Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• There is no evidence of a difference in efficacy between different formulations of nicotine replacement therapy (NRT). Points to discuss with the smoker when choosing a product include:
• The number of cigarettes smoked per day.
• The time to the first cigarette of the day.
• Speed of nicotine delivery.
• Ease of use.
• Local irritant effects.
• Amount of behavioural replacement provided.
• Ability for the smoker to adjust and titrate the nicotine dose as required.
• Use of intermittent formulations as required to relieve cravings.
• Nicotine transdermal patches are available in 16-hour and 24-hour preparations. Steady-state nicotine levels are achieved 6–8 hours after application.
• Oral products allow nicotine absorption via the buccal mucosa, with peak plasma concentration occurring after 20–30 minutes. Oral formulations include gum, inhalator, sublingual tablets, and lozenges.
• Nicotine inhalator may provide more behavioural replacement than other products, although there is no good evidence to support this. Nicotine from the inhalator is deposited on the oral mucosa from where it is absorbed.
• Nicotine nasal spray is the most rapidly acting form of NRT available.
• For pregnant women intermittent dosing formulations may be preferable to continuous delivery products (i.e. patches); however, patches may be preferred if the woman has nausea during pregnancy. If patches are used, they should be removed before going to bed. Liquorice-flavoured NRT products are not recommended during pregnancy.
• For breastfeeding woman intermittent dosing formulations are preferable if NRT is used during breastfeeding, and the woman should avoid using the products for at least 1 hour before breastfeeding.
• All formulations are available on NHS prescription and over-the-counter from pharmacies. NRT patches, gum, inhalator, lozenges, and microtabs are also available from supermarkets and other retail outlets.

• Pregnancy: intermittent formulations of nicotine replacement therapy (NRT) (e.g. gum, lozenge, spray, sublingual tablet, or inhalator) are recommended by some experts because these usually provide a lower daily dose of nicotine than patches [RCP, 1999; Dempsey and Benowitz, 2001].
• Breastfeeding: NRT formulations that are used intermittently are preferred as their use can be adjusted to allow the maximum time between their administration and feeding of the infant, to minimize the amount of nicotine in the milk. Breastfeeding within 1 hour of maternal nicotine use (from any source) can significantly increase the levels of nicotine in breast milk [Micromedex, 2005].

• Nicotine replacement products may be combined to gain better control of withdrawal symptoms [MHRA, 2005b].
• This is usually done by providing a steady delivery of nicotine using a patch, with an intermittent formulation to provide relief from breakthrough cravings.

• Evidence from a Cochrane systematic review suggests that combination treatment can provide a small but significant increase in abstinence rates compared with a single product [Stead et al, 2008].
• Research also confirms the safety of combining nicotine replacement therapy in this way [Fiore et al, 2000; West et al, 2000].

• Smokers must use sufficient nicotine replacement therapy (NRT) in order to achieve good success rates. As insufficient use is the main problem with intermittent (non-patch) formulations of NRT some expert reviewers advise regular hourly use with topping-up as needed for all intermittent formulation products.
• NRT patches:
• Patches are available in two preparations (16-hour and 24-hour), each with three strengths:
• 16-hour patch: 15 mg, 10 mg, 5 mg (Nicorette^®).
• 24-hour patch: 21 mg, 14 mg, 7 mg (Nicotinell^®, NiQuitin^®).
• Patches are usually prescribed in a programme of reducing doses over 8–12 weeks (see Table 1).
• NRT gum:
• Gum is available in two strengths: 2 mg and 4 mg.
• People who smoke more than 20 cigarettes per day should start treatment with the 4 mg gum.
• People who start using the 2 mg gum and find they need to use more than 15 pieces per day should use the 4 mg gum.
• NRT lozenges:
• Lozenges are available in four strengths: 1 mg, 1.5 mg, 2 mg, and 4 mg.
• Nicotinell^®:
• For people with low–moderate dependency (less than 20 cigarettes per day), 1 mg lozenges are preferable.
• For people with moderate–strong dependency (20 to 30 cigarettes per day), 1 mg or 2 mg lozenges are acceptable, depending on the person's characteristics and preference.
• For people with strong dependency (more than 30 cigarettes per day), 2 mg lozenges are preferable.
• Niquitin^®:
• For people who have their first cigarette of the day more than 30 minutes after waking up, 2 mg lozenges are suitable.
• For people who have their first cigarette of the day within 30 minutes of waking up, 4 mg lozenges are preferable.
• NRT sublingual tablets:
• Sublingual tablets are available as 2 mg tablets only.
• People who smoke 20 cigarettes or more each day should start taking two tablets (4 mg) sublingually each hour.
• People who smoke fewer than 20 cigarettes per day should start taking one tablet (2 mg) sublingually each hour. This can be increased to two tablets (4 mg) each hour if the person fails to stop smoking or has significant withdrawal symptoms.
• Duration of NRT in people maintaining abstinence from cigarettes is usually 8–12 weeks (depending on which form of NRT is used and which dose is initiated), followed by a gradual reduction in dose. Use should normally be restricted to the licensed duration of the form of NRT used. See Table 1 for the licensed duration of different NRT products.
• Most people do not need to use NRT for longer than 3 months. However, more dependent smokers may need to use NRT for longer, and if treatment is stopped too soon these people might relapse [McRobbie and McEwen, 2005].

• Dosage instructions vary between brands of NRT, therefore it seems sensible to prescribe NRT by brand name.

• Higher doses of NRT may be more effective in people who smoke more cigarettes per day, and in those who are more highly dependent:
• In a Cochrane review of NRT and smoking cessation, the pooled results of four randomized controlled trials (RCTs) of highly dependent smokers found a significant benefit of 4 mg gum compared with 2 mg gum (relative risk 1.43, 95% CI 1.12 to 1.83). In low-dependence or unselected smokers, there was no evidence of a dose effect.
• The pooled results of six RCTs comparing a high-dose patch to a standard-dose patch suggested that higher doses may provide a small benefit (relative risk 1.15, 95% CI 1.01 to 1.30).

[Stead et al, 2008]

• Treatment can be stopped abruptly or tapered gradually. Most nicotine replacement therapy (NRT) product licences advise a gradual reduction in dosage (see the table in Dose and duration of NRT). However, abruptly stopping NRT does not seem to reduce its effectiveness:
• A Cochrane review of NRT and smoking cessation found no difference in effect between trials where the dose was tapered and trials where withdrawal was abrupt [Stead et al, 2008]. In two trials that directly compared weaning with abrupt withdrawal, no difference was found.

• The most common adverse effects include localized reactions (e.g. skin irritation with patches; irritation of the nose, throat, and eyes with nasal spray), sleep disturbances (e.g. vivid dreams), gastrointestinal disturbances, dizziness, and headache. These are unlikely to lead to discontinuation of treatment, but people may prefer to try an alternative formulation (e.g. changing from a 24-hour patch to a 16-hour patch if sleep is disturbed).
• Driving: nicotine replacement therapy is not known to affect people's ability to drive. The nasal spray can cause sneezing and watering eyes for a short time after use, so advise people not to use it while they are driving.

• Nicorette^® gum, inhalator, and sublingual tablet and Niquitin^® gum and lozenges have been licensed for use in a programme of cutting down smoking to quit.
• Nicotine gum, lozenges, inhalator, or sublingual tablets should be used between smoking episodes to manage the urge to smoke, to prolong smoke-free intervals, and with the intention to reduce smoking as much as possible.
• Smoking should be reduced within 6 weeks and complete cessation should be attempted as soon as possible, but not later than 6 months. If abstinence is not achieved within 9 months, treatment should be reviewed.

[BNF 54, 2007]

• Bupropion has been used as an antidepressant, but it is licensed in the UK for use as an aid to smoking cessation in conjunction with behavioural support. It is a relatively weak but selective inhibitor of the neuronal re-uptake of dopamine and noradrenaline. Although the exact mechanism by which it aids smoking cessation is unclear, it is presumed to work directly on the brain pathways involved in addiction and withdrawal.

• The recommended treatment dose is 150 mg once a day for 6 days, increasing to 150 mg twice a day (doses at least 8 hours apart).
• Continue the lower dose of 150 mg once a day if the person:
• Is older than 65 years of age.
• Has hepatic impairment (mild to moderate).
• Has renal impairment (glomerular filtration rate < 50 mL/min) [Ashley and Currie, 2004].
• Advise the person to stop smoking 7–14 days after starting bupropion.

[ABPI Medicines Compendium, 2006]

• The recommended course of treatment is for 7–9 weeks, after which time bupropion should be stopped.
• If no effect is seen after 7 weeks, treatment should be discontinued at this stage.
• Evidence is conflicting regarding longer-term use (up to 1 year) of bupropion to prevent relapse in people who are abstinent after 7–9 weeks of bupropion. This is an unlicensed use of bupropion, and further evidence is needed before this approach can be recommended:
• In one randomized controlled trial (RCT), people who were abstinent after 7 weeks of bupropion were randomized to receive bupropion (n = 214) or placebo (n = 215) for a further 45 weeks (total duration of treatment = 52 weeks) [Hays et al, 2001]. Abstinence at week 52 was significantly greater in the bupropion group than in the placebo group (55.1% compared to 42.3%, p = 0.008), but by week 104, the difference was no longer significant.
• In a second RCT, people who were abstinent after 8 weeks of tailored nicotine replacement therapy were randomized to receive bupropion (n = 88) or placebo (n = 88) for a further 26 weeks [Hurt et al, 2003]. At the end of the 26-week continuation phase, the abstinence rates between the bupropion and placebo groups did not significantly differ (28% compared with 25%).

• After a usual course of 7–9 weeks, discontinuation reactions are unlikely and bupropion can be stopped without tapering the dose.
• Because bupropion inhibits serotonin, there is a theoretical possibility that people on longer courses (typically 6 months or more) may experience a discontinuation reaction similar to people who discontinue antidepressants. Expert reviewers agree that this is very unusual, but if the person prefers, the dose could be halved 1–2 weeks before stopping.

• Pregnancy: bupropion should not be used during pregnancy, as information is limited on its safety during pregnancy [ABPI Medicines Compendium, 2006].
• Breastfeeding: bupropion should not be used during breastfeeding, as its safety has not been established [ABPI Medicines Compendium, 2006].
• Children and adolescents: bupropion should not be used in smokers younger than 18 years of age, as its safety and efficacy have not been evaluated and it is not licensed for use in this age group.
• Epilepsy (or increased risk of seizures): bupropion is associated with a dose-related risk of seizure. The Committee on Safety of Medicines reminds prescribers that:
• Bupropion is contraindicated in people with:
• A current seizure disorder or any history of seizures.
• A current or previous diagnosis of bulimia or anorexia nervosa.
• A central nervous system tumour.
• Abrupt withdrawal from alcohol or benzodiazepines.
• Severe hepatic cirrhosis.
• Bipolar disorder.
• Do not prescribe bupropion to people with other risk factors for seizures unless there is compelling clinical justification for which the potential benefit outweighs the increased risk of seizure. If bupropion is prescribed, consider using the lower dose of 150 mg daily throughout the entire treatment period. Risk factors for seizures include:
• Concomitant use of any drug known to lower the seizure threshold (including antipsychotics; antidepressants; some antimalarials, such as mefloquine; theophylline; systemic corticosteroids; tramadol; quinolones; and sedating antihistamines).
• Alcohol abuse.
• A history of head trauma.
• Diabetes treated with hypoglycaemic drugs or insulin.
• Use of stimulants or anorectic products.
• Stop bupropion if an individual has a seizure while taking it.

[CSM, 2001a]

• The most common adverse effects include dry mouth, gastrointestinal disturbances, insomnia (which can be reduced by not giving the last dose at bedtime), headache, impaired concentration, and dizziness.
• Seizures occur rarely in people taking bupropion; the risk of seizures is dose related, and it is therefore important not to exceed the recommended daily dose:
• At doses up to the maximum recommended daily dose, the incidence of seizures is approximately 0.1%.
• Stop bupropion if an individual has a seizure while taking it.
• The risk of seizures is increased in the presence of predisposing factors that lower the seizure threshold.

[ABPI Medicines Compendium, 2006]

• Driving:
• Bupropion may cause drowsiness and impair the ability to carry out skilled tasks; warn people not to drive or operate machinery if they are affected [BNF 54, 2007].
• The Driver and Vehicle Licensing Authority (DVLA) states that reports of seizures as an adverse effect of prescribed medication do not automatically imply that such events will be considered as provoked. The person may, therefore, be disallowed from driving for 1 year (car or motorcycle) or 5 years (large goods vehicle or passenger carrying vehicle) [DVLA, 2010].

• Co-administration of bupropion with other drugs known to lower the seizure threshold will increase the likelihood of seizures and should only be done under exceptional circumstances. Such drugs include antipsychotics; antidepressants; some antimalarials, such as mefloquine; theophylline; systemic corticosteroids; tramadol; quinolones; and sedating antihistamines [CSM, 2001b].
• Bupropion should not be given within 2 weeks of stopping a monoamine oxidase inhibitor (MAOI). For moclobemide (a reversible MAOI), this period can be reduced to 2–3 days [Baxter, 2006].

• Varenicline is a partial nicotinic receptor agonist. It alleviates symptoms of craving and withdrawal, and reduces the rewarding and reinforcing effects of smoking by preventing nicotine binding to the receptors [NICE, 2007].

• The recommended treatment dose is 1 mg varenicline twice daily following a 1-week titration as follows:
• Days 1–3: 500 micrograms once a day.
• Days 4–7: 500 micrograms twice a day.
• Day 8 onwards: 1 mg twice a day.
• For people who cannot tolerate the adverse effects of higher doses (1 mg twice daily) of varenicline, the dose may be reduced to 500 micrograms twice a day.
• Advise the person to stop smoking 7–14 days after starting varenicline.

[ABPI Medicines Compendium, 2008]

• The recommended course of treatment is 12 weeks.
• For people who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with varenicline at 1 mg twice daily may be considered to help maintain abstinence.

• One study assessed the benefit of an additional 12 weeks of varenicline therapy on the maintenance of abstinence. Participants in an open-label study who were abstinent after 12 weeks of varenicline 1 mg twice a day were randomized to continue varenicline or to receive placebo for an additional 12 weeks. The primary study end point was the continuous abstinence rate from week 13 to week 24 in the double-blind treatment phase. A key secondary end point was the continuous abstinence rate for week 13 to week 52.
• At week 24, the odds of maintaining abstinence following an additional 12 weeks of treatment with varenicline were 2.5 times those for placebo (odds ratio 2.47, 95% CI 1.95 to 3.15).
• At week 52, the odds of maintaining abstinence following an additional 12 weeks of treatment with varenicline were 1.4 times those for placebo (odds ratio 1.35, 95% CI 1.07 to 1.70).
• No data are available on the efficacy of an additional 12 weeks course of treatment for people who do not succeed in stopping smoking during initial therapy or who relapse after treatment.

[ABPI Medicines Compendium, 2008]

• Varenicline may be stopped without tapering the dose. However, immediately after stopping treatment with varenicline, up to 3% of people experience an increase in irritability, urge to smoke, depression, and/or insomnia.
• Inform the person accordingly and discuss or consider the need for dose tapering.

[ABPI Medicines Compendium, 2008]

• Pregnancy: varenicline should not be used during pregnancy, because data on its safety during pregnancy are inadequate.
• Breastfeeding: the safety of varenicline during breastfeeding has not been established.
• Children and adolescents: varenicline is not recommended for use in smokers younger than 18 years of age, as data are insufficient on safety and efficacy.
• Epilepsy: there is no clinical experience of varenicline in people with epilepsy.
• Renal impairment:
• No dosage adjustment is necessary for people with mild-to-moderate renal impairment.
• For people with severe renal impairment (estimated creatinine clearance < 30 mL/min), the recommended dose is varenicline 1 mg once daily. Dosing should begin at 0.5 mg once a day for the first 3 days, then increased to 1 mg once daily.
• Varenicline is not recommended for people who have end-stage renal disease.

[ABPI Medicines Compendium, 2008]

• The most common adverse effect is nausea, which usually occurs early in the treatment period. Nausea is mild-to-moderate in severity and seldom results in discontinuation of treatment [ABPI Medicines Compendium, 2008].
• Other common adverse effects include headache, insomnia, abnormal dreams, increased appetite, somnolence, dizziness, vomiting, constipation, diarrhoea, abdominal distension and discomfort, dyspepsia, flatulence, dry mouth, and fatigue [ABPI Medicines Compendium, 2008].
• Post-marketing cases of myocardial infarction have been reported in people taking varenicline. No causal relationship has been established [ABPI Medicines Compendium, 2008].
• Driving: varenicline may cause dizziness and somnolence, and therefore may influence the ability to drive and use machines. People are advised not to drive, operate complex machinery, or engage in other potentially hazardous activities until it is known whether varenicline affects their ability to perform these activities [ABPI Medicines Compendium, 2008].
• Psychiatric illness: depression has been reported in people using varenicline who are trying to stop smoking, and symptoms of depression may include suicidal thoughts and behaviour [MHRA, 2008a]. Suicidal thoughts and behaviour have been reported in users of varenicline who have no known pre-existing psychiatric conditions, and while they continue to smoke.
• A more recent nested cohort study which used the General Practice Research Database found no clear evidence that varenicline was associated with an increased risk of fatal or non-fatal self-harm [Gunnell et al, 2009]. However, a two-fold increased risk cannot be ruled out on the basis of the upper 95% confidence interval (CI) [MHRA, 2009a]. Compared with NRT:
• The hazard ratio for self-harm in people prescribed varenicline was 1.12 (95% CI 0.67–1.88).
• The hazard ratio for self-harm in people prescribed bupropion was 1.17 (95% CI 0.59–2.32).
• The hazard ration for suicidal thoughts in people prescribed varenicline was 1.43 (95% CI 0.53–3.84).
• There was no evidence that varenicline was associated with increased risk of depression (hazard ratio 0.88, 95% CI 0.77–1.00).
• The MHRA has issued the following advice for healthcare professionals [MHRA, 2008b]:
• Patients should be told to stop treatment and contact their doctor immediately if they develop suicidal thoughts or behaviour.
• Varenicline should be stopped immediately if agitation, depressed mood, or changes in behaviour are observed that are of concern to the patient, family, or caregivers.
• The safety and efficacy of varenicline in people with serious psychiatric illness have not been established. Patients who have a history of psychiatric illness should be monitored closely while taking varenicline.

• Varenicline has no known clinically meaningful drug interactions.
• The safety and efficacy of varenicline in combination with other smoking cessation treatments have not been studied.

[ABPI Medicines Compendium, 2008]

• Polycyclic aromatic hydrocarbons found in tobacco smoke are potent inducers of the hepatic enzymes CYP1A1 and CYP1A2.
• Levels of drugs metabolized by these enzymes are therefore lower in people who smoke, and will rise once the effect of induction wears off (about 1 week) after smoking cessation.
• During smoking cessation:
• Check whether the person is taking a medicine that interacts with smoking cessation.
• The most clinically important interactions are with theophylline, olanzapine, clozapine, caffeine, and warfarin.
• Monitor for adverse effects after smoking cessation.
• Adjust dose if necessary.
• Dose adjustment is not usually necessary in situations where there is temporary smoking cessation for 1 week or less (e.g. during an acute hospital stay).

[MHRA, 2009b]