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1. Nicabate Opaque 21 Mg Transdermal Patch
2. Nicabate Opaque 21 Mg Transdermal Patch

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nicabate Opaque 21 mg Transdermal Patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 22 cm² transdermal patch contains 114 mg nicotine, equivalent to 5.1 mg/cm² of nicotine and delivering 21 mg over 24 hours.

For excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal Patch (Patch).

Each patch is rectangular and is comprised of an outer matt pinkish tan-coloured layer, a middle silver layer and an outer clear layer which is removed prior to use.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The product 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.

The product is indicated in pregnant and lactating women making a quit attempt.

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

4.2 Posology and method of administration

The product 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 product 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 the product.

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

Dose    Duration

Step 1 21 mg patch Step 2 14 mg patch Step 3 7 mg patch

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 a 7 mg patch for the final 2 weeks.

Patients on 21 mg patches who experience excessive side-effects (please refer to precautions), which do not resolve within a few days, should change to 14mg patches. This strength should then be continued for the remainder of the 6 week course before stepping down to 7mg patches 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 the product 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 the product 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. The product is not recommended for use in children under 12 years of age.

4.3 Contraindications

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

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

4.4 Special warnings and precautions for use

The risks associated with the use of NRT are substantially outweighed in virtually all circumstances by the well established dangers of continued smoking.

Patients hospitalised for MI, severe dysrhythmia or CVA who are considered to be haemodynamically unstable should be encouraged to stop smoking with nonpharmacological interventions. If this fails, the product may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision. Once patients are discharged from hospital they can use NRT as normal.

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

Allergic reactions: Susceptibility to angioedema and urticaria.

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 the product 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.

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: The product 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.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically relevant interactions between nicotine replacement therapy and other drugs has definitely been established, however nicotine may possibly enhance the haemodynamic effects of adenosine. Healthcare professionals are reminded that smoking cessation itself may require the adjustment of some drug therapy.

4.6 Fertility, pregnancy and lactation

Pregnancy

Stopping smoking is the single most effective intervention for improving the health of both the pregnant smoker and her baby, and the earlier abstinence is achieved the better. However, if the mother cannot (or is considered unlikely to) quit without pharmacological support, NRT may be used as the risk to the foetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but

NRT may be used in pregnancy as a safer alternative to smoking. Because of the potential for nicotine-free periods, intermittent dose forms are preferable, but patches may be necessary if there is significant nausea and/or vomiting. If patches are used they should, if possible, be removed at night when the foetus would not normally be exposed to nicotine.

Lactation

The relatively small amounts of nicotine found in breast milk during NRT use are less hazardous to the infant than second-hand smoke. Intermittent dose forms would minimize the amount of nicotine in breast milk and permit feeding when levels were at their lowest.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

NRT may cause adverse reactions similar to those associated with nicotine administered by other means, including smoking. These may be attributable to the pharmacological effects of nicotine, some of which are dose dependent. At recommended doses, the product has not been found to cause any serious adverse effects. Excessive use of the product by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

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 the product. The product 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

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 the product. 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 the product and contact their physician.

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

4.9 Overdose

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

Symptoms

Signs and symptoms of an overdose from 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 gastro-intestinal absorption of nicotine.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic classification: N07BA01 (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, the product was shown to alleviate nicotine withdrawal symptoms as well as craving. The product 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).

5.2 Pharmacokinetic properties

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

Plasma concentrations of nicotine are proportional to dose for the three dosage forms of the product. 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 the product.

Distribution

Following removal of the product, 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 the product 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 the product. Obese men using the product 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.

5.3 Preclinical safety data

The general toxicity of nicotine is well known and taken into account in the recommended posology. Nicotine was not mutagenic in appropriate assays. The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine. In studies in pregnant animals, nicotine showed maternal toxicity, and consequential mild fetal toxicity. Additional effects included pre- and postnatal growth retardation and delays and changes in postnatal CNS development.

Effects were only noted following exposure to nicotine at levels in excess of those which will result from recommended use of the product. 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 the product indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, the product should only be used by pregnant women on medical advice if other forms of treatment have failed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethylene Vinyl Acetate Copolymer

Polyethylene/Aluminium/Polyethylene Terephthalate/ Ethylene vinyl acetate

Polyisobutylene Adhesive Laminate PMS 465 Brown Ink

8    MARKETING AUTHORISATION NUMBER(S)

PL 00079/0681

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 DATE OF REVISION OF THE TEXT