NiQuitin Clear 21 mg

NiQuitin Clear is a transdermal delivery system for topical application available in systems of 22 cm² containing 114 mg nicotine, equivalent to 5.1 mg/cm² of nicotine and delivering 21 mg over 24 hours.

Transdermal patch.

NiQuitin Clear is indicated for the relief of nicotine withdrawal symptoms including cravings as an aid to smoking cessation. If possible, when stopping smoking, NiQuitin Clear should be used in conjunction with a behavioural support programme.

The patches should be used as directed below. Prior to initiation of therapy users should be committed to stopping smoking. During a quit attempt every effort should be made to stop smoking during treatment with NiQuitin Clear. Concurrent behavioural support is recommended, as such programmes have been shown to be beneficial for smoking cessation.

Adults (18 years and over)

NiQuitin Clear 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 NiQuitin Clear 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.

NiQuitin Clear therapy should usually begin with NiQuitin Clear 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 NiQuitin Clear 7 mg for the final 2 weeks.

Patients on NiQuitin Clear 21 mg who experience excessive side-effects (please refer to precautions), which do not resolve within a few days, should change to NiQuitin Clear 14mg. This strength should then be continued for the remainder of the 6 week course before stepping down to NiQuitin Clear 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 NiQuitin Clear patch may be continued beyond 10 weeks if you need it to stay cigarette free, however, those who use the patches beyond 9 months are recommended to seek additional help and advice from a healthcare professional.

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

Adolescents and children

Adolescents (12 to 17 years) should follow the schedule of treatment for adults presented above for steps 1, 2 and 3, but as data are limited, duration of NRT in this age group is restricted to 12 weeks. If longer treatment is required advice from a healthcare professional should be sought.

NiQuitin Clear is not recommended for use in children under 12 years of age.

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

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

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, NiQuitin Clear 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.

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 NiQuitin Clear and contact their physicians.

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:

NiQuitin Clear 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.

Pregnancy

Smoking during pregnancy is associated with risks such as intra-uterine growth retardation, premature birth or stillbirth. Stopping smoking is the single most effective intervention for improving the health of both pregnant smoker and her baby. The earlier abstinence is achieved the better.

Ideally smoking cessation during pregnancy should be achieved without NRT. However for women unable to quit on their own, NRT may be recommended to assist a quit attempt. The risk of using NRT to the fetus is lower than that expected with tobacco smoking, due to lower maximal plasma nicotine concentration and no additional exposure to polycyclic hydrocarbons and carbon monoxide.

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

Intermittent dosing products may be preferable as these usually provide a lower daily dose of nicotine than patches. However patches may be preferred if the woman is suffering from nausea during pregnancy. If patches are used they should be removed before going to bed.

Lactation

Nicotine from smoking and NRT is found in breast milk. However the amount of nicotine the infant is exposed to from NRT is relatively small and less hazardous than the second-hand smoke they would otherwise be exposed to.

Using intermittent dose NRT preparations, compared with patches, may minimize the amount of nicotine in the breast milk as the time between administrations of NRT and feeding can be more easily prolonged.

Not applicable.

Symptoms:

The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60mg. Symptoms of acute nicotine poisoning include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of an overdose:

All nicotine intake should stop immediately and the patient should be treated symptomatically. Artificial respiration with oxygen should be instituted if necessary. Activated charcoal reduces the gastro-intestinal absorption of nicotine

Overdose from topical exposure:

The NiQuitin Clear system should be removed immediately if the patient shows signs of overdosage and the patient should seek immediate medical care. 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.

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, nicotine withdrawal symptoms were alleviated as well as craving. The severity of craving was reduced by at least 35% at all times of day during the first two weeks of abstinence, compared to placebo (p<0.05).

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

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

Distribution

Following removal of NiQuitin Clear, 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 NiQuitin Clear is removed most non-smoking patients will have non-detectable nicotine concentrations in 10 to 12 hours.

A dose of radio-labelled 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 trans3hydroxycotinine. 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 (pH5).

There were no differences in nicotine kinetics between men and women using nicotine patches. Obese men using nicotine patch 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.

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

Not applicable.

36 months

None stated.

7 or 14 patches in a carton. Each patch is rectangular and is comprised of clear backing and a protective liner which is removed prior to use. Each patch is contained in a laminate sachet.

Not applicable.

Beecham Group PLC

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

T/A GlaxoSmithKline Consumer Healthcare

Brentford

TW8 9GS

PL 00079/ 0356

23^rd June 2000

6^th August 2009