

(See WARNINGS sections). The harmful effects of cigarette smoking on maternal and fetal health are clearly established. These include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. The specific effects of Nicomild (nicotine inhalation system) Inhaler therapy on fetal development are unknown. Therefore pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before using pharmacological approaches.

Spontaneous abortion during nicotine replacement therapy has been reported; as with smoking, nicotine as a contributing factor cannot be excluded.

Nicomild (nicotine inhalation system) Inhaler therapy should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of using it by the pregnant patient, who might continue to smoke.

Nicotine was shown to produce skeletal abnormalities in the offspring of mice when toxic doses were given to the dams (25 mg/kg IP or SC).

Nicotine teratogenicity has not been studied in humans except as a component of cigarette smoke (each cigarette smoked delivers about 1 mg of nicotine). It has not been possible to conclude whether cigarette smoking is teratogenic to humans.

A nicotine bolus (up to 2 mg/kg) to pregnant rhesus monkeys caused acidosis, hypercarbia, and hypotension (fetal and maternal concentrations were about 20 times those achieved after smoking one cigarette in 5 minutes). Fetal breathing movements were reduced in the fetal lamb after intravenous injection of 0.25 mg/kg nicotine to the ewe (equivalent to smoking 1 cigarette every 20 seconds for 5 minutes). Uterine blood flow was reduced about 30% after infusion of 0.1 μg/kg/min nicotine to pregnant rhesus monkeys (equivalent to smoking about six cigarettes every minute for 20 minutes).

Cigarette smoking during pregnancy is associated with an increased risk of spontaneous abortion, low birth weight infants and perinatal mortality. Nicotine and carbon monoxide are considered the most likely mediators of these outcomes. The effects of cigarette smoking on fetal cardiovascular parameters have been studied near term. Cigarettes increased fetal aortic blood flow and heart rate and decreased uterine blood flow and fetal breathing movements. Nicomild (nicotine inhalation system) Inhaler therapy has not been studied in pregnant women.

Nicomild (nicotine inhalation system) Inhaler is not recommended for use during labor and delivery. The effect of nicotine on a mother or the fetus during labor is unknown.

Caution should be exercised when the Nicomild (nicotine inhalation system) Inhaler is administered to nursing mothers. The safety of Nicomild Inhaler therapy in nursing infants has not been examined. Nicotine passes freely into breast milk; the milk to plasma ratio averages 2.9. Nicotine is absorbed orally. An infant has the ability to clear nicotine by hepatic first-pass clearance; however, the efficiency of removal is probably lowest at birth. Nicotine concentrations in milk can be expected to be lower with Nicomild (nicotine inhalation system) Inhaler when used as recommended than with cigarette smoking, as maternal plasma nicotine concentrations are generally reduced with nicotine replacement. The risk of exposure of the infant to nicotine from Nicomild (nicotine inhalation system) Inhaler therapy should be weighed against the risks associated with the infant's exposure to nicotine from continued smoking by the mother (passive smoke exposure and contamination of breast milk with other components of tobacco smoke) and from the Nicomild (nicotine inhalation system) Inhaler alone, or in combination with continued smoking.

Safety and effectiveness in pediatric and adolescent patients below the age of 18 years have not been established for any nicotine replacement product. However, no specific medical risk is known or expected in nicotine dependent adolescents. Nicomild (nicotine inhalation system) Inhaler should be used for the treatment of tobacco dependence in the older adolescent only if the potential benefit justifies the potential risk.

Clinical studies of Nicomild (nicotine inhalation system) Inhaler did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reports on clinical experience have not identified differences between older and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosage range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease.

Effects on ability to drive and use machines

This medicinal product has no or negligible influence on the ability to drive and use machines.

Not applicable.

There is no evidence of any risks associated with driving or operating machinery when Nicomild TTS is used following the recommended dose.

Dosage (Posology) and method of administration

Adults and Children over 12 years of age

Nicomild Inhalator should be used whenever the urge to smoke is felt or to prevent cravings in situations where these are likely to occur.

Smokers willing or able to stop smoking immediately should initially replace all their cigarettes with the Inhalator and as soon as they are able, reduce the number of cartridges used until they have stopped completely.

Smokers aiming to reduce cigarettes should use the Inhalator, as needed, between smoking episodes to prolong smoke-free intervals and with the intention to reduce smoking as much as possible.

As soon as they are ready smokers should aim to quit smoking completely.

Maximum daily dose: 6 cartridges.

When making a quit attempt behavioural therapy, advice and support will normally improve the success rate. Those who have quit smoking, but are having difficulty discontinuing their Inhalator are recommended to contact their pharmacist or doctor for advice.

Each cartridge can be used for approximately eight 5-minute sessions, with each cartridge lasting approximately 40 minutes of intense use. The more the subject is able to use the inhalator, the easier it will be to achieve maximum reduction of cigarettes and/or quit smoking completely.

Method of administration

The cartridge is inserted into the mouthpiece according to the instructions.

When a patient draws air into the mouth through the mouthpiece, nicotine is vaporised and absorbed by the buccal mucosa. Minimal nicotine reaches the lungs. The amount of nicotine from a puff is less than that from a cigarette. To compensate for less nicotine delivery from a puff it is necessary to inhale more often than when smoking a cigarette.

The number of cartridges, frequency, puffing/inhalation time and technique does vary between individuals.

The actual time that the cartridge is active depends on the intensity of use. After about 40 minutes of intense use the maximal dose is achieved and it is about then that the nicotine amounts released from the cartridge begin to fall away, such that the cartridge is rejected by the user.

Nicomild patches should be applied once a day, at the same time each day and preferably soon after waking, to a non-hairy, clean, dry skin site and worn continuously for 24 hours. The Nicomild patch should be applied promptly on removal from its protective sachet.

Avoid applying to any skin which is broken, red or irritated. After 24 hours the used patch should be removed and a new patch applied to a fresh skin site. The patch should not be left on for longer than 24 hours. Skin sites should not be reused for at least seven days. Only one patch should be worn at a time.

Patches may be removed before going to bed if desired. However use for 24 hours is recommended to optimise the effect against morning cravings.

Concurrent behavioural support is recommended, as such programmes have been shown to be beneficial for smoking cessation.

Adults 18 years and over

Abrupt cessation of smoking:

During a quit attempt every effort should be made to stop smoking with Nicomild patches.

Nicomild therapy should usually begin with Nicomild 21 mg and be reduced according to the following dosing schedule:-

Light smokers (e.g. those who smoke less than 10 cigarettes per day) are recommended to start at Step 2 (14 mg) for 6 weeks and decrease the dose to Nicomild 7 mg for the final 2 weeks.

Patients on Nicomild 21 mg who experience excessive side-effects (please refer to precautions), which do not resolve within a few days, should change to Nicomild 14mg. This strength should then be continued for the remainder of the 6 week course before stepping down to Nicomild 7mg for two weeks. If the symptoms persist the patient should be advised to seek the advice of a healthcare professional.

For optimum results, the 10 week treatment course (8 weeks for light smokers or patients who have reduced strength as above), should be completed in full. Treatment with Nicomild patch may be continued beyond 10 weeks if needed to stay cigarette free, however, those who have quit smoking but are having difficulty discontinuing using the patches recommended to seek additional help and advice from a healthcare professional.

Further courses may be used at a later time, for Nicomild patch users who continue or resume smoking.

Gradual Cessation:

For smokers who are unwilling or unable to quit abruptly.

The 21 mg patch can be used daily for 2-4 weeks while the user continues to smoke as needed. At the end of the 2-4 weeks the user should quit completely and continue using Step 1 21 mg patch for 6 weeks daily without smoking. Thereafter following the Step 2 and 3 directions for abrupt cessation above. Should the patient feel able to quit completely before their designated quit date they can do so.

Reduction in smoking:

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

A patch can be used while the user continues to smoke as needed. The user should 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.

If users are still feeling the need to use the patches 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

Apply a patch to control troublesome withdrawal symptoms including craving during the period when smoking is being avoided. Users should be encouraged to stop smoking completely as soon as possible.

If users are still feeling the need to use the patches 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 to 17 years) should follow the schedule of treatment for abrupt cessation of smoking as given above. Where adolescents are not ready or not able to stop smoking abruptly, advice from a healthcare professional should be sought.

Safety and effectiveness in children who smoke has not been evaluated. Nicomild is not recommended for use in children under 12 years of age.

Adults:

For individuals smoking 20 cigarettes or more a day, it is recommended that treatment be started with Nicomild TTS 30 (Step 1) once daily, applied to a dry non-hairy area of the skin on the trunk or upper arm. Those smoking less than this are recommended to start with Nicomild TTS 20 (Step 2). Sizes of 30cm2, 20cm2 and 10cm2 are available to permit gradual withdrawal of nicotine replacement, using treatment periods of 3-4 weeks (for each size). The size of patch may be adjusted according to individual response, maintaining or increasing the dose if abstinence is not achieved or if withdrawal symptoms are experienced. Total treatment periods of more than 3 months and daily doses above 30cm2 have not been evaluated. The treatment is designed to be used continuously for 3 months but not beyond. However, if abstinence is not achieved at the end of the 3 month treatment period, further treatments may be recommended.

The dosage must not be adjusted by cutting a patch.

The patch should be used as soon as it has been removed from the child-resistant pouch. Following removal of the metallic backing, the patch should be applied to an area of dry skin with no skin lesion and little hair (shoulder blade, hip, lateral surface of the arms, etc) and held in position for 10-20 seconds with the palm of the hand. Each patch should be removed after 24 hours and disposed of safely (see “Warnings”). A different site of application should be chosen each day and several days should be allowed to elapse before a new patch is applied to the same area of skin.

Use for 24 hours optimizes the effect against morning cravings but in pregnant patients, it is recommended that the patch is removed before going to bed

During handling, avoid contact with the eyes and nose and wash your hands after application.

Children and young adults:

The above recommendation can be used for adolescences between 12 and 18 years of age. As data are limited in this age group, medical advice should be obtained should it be found necessary to use the patch beyond 12 weeks.

Elderly:

Experience in the use of these patches in smokers over the age of 65 years is limited. Nicomild TTS does not appear to pose safety problems in this age group.

Potential for abuse and dependence:

Patients must desire to stop smoking and should be instructed to stop smoking completely as they begin using Nicomild (nicotine inhalation system) Inhaler. It is important that patients understand the instructions, and have their questions answered. They should clearly understand the directions for using the Nicomild (nicotine inhalation system) Inhaler and safely disposing of the used cartridges.

The initial dosage of Nicomild (nicotine inhalation system) Inhaler is individualized. Patients may selftitrate to the level of nicotine they require. Most successful patients in the clinical trials used between 6 and 16 cartridges a day. Best effect was achieved by frequent continuous puffing (20 minutes). The recommended duration of treatment is 3 months, after which patients may be weaned from the Nicomild (nicotine inhalation system) Inhaler by gradual reduction of the daily dose over the following 6 to 12 weeks. The safety and efficacy of the continued use of Nicomild (nicotine inhalation system) Inhaler for periods longer than 6 months have not been studied and such use is not recommended.

Dosing recommendations are summarized in the table below.

RECOMMENDED DOSING

For best results, patients should be encouraged to use at least 6 cartridges per day at least for the first 3 to 6 weeks of treatment. In clinical trials, the average daily dose was > 6 (range 3 to 18) cartridges for patients who successfully quit smoking. Additional doses may be needed to control the urge to smoke with a maximum of 16 cartridges daily for up to 12 weeks. Regular use of Nicomild (nicotine inhalation system) Inhaler during the first week of treatment may help patients adapt to the irritant effects of the product. Some patients may exhibit signs or symptoms of nicotine withdrawal or excess which will require an adjustment of the dosage (see Individualization of Dosage).

Most patients will need to gradually discontinue the use of Nicomild (nicotine inhalation system) Inhaler after the initial treatment period. Gradual reduction of dose may begin after twelve weeks of initial treatment and may last for up to twelve weeks. Recommended strategies for discontinuing use include suggesting to patients that they use the product less frequently, keep a tally of daily usage, try to meet a steadily reducing target or set a planned quit date for stopping use of the product.

The Nicomild Inhaler provides the smoker with adequate amounts of nicotine to reduce the urge to smoke, and may provide some degree of comfort by providing a hand-to-mouth ritual similar to smoking, although the importance of such an effect in smoking cessation is, as yet, unknown.

The success or failure of smoking cessation is influenced by the quality, intensity and frequency of supportive care. Patients are more likely to quit smoking if they are seen frequently and participate in formal smoking cessation programs.

The goal of Nicomild (nicotine inhalation system) Inhaler therapy is complete abstinence. If a patient is unable to stop smoking by the fourth week of therapy, treatment should probably be discontinued.

Patients who fail to quit on any attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who were unsuccessful should be counseled and should then probably be given a therapeutic holiday before the next attempt. A new quit attempt should be encouraged when conditions are more favorable.

Based on the clinical trials, a reasonable approach to assisting patients in their attempt to quit smoking is to begin initial treatment, using the recommended dosage (See DOSAGE AND ADMINISTRATION). Dosage can then be adjusted in those patients with signs or symptoms of nicotine withdrawal or excess. Patients who are successfully abstinent on Nicomild (nicotine inhalation system) Inhaler should be treated at the selected dosage for up to 12 weeks, after which use of the Inhaler should be gradually reduced over the next 6 to 12 weeks. Some patients may not require gradual reduction of dosage and may abruptly stop treatment successfully. The safe use of this product for longer than 6 months has not been established.

The symptoms of nicotine withdrawal overlap those of nicotine excess (See Pharmacodynamics and ADVERSE REACTIONS sections). Since patients using Nicomild (nicotine inhalation system) Inhaler may also smoke intermittently, it is sometimes difficult to determine if they are experiencing nicotine withdrawal or nicotine excess. Controlled clinical trials of nicotine products suggest that palpitations, nausea and sweating are more often symptoms of nicotine excess, whereas anxiety, nervousness and irritability are more often symptoms of nicotine withdrawal.

See PATIENT INFORMATION sheet for instructions on handling and disposal. After using the Nicomild (nicotine inhalation system) Inhaler, carefully separate the mouthpiece, remove the used cartridge and throw it away, out of the reach of children and pets. Store the mouthpiece in the plastic storage case for further use. The mouthpiece is reusable and should be cleaned regularly with soap and water. The Nicomild (nicotine inhalation system) Inhaler cartridges can be detected on a radiogram.

Special precautions for disposal and other handling

Potential choking hazard: This product contains some small parts. Any unused cartridges should remain in the cartridge tray to minimise the risk of swallowing.

Because of residual nicotine, used cartridges may be a hazard to children, animals and fish and so should never be thrown away or left lying around. They should be kept in the case and disposed of with household rubbish.

No special requirements.

Keep all medicines out of the reach of children.