Pharmacological Treatment

Nicotine Replacement Therapies
Varenicline (Chantix)
Bupropion Hydrochloride (HCl)
Fluoxetine HCl
Lobeline (Bantron)
Summary

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 Tables 1 through 7 for more information.)

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.[1]

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.[2][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 release of dopamine, and the antagonist properties prevent inhaled nicotine from binding at the nicotinic receptor sites.[3]

In a pooled analysis of two randomized studies (total N = 2,052) in which varenicline was directly tested against bupropion SR and a placebo,[3] 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 baseline cigarettes, 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.[3]

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.[4] The change is based on findings from a clinical trial of 700 smokers who had cardiovascular disease.

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.[5] One study [6][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.

There are concerns that varenicline and bupropion HCl may be associated with an increased risk of depression and other neuropsychiatric events, including suicidal behaviors.[7,8] This concern is based on postmarketing reports and post hoc analyses.[7,8] Attempted and completed suicides have also been reported in patients taking these medications.[9] These neuropsychiatric events have been reported in patients with or without preexisting psychiatric illness.

In July 2009, the FDA required the manufacturers of both varenicline and bupropion HCl to add a boxed warning to the product labeling, based on the continued review of postmarketing adverse event reports.[9] The warning describes the risk of the following neuropsychiatric events from postmarketing reports:[7,9]

• Changes in mood (including depression and mania).
• Psychosis.
• Hallucinations.
• Paranoia.
• Delusions.
• Homicidal ideation.
• Hostility.
• Agitation.
• Anxiety.
• Panic.
• 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.

It is recommended that clinicians closely monitor all patients taking varenicline and bupropion 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.[7,9] Therefore, during smoking cessation, it is important to especially monitor patients with preexisting psychiatric illness who are receiving varenicline and bupropion HCl for smoking cessation.

Patients can be carefully matched to specific smoking cessation strategies. Some smokers can quit with the help of counseling or psychological interventions, while others might need nicotine replacement therapies. Some smokers might need medications to successfully quit smoking. Given the significant health benefits derived from smoking cessation, medications can be used in these patients with careful monitoring.

Although bupropion HCl (Zyban) is the only FDA-approved antidepressant for smoking cessation, fluoxetine HCl (Prozac) has been studied and shown to be effective.[5][Level of evidence: I] However, fluoxetine HCl also carries a boxed warning describing an increased risk of suicidality in adults younger than 25 years.[10] (Refer to the Depression and Suicide section in the PDQ summary on Pediatric Supportive Care for more information.)

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.[11]

• Continued smoking substantially increases the likelihood of recurrence or occurrence of a second cancer in survivors, particularly in those who received radiation therapy.

• Most patients with smoking-related cancer appear motivated to quit smoking at the time of diagnosis.

• A stepped-care approach is recommended, with strong physician advice and brief counseling to quit and provision of basic information to all patients at each contact during the first month of diagnosis, followed by more intensive treatment (pharmacologic and counseling by a smoking specialist) for those having difficulty quitting or remaining abstinent.

References

1. 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. 
   
   
2. 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]
   
   
3. 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]
   
   
4. U.S. Food and Drug Administration.: FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease. Silver Spring, Md: U.S. Food and Drug Administration, 2011. Available online. Last accessed January 6, 2012. 
   
   
5. Hitsman B, Pingitore R, Spring B, et al.: Antidepressant pharmacotherapy helps some cigarette smokers more than others. J Consult Clin Psychol 67 (4): 547-54, 1999.  [PUBMED Abstract]
   
   
6. Hurt RD, Krook JE, Croghan IT, et al.: Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking. J Clin Oncol 21 (5): 914-20, 2003.  [PUBMED Abstract]
   
   
7. CHANTIX (varenicline) Tablets. New York, NY: Pfizer Inc., 2011. Available online. Last accessed January 6, 2012. 
   
   
8. Hughes JR: Smoking and suicide: a brief overview. Drug Alcohol Depend 98 (3): 169-78, 2008.  [PUBMED Abstract]
   
   
9. U.S. Food and Drug Administration.: Information for Healthcare Professionals: Varenicline (Marketed as Chantix) and Bupropion (Marketed as Zyban, Wellbutrin, and Generics). Rockville, Md: U.S. Food and Drug Administration, 2009. Available online. Last accessed January 6, 2012. 
   
   
10. U.S. Food and Drug Administration.: Antidepressant Use in Children, Adolescents, and Adults. Rockville, Md: Food and Drug Administration, Center for Drug Evaluation and Research, 2007. Available online. Last accessed January 4, 2012. 
    
    
11. Drug Facts and Comparisons. St. Louis, Mo: Facts and Comparisons, 1998.