The following information is based on the successful use of pharmacological agents in the cessation of smoking in the general population. None of the following agents have been studied in large placebo-controlled studies in cancer patients for aid in smoking cessation. Dosage adjustments or titrations may be required when administering these agents to oncology patients. (Refer to Table 1 through Table 6 for more information.)
Nicotine Replacement Therapies
Nicotine replacement therapies are designed to aid in the treatment of withdrawal symptoms associated with nicotine. Several precautions must be considered before therapy is initiated, but these precautions do not constitute absolute contraindications.
- Patients who are pregnant or nursing should obtain advice from a health care professional before using these products.
- Patients should be advised to not use these products if they continue to smoke, chew tobacco, use snuff, or use other nicotine-containing products.
- Patients should be instructed to consult a physician before using these products if they are younger than 18 years, have heart disease or an irregular heartbeat, have high blood pressure not controlled by medication, have a history of or currently have esophagitis or peptic-ulcer disease, use insulin for diabetes, or take prescription medications for depression or asthma.
|Rx = prescription.|
|Rx||Nicotrol NS||≤40 mg/d||Local irritation||Use ≤3 months.|
|Rx||Nicotrol Inhaler||Individualized||Local irritation||Use ≤24 weeks.|
|OTC = over the counter.|
|OTC||Nicorette||18–24 mg/d||Sore throat, stomatitis||≤30 pieces/d; decrease 1 piece every 4–7 days.|
|OTC||Nicorette DS||36–48 mg/d||Jaw ache||≤20 pieces/d; decrease 1 piece every 4–7 days.|
|OTC = over the counter.|
|OTC||Commit||40–80 mg/d||Local irritation (warmth and tingling)||Use for 12 weeks; ≤20 lozenges/d. Weeks 1–6: 1–2 lozenges every 1–2 hours; weeks 7–9: 1 lozenge every 2–4 hours; weeks 10–12: 1 lozenge every 4–8 hours.|
|OTC = over the counter; Rx = prescription.|
|Rx||Habitrol||7–21 mg/d||Erythema||Use for 6–12 weeks.|
|OTC||NicoDerm CQ||7–21 mg/d||Pruritus||Use for 6–12 weeks.|
|OTC||Nicotrol||5–15 mg/d||Burning at site||Use for 14–20 weeks.|
|Rx||ProStep||11–22 mg/d||Local irritation||Use for 6–12 weeks.|
Other Pharmacological Treatments
Other pharmacological treatments include agents targeting nicotine receptors (e.g., varenicline) and agents targeting neurotransmitters (e.g., bupropion HCl) involved in the pathogenesis of nicotine withdrawal and craving. Fluoxetine HCl (Prozac) has also been studied as a treatment for smoking cessation. All three of these treatments carry boxed warnings.
Varenicline is a nicotinic acetylcholine receptor partial agonist and the first U.S. Food and Drug Administration (FDA)–approved prescription pharmacologic agent targeted to these nicotinic receptors.[Level of evidence: I] Although specific mechanisms of action are unknown, it is thought that the agonist properties result in reduced craving and withdrawal by stimulating the release of dopamine and that the antagonist properties prevent inhaled nicotine from binding at the nicotinic receptor sites.
At least 12 published randomized, controlled trials have evaluated varenicline versus placebo (or other approved agents for smoking cessation) for its ability to affect abstinence rates related to smoking or the use of smokeless tobacco.[2,4-14] All studies were relatively large (129–607 patients per arm) and involved multiple sites and countries. In all studies, varenicline was statistically better in achieving abstinence rates as assessed by self-report and carbon monoxide measures than was placebo, and was often better than the other approved smoking cessation comparator arm. Abstinence rates at 12 weeks can be expected to range from 44% to 49% for varenicline versus 11% to 17% for placebo; longer-term rates (52 weeks) range from 14% to 22% for varenicline versus 4% to 8% for placebo.
Most studies evaluated varenicline 1 mg twice a day, using a 1-week titration of 0.5 mg daily for 3 days, 0.5 mg twice a day for 4 days, and then 1 mg twice a day for 11 weeks. However, a few studies evaluated different doses, such as 0.3 mg or 0.5 mg daily or 0.5 mg twice a day, and one study evaluated a flexible dosing schedule during weeks 2 to 12 after all participants were titrated up to 1 mg twice a day in an open-label fashion. From these data, varenicline 0.5 mg twice a day appears to be the minimum dose required to achieve statistically significantly better abstinence rates over placebo.[9,10]
Most studies included healthy smokers, i.e., those without significant comorbidities such as cardiovascular disease or psychiatric disease. One study evaluated varenicline in patients with chronic obstructive pulmonary disease, and another study focused on patients with stable cardiovascular disease. However, no studies have evaluated varenicline use in cancer populations.
More than 3,000 patients in clinical trials have received varenicline 1 mg twice a day for 12 to 24 weeks. The side effect profile across these 12 studies [2,4-14] was very consistent (although incidence varied) and comprised the following:
- Nausea (13%–52%).
- Insomnia (10%–35%).
- Headache (8%–24%).
- Abnormal dreams (6%–22%).
- Dyspepsia (6%–13%).
- Constipation (7%–12%).
- Flatulence (6%–12%).
- Fatigue or somnolence (6%–10%).
Cardiovascular events often occurred as frequently in the placebo and nicotine replacement arms as in the varenicline arm and overall were rare.
Only one study evaluated varenicline in patients with stable cardiovascular disease. At week 24, this study demonstrated 7-day abstinence rates of 34.9% for varenicline versus 15.9% for placebo (P < .0001); at week 52, these rates were 27.9% for varenicline and 15.9% for placebo (P = .0001). The prevalence of any adjudicated cardiovascular event was 7.1% in the varenicline arm and 5.7% in the placebo arm, for a difference of 1.4%.
The dose-finding trial and package insert provide evidence that the incidence of adverse events is somewhat dose dependent.[10,15] It is not known, however, whether cardiovascular risks—in particular, in patients with cardiac comorbidities—are dose related because the study that evaluated varenicline in patients with stable cardiovascular disease studied varenicline at only the dose of 1 mg twice a day. This is an area in need of investigation.
In June 2011, the FDA updated the prescribing information label for varenicline to warn that the drug may increase the risk of cardiovascular adverse events in patients who have cardiovascular disease. In December 2012, the FDA updated the drug safety information for varenicline to include the results of a large meta-analysis that evaluated cardiovascular adverse events in patients who received either varenicline or placebo. Although a higher occurrence of adverse cardiovascular events that was not statistically significant was reported, there was an increased risk in patients using varenicline over those treated with placebo.
In a pooled analysis of two randomized studies (N = 2,052) in which varenicline was directly tested against bupropion SR and a placebo, results showed continuous abstinence rates of 44% with varenicline, 29.7% with bupropion SR, and 17.7% with placebo at weeks 9 through 12. Abstinence rates were followed through week 52 at study end, with varenicline at 22.4%, bupropion SR at 15.4%, and placebo at 9.3%. Factors found in previous studies to predict better quit rates—such as being older, being male, having a lower level of nicotine dependence, smoking fewer cigarettes at baseline, and having the first cigarette of the day at a later time—were not found to be predictive of higher quit rates in this pooled analysis.
Bupropion hydrochloride (HCl)
Also used as an antidepressant, bupropion HCl (Zyban) is a non-nicotine aid to smoking cessation. It is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine and does not inhibit monoamine oxidase. The exact mechanism by which bupropion HCl enhances the ability of patients to abstain from smoking is unknown; however, it is presumed that this action is mediated by noradrenergic or dopaminergic mechanisms. One study [Level of evidence: I] failed to find any additional value of bupropion HCl in reducing relapse in individuals using the nicotine patch compared with a placebo either as part of a relapse prevention program (after the end of successful patch therapy) or as a second-level treatment for individuals who were still smoking after nicotine-patch therapy.
|bid = twice a day; HCl = hydrochloride; Rx = prescription; SR = sustained release.|
|aClinicians need to closely monitor all patients taking varenicline and bupropion hydrochloride (HCl). The premarketing smoking cessation studies of these medications excluded patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, and major depressive disorder), suggesting that the safety of these medications for these patients has not been investigated.[15,20] Therefore, during smoking cessation, patients with preexisting psychiatric illness who are receiving varenicline and bupropion HCl for smoking cessation need to be especially monitored.|
|Rx||Chantix (varenicline)||0.5 mg/d, days 1–3; 0.5 mg bid, days 4–7; then 1.0 mg bid through week 12||Nausea, insomnia||Risk of toxicity higher in patients with impaired renal function.|
|Not tested in children and pregnant women.|
|Rx||Zyban (bupropion HCl)||150 mg/d × 3 days, then increase to 300 mg/d × 7–12 weeks||Insomnia, dry mouth, dizziness, rhinitis||Do not take with Wellbutrin or Wellbutrin SR.|
|Higher incidence of seizures in patients treated for bulimia or anorexia.|
Risk of neuropsychiatric events with varenicline and bupropion
There are concerns that varenicline and bupropion HCl may be associated with an increased risk of depression and other neuropsychiatric events, including suicidal behaviors.[15,21] This concern is based on postmarketing reports and post hoc analyses.[15,21] Attempted and completed suicides have also been reported in patients taking these medications. These neuropsychiatric events have been reported in patients with or without preexisting psychiatric illness.
In July 2009, on the basis of the continued review of postmarketing adverse event reports, the FDA required the manufacturers of both varenicline and bupropion HCl to add a boxed warning to the product labeling. The warning describes the risk of the following neuropsychiatric events from postmarketing reports:[15,20]
- Changes in mood (including depression and mania).
- Homicidal ideation.
- Suicidal ideation, suicide attempts, and completed suicides.
The warning acknowledges that nicotine withdrawal related to smoking cessation may contribute to these neuropsychiatric events. The warning also acknowledges that causality between the medication exposure and these events cannot be conclusively established and states that the risks of these medications should be weighed against the potential health benefits of quitting smoking.
Although bupropion HCl (Zyban) is the only FDA-approved antidepressant for smoking cessation, fluoxetine HCl (Prozac) has been studied and shown to be effective in individuals with a history of depression. People with active depression were not included in the trial.[Level of evidence: I] However, fluoxetine HCl also carries a boxed warning describing an increased risk of suicidality in adults younger than 25 years. (Refer to the Depression and Suicide section in the PDQ summary on Pediatric Supportive Care for more information.)
|HCl = hydrochloride; Rx = prescription.|
|Rx||Prozac||30–60 mg/d||Insomnia, dizziness, anorexia, sexual dysfunction, confusion||Limited data available on use in combination with cognitive-behavioral therapy.|
Lobeline (Bantron) is classified as a category III agent by the FDA (safe but no proven effectiveness). This product is not recommended for use in any smoking cessation program because of its lack of efficacy.
- Fincham JE: Smoking cessation products. In: Covington TR, Berardi RR, Young LL, et al., eds.: Handbook of Nonprescription Drugs. 11th ed. Washington, DC: American Pharmaceutical Association, 1996, pp 715-723.
- Tonstad S, Tønnesen P, Hajek P, et al.: Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 296 (1): 64-71, 2006. [PUBMED Abstract]
- Nides M, Glover ED, Reus VI, et al.: Varenicline versus bupropion SR or placebo for smoking cessation: a pooled analysis. Am J Health Behav 32 (6): 664-75, 2008 Nov-Dec. [PUBMED Abstract]
- Aubin HJ, Bobak A, Britton JR, et al.: Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 63 (8): 717-24, 2008. [PUBMED Abstract]
- Fagerström K, Gilljam H, Metcalfe M, et al.: Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial. BMJ 341: c6549, 2010. [PUBMED Abstract]
- Gonzales D, Rennard SI, Nides M, et al.: Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296 (1): 47-55, 2006. [PUBMED Abstract]
- Nakamura M, Oshima A, Fujimoto Y, et al.: Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 29 (6): 1040-56, 2007. [PUBMED Abstract]
- Niaura R, Hays JT, Jorenby DE, et al.: The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial. Curr Med Res Opin 24 (7): 1931-41, 2008. [PUBMED Abstract]
- Nides M, Oncken C, Gonzales D, et al.: Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 166 (15): 1561-8, 2006 Aug 14-28. [PUBMED Abstract]
- Oncken C, Gonzales D, Nides M, et al.: Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 166 (15): 1571-7, 2006 Aug 14-28. [PUBMED Abstract]
- Rigotti NA, Pipe AL, Benowitz NL, et al.: Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 121 (2): 221-9, 2010. [PUBMED Abstract]
- Tashkin DP, Rennard S, Hays JT, et al.: Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial. Chest 139 (3): 591-9, 2011. [PUBMED Abstract]
- Tsai ST, Cho HJ, Cheng HS, et al.: A randomized, placebo-controlled trial of varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 29 (6): 1027-39, 2007. [PUBMED Abstract]
- Williams KE, Reeves KR, Billing CB Jr, et al.: A double-blind study evaluating the long-term safety of varenicline for smoking cessation. Curr Med Res Opin 23 (4): 793-801, 2007. [PUBMED Abstract]
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- U.S. Food and Drug Administration: FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of cardiovascular adverse events. Rockville, Md: U.S. Food and Drug Administration, 2012. Available online. Last accessed June 12, 2014.
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