Consultant. patient care through drug education

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1 The Improving Consultant patient care through drug education December 2017 Volume XXVI Number 11 Smoking Cessation For the Busy Clinician 2 Robin L. Corelli, PharmD, Lisa A. Kroon, PharmD and Karen S. Hudmon, DrPH, MS, RPh Hours CE Introduction More than 50 years after the landmark 1964 Surgeon General s Report on the health consequences of smoking, 1 an estimated 15% of adult Americans still smoke. 2 Smoking remains the leading cause of preventable death in the United States accounting for 480,000 deaths per year (1 of every 5. People who quit smoking greatly reduce their risk for tobacco-related diseases, including cancer, heart disease, and lung disease, while also increasing life expectancy and improving quality of life. 3 Each year, the economic costs due to tobacco use, including direct medical care and lost productivity, exceed $289 billion. 3 For each pack of cigarettes sold, the societal costs due to smoking-related health care costs and lost productivity are estimated at $19.16 per pack, nearly 3 times the average cost of a pack of cigarettes ($ The good news is that 68% of all adults who smoke want to quit. 5 Effective treatments are available medications, behavioral counseling, or both with successful quit rates of around 20-37% at least 6 months after quitting. 6 However, most patients attempt to quit unassisted (without using proven cessation treatments. During 2015 only about one third of smokers used behavioral counseling and/or medications to assist them when trying to quit. 5 Over the past several years, research has guided our clinical approach to treating tobacco use and dependence. When used correctly, the FDA-approved medications for smoking cessation approximately double the likelihood of quitting. Further benefit is seen when medications are combined with behavioral counsel- About The Authors Robin L. Corelli, PharmD, Professor of Clinical Pharmacy, Department of Clinical Pharmacy, at the University of California, San Francisco, School of Pharmacy. Lisa A. Kroon, PharmD, Chair of the Department of Clinical Pharmacy and Professor of Clinical Pharmacy at the University of California, San Francisco, School of Pharmacy; Co-Director of the Fontana Tobacco Treatment Center at UCSF Health. Karen S. Hudmon, DrPH, MS, RPh, Professor of Pharmacy Practice at Purdue University, West Lafayette, Indiana and Professor of Clinical Pharmacy at the University of California, San Francisco. All authors helped develop "Rx for Change," a nationally recognized clinician-assisted tobacco cessation training program. The Bottom Line Cigarette smoking is the leading preventable cause of premature death in the US. Because many patients desire to quit smoking, clinicians can play an important role in the process. Effective medications are available, including nicotine replacement therapy (NRT products (gum, lozenge, patch, nasal spray, and oral inhaler, combination NRT (eg, patch plus gum, lozenge, nasal spray or oral inhaler, sustained-release (SR bupropion, and varenicline. Unless medically contraindicated, all patients who are trying to quit should be encouraged to use 1 or more FDA-approved medications. Medication therapy should be combined with behavioral counseling to further increase patients chances for success. What You Can Do For the busy clinician, Ask-Advise-Refer: ask all patients about tobacco use, advise tobacco users to quit, and refer tobacco users who are ready to quit (eg, in the next month to other resources and programs. In states where authorized, become engaged in prescribing smoking cessation medications. In other states, become active in promoting legislation for prescribing of smoking cessation medications. Consider smoking cessation counseling as part of routine services, similar to immunizations and diabetes care. ing. 6-8 Although more intensive interventions provide higher quit rates, even brief advice from healthcare providers as few as 3 minutes has been shown to have an impact on patients likelihood of quitting. 6 Disclosure: Dr. Corelli, Dr. Kroon, and Dr. Hudmon report no financial relationship with the manufacturer(s or provider(s of any commercial product(s or service(s that appear in this issue.. 1

2 Continuing Education Objectives ACPE# H01-P CA BRN# After reading this article, the clinician should be able to: 1. Discuss tobacco dependence and the symptoms of withdrawal from nicotine. 2. List the 5 key components of comprehensive smoking cessation counseling. Apply the abbreviated Ask-Advise-Refer counseling approach. Be familiar with smoking cessation resources for patient referral. 3. Assist patients with smoking cessation product selection and dosing based on tobacco use history. Discuss the advantages and disadvantages of each product. Describe the types of patients who might benefit from combination therapy. 4. Discuss the contraindications and potential adverse effects of the FDA-approved medications for smoking cessation. Tobacco Dependence & Withdrawal While US cigarettes generally contain mg of nicotine, most smokers absorb only 1-2 mg of nicotine per cigarette. 9 Nicotine is readily absorbed across the respiratory tract epithelium, buccal mucosa (cheek, and skin. After inhalation, nicotine reaches the brain in about seconds, 10 resulting in the rapid onset of behaviorallyreinforcing effects on the nervous system, including pleasure, relief of anxiety, improved repetitive task performance, improved memory, mood modulation, and skeletal muscle relaxation. 11 In the absence of nicotine, these positive effects give way to negative withdrawal effects among dependent tobacco users. Withdrawal symptoms include anger, irritability, anxiety, difficulty concentrating, drowsiness, fatigue, hunger, weight gain, impatience, and restlessness. These symptoms typically manifest hours after cessation and gradually diminish over 2-4 weeks. 12 However, cravings for tobacco can persist for months to years after quitting. 13 Helping Patients Quit The US Public Health Service Clinical Practice Guideline for Treating Tobacco Use and Dependence 6 recommends 5 key components of comprehensive tobacco cessation counseling. Known as the 5 A s, these are: 1 Ask all patients whether they use tobacco, 2 Advise all tobacco users to quit, 3 Assess tobacco users readiness to quit, 4 Assist patients with the quitting process, and 5 Arrange follow-up care. When time, logistics, or lack of expertise are not conducive to providing comprehensive tobacco cessation counseling, clinicians are encouraged to implement an abbreviated approach. Ask about tobacco use, Advise tobacco users to quit, and Refer patients who are ready to quit in the next month to other resources. Even the busiest of clinicians can have an important role in initiating the quitting process for patients who smoke. Ask: Because smoking interacts with many medications, 14,15 and contributes to the onset or exacerbation of many medical conditions, it is important for providers to ask about tobacco use as part of the medication history. (See Table 1 for examples of drug interactions with tobacco smoke; see the Appendix for a comprehensive list. Tobacco use status (current, former, never and level of use (eg, number of cigarettes per day should be documented in the patient s medical record and/or pharmacy patient profile. Suggested phrases include: Do you smoke or use any type of tobacco or electronic nicotine delivery system (ENDS such as an e-cigarette? or Smoking interacts with many medications. It s important to know whether you smoke tobacco, so we can adjust your dosages if necessary. Failure to ask patients about tobacco use might imply that it is not clinically relevant or that quitting is not important. Advise: Providers should advise all tobacco users to quit. This advice should be clear, strong, personalized, and delivered in a tone conveying concern for the patient s health and a commitment to help with quitting when the Table 1. Examples of Significant Drug Interactions With Tobacco Smoke 14 Drug / Class Caffeine Clopidogrel (Plavix Hormonal contraceptives (combined Olanzapine (Zyprexa Mechanism of Interaction and Effects metabolism (induction of CYP1A2; clearance (56%. Caffeine levels will likely following cessation of smoking. metabolism (induction of CYP1A2 of clopidogrel to its active metabolite; clopidogrel s effects are enhanced in smokers ( 10 cigarettes/day. While improved clinical outcomes have been shown (smokers paradox; may be dependent on CYP1A2 genotype; smoking may also risk of bleeding. risk of cardiovascular adverse effects (eg, stroke, heart attack, thromboembolism in women who smoke; risk with age (especially 35 years old and with heavy smoking ( 15 cigarettes/day. Ortho Evra patch users have 2-fold risk of venous thromboembolism compared to OC users, likely due to estrogen exposure (60% higher levels. metabolism (induction of CYP1A2; clearance (40%; plasma concentrations (by 12%; smokers may need dosages. Abbreviations: CYP, cytochrome P450; OC, oral contraceptive 2

3 Smoking Cessation Counseling Tips patient is ready. Personalize advice by linking the importance of quitting to the individual s health status, medication use for conditions caused or exacerbated by smoking, readiness to quit, tobacco s social and economic costs, and the effects of tobacco use on others. One suggested phrase is Quitting is the single most important thing you can do to improve your health now and in the future, and I strongly encourage you to quit. What are your thoughts about this? Refer: Quitting tobacco often requires a multi-component treatment plan involving 1 or more medications and behavioral counseling. The inset provides tips for assisting patients with cessation. Although busy clinicians can prescribe medications with minimal time commitment, behavioral therapy can require significant time. In the absence of time or expertise for providing comprehensive behavioral counseling, patients can be referred to other resources, such as those listed in the Patient Connection. The following phrases can be used by clinicians to provide patient referrals: Consider calling the tobacco quitline, at QUIT-NOW. Smoking cessation specialists will give you personalized help, by telephone, at no cost, or Here s a list of resources to consider. We can review the list, and we can discuss which would be best for you. Telephone quitlines are a primary resource to assist patients with the quitting process. These services provide one-on-one counseling, self-help materials, and individualized cessation information at no charge to patients. Quitlines are capable of serving a broad, diverse population, reaching patients who might otherwise have limited access to medical care because of geographic location, lack of insurance, language barriers, or financial resources. There is a significant, increased odds of quitting among patients who receive counseling from a quitline, and the odds are increased further with the addition of drug therapy. 6,16 Update on Pharmacy-Based Smoking Cessation Legislation In recent years, the role of the pharmacist in tobacco cessation has evolved through national efforts to enhance pharmacy school graduates capacity to help patients quit. 17 State-specific initiatives have also advanced legislation in support of pharmacists prescriptive authority for smoking cessation medications. 18 As of September 2017, 8 states allow, or are in the process of developing legislation that allow, autonomous models for prescribing of smoking cessation medications by either statewide protocols (Arizona 19, California 20, Colorado 21, Indiana 22, Maine 23, New Mexico 24, Oregon 25 or independent prescribing (Idaho 26. Four states (CO, ID, IN, NM currently include all 7 FDA-approved medica- What type and amount of tobacco is used? Necessary for determining NRT dosing and for understanding the patient s level of nicotine addiction. Review previous quit attempts What worked, what didn t? Why or why not? Assess adequacy of dose, adherence, and treatment duration with previous regimens. Understand patient's beliefs about the various medications for quitting before recommending therapy. Help identify reasons for the last relapse and techniques to avoid it. How much confidence do you have in your ability to quit? Patients must believe that they are able to quit. If not, failure is likely. Work with patients to build confidence. Patients should be advised to set a quit date only if they are ready to do so. Ask about use of electronic nicotine delivery systems (ENDS. ENDS (eg, electronic cigarettes, vape pens are battery-operated devices that heat a nicotine solution and generate a vapor that is inhaled by the user. While there are substantially lower concentrations of some toxins in ENDS aerosols compared to tobacco smoke, there is insufficient evidence to recommend these devices as a safe and effective approach for smoking cessation. Discuss medication options and consider potential contraindications to drug therapy. Consider patients' willingness to use a medication for quitting. Encourage use of medication, particularly for patients who have been unsuccessful in prior quit attempts. Discuss pros and cons of different options; rule out medications that are medically contraindicated or otherwise not acceptable to a patient. Let the patient decide which therapy to use. If an NRT product is selected, assess ability to adhere to frequent dosing (eg, 9 or more times daily with short-acting NRT formulations (gum, lozenge, nasal spray, inhaler. If adherence is a challenge, consider the nicotine patch, bupropion SR, or varenicline, which are dosed once or twice a day. Combination therapy is also an option that should be considered. Counsel on appropriate use of medication(s. For patients who are ready to quit and have selected a medication(s, provide instructions for proper use, emphasizing the importance of adherence with the treatment regimen. Counsel patients taking bupropion SR or varenicline to start treatment early (1-2 weeks before the quit date for bupropion SR and 1 week before the quit date for varenicline. Strongly advise patients to seek additional professional advice; provide a referral (quitline, local group program, web-based program, etc. to address the behavioral aspects of quitting: Advise patients that these programs will help them with reasons and motivations for quitting, routines and triggers associated with tobacco use, selecting a quit date, coping strategies, social support, withdrawal symptoms and cravings, weight gain concerns, and ongoing support for quitting (relapse prevention. Commend and reinforce patients decision to quit. Discuss the importance of receiving follow-up care, as a way to maximize chances for long-term success and improved health. The Rx Consultant (ISSN is published monthly except August for $127 per year by CEN, Inc. PO Box 1516, Martinez, CA Periodicals Postage Paid at Martinez, CA and additional mailing offices. POSTMASTER: Send address changes to THE RX CONSULTANT, P.O. Box 1516, Martinez, CA

4 tions for smoking cessation, and 3 states (AZ, CA, ME include nicotine replacement therapy products only. As of September 2017, Oregon's protocol was under development. For most state protocols, pharmacists must complete an approved tobacco cessation training program, and specific elements are required for cessation interventions provided to patients (eg, patient screening, healthcare provider notification, cessation intervention components, and documentation. This advancement in pharmacists scope of practice provides greater access to care for patients who want to quit, while circumventing barriers associated with seeing a prescriber for prescription-only medications. Drug Therapy FDA-approved first-line agents for smoking cessation include 5 dosage forms of nicotine replacement therapy (NRT, bupropion sustained-release (SR, and varenicline. See Table 2. For many of these agents, the daily costs of medications are comparable to the daily cost of smoking. Indirect comparisons suggest that available NRT products and bupropion SR exhibit comparable efficacy, approximately doubling long-term ( 6 months quit rates compared with placebo. 6,27-29 Evidence suggests that varenicline and combinations of NRT are somewhat more effective, with long-term quit rates nearly 3-fold higher than those observed with placebo 30 (Table 3. Selection of a specific drug for smoking cessation should be individualized, considering factors such as patient preference, previous experience, existing medical conditions, challenges associated with medication adherence, and out-of-pocket treatment costs. Nicotine Replacement Therapy (NRT NRT formulations currently available in the US are the nicotine gum, lozenge, patch, nasal spray, and oral inhaler. Table 2 presents the various products, dosing, adverse effects, advantages, and daily costs of treatment. 14 The use of NRT helps patients with quitting by reducing nicotine withdrawal symptoms while they focus on the behavioral and psychological aspects of smoking. Additionally, because NRT formulations deliver nicotine more slowly and at lower concentrations, patients become less accustomed to the nearly immediate, reinforcing effects of inhaled tobacco. Contrary to widespread belief, NRT is not contraindicated in patients with a history of cardiovascular disease. Although nicotine can increase heart rate and blood pressure, and is a coronary vasoconstrictor 31, a meta-analysis of randomized trials found no significant increase in the incidence of serious cardiovascular events among patients receiving NRT compared with placebo. 32 NRT also does not appear to increase the risk of serious cardiovascular events in patients with preexisting cardiovascular disease However, these trials specifically excluded patients with unstable angina (angina that is worsening or that occurs with little or no physical exertion, serious arrhythmias, and recent heart attacks. Due to the lack of safety data, the Clinical Practice Guideline recommends that NRT be used with caution among patients who are in the immediate (within 2 weeks period after a heart attack, those with serious arrhythmias, and those with unstable angina. 6 Despite this caution, evidence suggests the risks of NRT use in patients with cardiovascular disease are minimal relative to the risks of continued smoking. 28,31,32 NRT should also be used with caution in women who are pregnant or lactating. Animal studies suggest that nicotine is harmful to the developing fetus, 36 and all prescribing and usage information for nicotine formulations carry warnings about use during pregnancy. Although NRT might pose risk, the danger is considered to be less than risks associated with continued smoking, because the exposure to nicotine is significantly lower, and the fetus is not exposed to other toxins in tobacco smoke (eg, carbon monoxide, heavy metals, carcinogens. 36,37 However, because it is assumed that NRT can cause fetal harm, and there is insufficient evidence establishing effectiveness in pregnant women, national guidelines do not recommend its use during pregnancy. 6,38 The American College of Obstetrics and Gynecology endorses counseling, including referral to tobacco quitlines, and recommends the use of NRT only for women who can be closely monitored and demonstrate a clear commitment to quitting. 39 Pregnant women who wish to use NRT should be referred to their obstetrics care provider. Nicotine Polacrilex Gum Nicotine polacrilex gum (Nicorette, others is a resin complex of nicotine and polacrilin in a sugar-free chewing gum base. The gum contains buffering agents (sodium carbonate, sodium bicarbonate to increase salivary ph, thereby enhancing absorption of nicotine across the buccal mucosa. 40 Nicotine plasma levels peak about minutes after chewing a single piece of gum, and approximately 1.0 mg and 2.5 mg of nicotine is absorbed from the 2- and 4-mg gum preparations respectively. 41 Due to the viscous nature of the resin, the nicotine gum should not be used in patients with active temporomandibular joint (TMJ disease. 4

5 Nicotine Polacrilex Lozenge The nicotine polacrilex lozenge (Nicorette, Nicorette Mini, others is a resin complex of nicotine and polacrilin in a sugar-free lozenge that is intended to be sucked and moved from side-to-side in the mouth until fully dissolved. Like the nicotine gum, the lozenge contains buffering agents (sodium carbonate, potassium bicarbonate to increase salivary ph and enhance buccal absorption of nicotine. The lozenge completely dissolves over about minutes with peak nicotine concentrations achieved after minutes of use. The amount of nicotine absorbed from the 2- and 4-mg lozenge formulation is 1.0 mg and 3.2 mg, respectively. 41,42 Transdermal Nicotine Patch The nicotine patch formulations (NicoDerm CQ, others consist of an impermeable surface layer, a nicotine reservoir, an adhesive layer, and a removable protective liner. Nicotine in the patch is well absorbed across the skin, with plasma nicotine concentrations rising slowly over 1-4 hours and peaking within 3-12 hours following application. 43 The currently marketed patches deliver nicotine continuously over 24 hours, and nicotine blood levels fluctuate less than do those achieved with tobacco products or other NRT formulations. Nicotine Nasal Spray The nicotine nasal spray (Nicotrol NS is an aqueous solution of nicotine for administration to the nasal mucosa. 44 Plasma nicotine levels following administration rise rapidly and generally peak within 4-15 minutes. 44,45 Nasal and oropharyngeal irritation are common with the nasal spray; 44 regular use during the first week of treatment can help users adapt to its irritant effects. 44,46 Nicotine nasal spray is not recommended for patients with known chronic nasal disorders (allergic rhinitis, polyps, sinusitis and, because bronchospasm has been reported in patients with asthma, this product is not recommended for use in individuals with severe reactive airway disease (asthma, chronic obstructive pulmonary disease. 44 Nicotine Oral Inhaler The nicotine inhaler (Nicotrol Inhaler consists of a mouthpiece and cartridge delivering nicotine as an inhaled vapor that is absorbed primarily across the oral mucosa and throat; only a small fraction of the dose (less than 5% reaches the lungs. 47 With an intensive inhalation regimen (80 deep inhalations over 20 minutes, about 4 mg of nicotine is delivered, of which 2 mg is absorbed. 47 It generally takes 20 minutes to deplete a cartridge, after which peak plasma nicotine concentrations are achieved approximately minutes later. 48 Because the nicotine vapor might be irritating and provoke bronchospasm, the inhaler should be used with caution in patients with underlying severe reactive airway disease. However, if a patient with airway disease does not experience bronchospasm when smoking, it is unlikely that the inhaler will trigger this. As such, the inhaler remains a viable treatment option in these patients, although the potential side effects should be monitored. Other forms of NRT might be preferable in patients who have severe bronchospastic disease. 47 Bupropion Sustained-Release (SR Bupropion SR (Zyban, generic is hypothesized to promote smoking cessation by blocking the reuptake of dopamine and norepinephrine in the central nervous system, 6 and possibly by acting as a nicotinic receptor antagonist. These neurochemical effects are believed to modulate the dopamine reward pathway and reduce cravings for nicotine and symptoms of withdrawal. Seizures are a dose-related toxicity linked with bupropion use. Clinicians should avoid use in patients who have underlying factors that increase the risk for seizures. See Table 2 for examples of seizure-related contraindications. Caution should be used in patients with other conditions that increase seizure risk (eg, hypoglycemia or with drugs that lower seizure threshold (eg, antipsychotics, tricyclic antidepressants. Bupropion SR should be initiated while the patient is still smoking, because approximately 1 week of treatment is necessary to achieve steady-state therapeutic blood concentrations. The manufacturer suggests a target quit date that falls within the first 2 weeks of treatment. 49 Because bupropion undergoes extensive hepatic metabolism, the dosage should be reduced in patients with liver impairment. The metabolites are eliminated renally, and dosage reduction should be considered in patients with impaired kidney function. Although epidemiological studies in humans suggest that bupropion is not harmful to the developing fetus, the manufacturer recommends behavioral counseling interventions in pregnant smokers before considering bupropion. 49 For patients experiencing side effects (eg, insomnia, difficulty concentrating, tremor, gastrointestinal problems with the 300 mg/day regimen, evidence suggests that 150 mg/day is better tolerated, with comparable long-term (12-month efficacy. 50,51 In 2009, the FDA mandated that the prescribing information for all bupropion-containing products include a boxed warning highlighting the risk of serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide. 52 These additional warnings were based on post-marketing adverse event surveillance reports received by the FDA. 53 The boxed warning was removed in December after a mandated clinical trial found that, 5

6 6, 14, 28, 44, 47, 49, 56, Table 2. FDA-Approved Medications for Smoking Cessation NICOTINE REPLACEMENT THERAPY (NRT FORMULATIONS GUM LOZENGE TRANSDERMAL PATCH NASAL SPRAY ORAL INHALER COMBINATION NRT BUPROPION SR VARENICLINE Dosing Product Nicorette 1, Generic OTC 2 mg, 4 mg 1st cigarette 30 minutes after waking: 4 mg 1st cigarette > 30 minutes after waking: 2 mg Weeks 1-6: 1 piece every 1-2 hours Weeks 7-9: 1 piece every 2-4 hours Weeks 10-12: 1 piece every 4-8 hours Nicorette, 1 Generic Nicorette 1 Mini OTC 2 mg, 4 mg 1st cigarette 30 minutes after waking: 4 mg 1st cigarette > 30 minutes after waking: 2 mg Weeks 1-6: 1 lozenge every 1-2 hours Weeks 7-9: 1 lozenge every 2-4 hours Weeks 10-12: 1 lozenge every 4-8 hours NicoDerm CQ 1 (OTC; Generic (OTC and Rx 7 mg, 14 mg, 21 mg (24-hour release > 10 cigarettes/day: 21 mg/day x 4-6 weeks 14 mg/day x 2 weeks 7 mg/day x 2 weeks 10 cigarettes/day: 14 mg/day x 6 weeks 7 mg/day x 2 weeks Nicotrol NS 2 Rx Metered spray 10 mg/ml nicotine solution 1 2 doses/hour (8 40 doses/day One dose = 2 sprays (one in each nostril; each spray delivers 0.5 mg of nicotine to the nasal mucosa Duration: weeks. Begin using at least 8 doses daily (max 40 daily for 6-8 weeks. Then taper over an additional 4-6 weeks. There is no single best method for dose tapering. Nicotrol Inhaler 2 Rx 10 mg cartridge delivers 4 mg inhaled nicotine vapor 6 16 cartridges/day Individualize dosing; initially use 1 cartridge every 1 2 hours Duration: up to 6 months. Begin using at least 6 cartridges daily (max 16 daily for 3-12 weeks. Then taper the daily number of cartridges used over an additional 6-12 weeks. There is no single best method for dose tapering. Combinations with demonstrated efficacy: Nicotine patch + nicotine gum Nicotine patch + nicotine lozenge Nicotine patch + nicotine nasal spray Nicotine patch + nicotine oral inhaler Reserve for patients smoking 10 cigarettes/day: Long-acting NRT (to prevent onset of severe withdrawal symptoms Nicotine patch 21 mg/day x 4-6 weeks 14 mg/day x 2 weeks 7 mg/day x 2 weeks PLUS Short-acting NRT (to control breakthrough withdrawal symptoms and situational urges for tobacco: Nicotine gum (2 mg 1 piece every 1 2 hours as needed OR Nicotine lozenge (2 mg 1 lozenge every 1 2 hours as needed OR Nicotine nasal spray 1 spray in each nostril every 1 2 hours as needed OR Nicotine inhaler 1 cartridge every 1 2 hours as needed Zyban 1, Generic Rx 150 mg sustained-release tablet 150 mg orally every AM x 3 days, then 150 mg orally twice daily x 7-12 weeks Initiate treatment within 2 weeks before target quit date. Patients who successfully quit after 12 weeks of treatment, but who do not feel ready to discontinue the medication, may be considered for an additional 12 weeks of treatment. Chantix 2 Rx 0.5 mg, 1 mg tablet Days 1-3: 0.5 mg orally each AM Days 4-7: 0.5 mg orally twice daily Weeks 2-12: 1 mg orally twice daily Initiate treatment 1 week before target quit date. Alternatively, may initiate up to 35 days before target quit date. OR may reduce smoking over a 12-week period of treatment prior to quitting and continue treatment for an additional 12 weeks. Adverse Effects Mouth/jaw soreness Hiccups Heartburn, upset stomach Hypersalivation Effects associated with incorrect chewing technique (due to rapid nicotine release: lightheadedness, nausea/vomiting, throat & mouth irritation Mouth irritation Nausea Hiccups Heartburn Headache Sore throat Dizziness Local skin reactions (redness, itching, burning Headache Sleep disturbances (abnormal/ vivid dreams, insomnia; associated with nocturnal nicotine absorption. If bothersome, remove patch at bedtime, and apply a new one in the AM Nasal and/or throat irritation (hot, peppery, or burning sensation Rhinitis Ocular irritation; tearing Sneezing Cough Headache Mouth and/or throat irritation Cough Headache Rhinitis Upset stomach Hiccups See adverse effects listed for individual agents Insomnia Nausea Dry mouth Rhinitis Dizziness Rash Constipation Difficulty concentrating Seizures (risk is 0.1% Nervousness/anxiety Serious neuropsychiatric symptoms (rare 3 Nausea Vomiting Sleep disturbances (insomnia, abnormal/vivid dreams, sleepwalking Constipation Flatulence Serious neuropsychiatric symptoms (rare 3 Advantages May provide oral gratification similar to that of smoking Might delay weight gain Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges Relatively inexpensive ($1.90 $3.60 for 9 pieces 4 May provide oral gratification similar to that of smoking Might delay weight gain Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges Relatively inexpensive ($3.33 $3.60 for 9 pieces 4 Once-daily dosing associated with fewer adherence problems Of all NRT products, its use is least obvious to others Can be used in combination with other agents; delivers consistent nicotine levels over 24 hours Relatively inexpensive ($1.52 $2.90 per patch 4 Can be titrated to rapidly manage withdrawal symptoms Can be used in combination with other agents to manage situational urges May provide oral gratification similar to that of smoking Mimics hand-to-mouth ritual of smoking Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges Patch provides consistent nicotine levels over 24 hours, and short-acting products allow patients to titrate therapy to manage withdrawal symptoms and situational urges Combination therapy provides statistically significant increases in success rates compared to single-agent NRT Attractive option for patients who have previously failed treatment with monotherapy Preferred approach for patients unable to adhere to monotherapy with short-acting NRT formulations (gum, lozenge, inhaler, nasal spray due to the need for frequent dosing See advantages listed for individual agents Twice-daily oral dosing is simple and associated with fewer adherence problems compared with NRT Might delay weight gain Might be beneficial in patients with depression Can be used in combination with NRT agents (FDA-approved for use with nicotine patch Relatively inexpensive ($2.58 for 2 generic formulation tablets 4 Twice-daily oral dosing is simple and associated with fewer adherence problems compared with NRT Offers a different mechanism of action for patients who have failed other agents Disadvantages Need for frequent dosing can compromise adherence Might be problematic for patients with significant dental work Proper chewing technique is necessary for effectiveness and to minimize adverse effects Gum chewing might not be acceptable or desirable for some patients Need for frequent dosing can compromise adherence People who chew the lozenges are more likely to experience gastrointestinal side effects (nausea, hiccups, heartburn; these may be bothersome Cannot be titrated to acutely manage withdrawal symptoms Not recommended for use by patients with dermatologic conditions (eg, psoriasis, eczema, atopic dermatitis Need for frequent dosing can compromise adherence Nasal administration might not be acceptable or desirable for some patients; nasal irritation often problematic Not recommended for use by patients with chronic nasal or sinus disorders or severe reactive airway disease Cost of treatment ($8 for 8 doses 4 Need for frequent dosing can compromise adherence Cartridges might be less effective in cold environments ( 60 F Cost of treatment ($13.62 for 6 cartridges 4 Combination therapy is more costly than monotherapy See disadvantages listed for individual agents Seizure risk is d. Use is contraindicated in patients with seizure disorders, history of bulimia or anorexia nervosa, abrupt discontinuation of alcohol or benzodiazepines/ sedatives; caution with other conditions that seizure risk Contraindicated within 14 days after stopping MAOI antidepressants, or concurrently with reversible MAOIs (eg, linezolid; d risk of hypertensive reaction Patients should be monitored for potential neuropsychiatric symptoms 3 Patients should be monitored for potential neuropsychiatric symptoms 3 Cost of treatment ($13.84 for 2 tablets 4 1 Marketed by GlaxoSmithKline. 2 Marketed by Pfizer. 3 In 2009, the FDA mandated that the prescribing information for all bupropion- and varenicline-containing products include a boxed warning highlighting the risk of serious neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior (including attempted suicide. Based on results of a mandated clinical trial, in 2016 the FDA removed the boxed warning; however, these products currently have a similarly worded non-boxed warning. Patients should be advised to stop taking varenicline or bupropion SR and contact their healthcare provider immediately if they experience agitation, depressed mood, or any changes in behavior that are not typical for the patient, or if they develop suicidal thoughts or behavior. If treatment is stopped due to neuropsychiatric symptoms, patients should be monitored until the symptoms resolve. 4 Approximate cost based on the recommended initial dosing for each agent and the wholesale acquisition cost from Red Book Online. Thomson Reuters, August Abbreviations: MAO, monoamine oxidase; NRT, nicotine replacement therapy; OTC, over-the-counter (non-prescription product; Rx, prescription product. Copyright The Regents of the University of California. All rights reserved. Updated August 22, 2017.

7 compared with placebo, participants both with and without serious psychiatric illnesses (eg, major depression, bipolar disorder, schizophrenia who received bupropion SR had significantly improved long-term (6-month quit rates without significantly higher rates of neuropsychiatric adverse events. 55 (Bupropion labeling currently has a nonboxed warning about serious neuropsychiatric events, and carries the class boxed warning about antidepressants and suicidality. 49 Varenicline Varenicline (Chantix is a partial agonist selective for the α 4 β 2 -nicotinic acetylcholine receptor subtype. The drug s efficacy is believed to be the result of sustained, low-level agonist activity at the receptor site, combined with competitive blockade of nicotine binding. The partial agonist activity modestly stimulates receptors, leading to increased dopamine levels that reduce nicotine withdrawal symptoms. In addition, by blocking the binding of nicotine to receptors in the central nervous system, varenicline inhibits the reward that occurs immediately following inhalation of tobacco smoke, thereby rendering smoking less pleasurable. 57 Varenicline therapy is generally started 1 week before the target quit date to attain steady-state, therapeutic plasma concentrations of the drug. 56 Varenicline is 92% excreted unchanged in urine and the dosage should be reduced in patients with severe renal impairment. 56 There are limited human data regarding risks of varenicline use among pregnant smokers; however animal data suggest potential for fetal harm 56 and as such, the drug should be used during pregnancy only if the potential benefit outweighs the potential fetal risk. As with bupropion, in 2009 the FDA required that the labeling for varenicline include a boxed warning about an increased risk of serious neuropsychiatric events. 53 This boxed warning was removed in December after a mandated clinical trial revealed no significantly increased risk for neuropsychiatric adverse events with varenicline compared to placebo among participants with or without serious psychiatric illnesses. Furthermore, participants randomized to varenicline were significantly more likely to quit smoking than those receiving placebo or other single first-line agents (bupropion SR, nicotine patch. 55 (Varenicline labeling still contains a nonboxed warning about serious neuropsychiatric adverse events. 56 Despite initial concerns about increased risk for serious cardiovascular events with use of varenicline, more recent studies have confirmed the cardiovascular safety of varenicline relative to placebo. 30,58,59 in participants with or without a history of cardiovascular disease. 30,58 Combination Therapy Although any of the FDA-approved cessation medications when used alone improve long-term quit rates, data from clinical trials suggest that only 16-29% of patients remain abstinent for at least 6 months Given these low success rates, modified approaches (eg, combination therapy have been explored. Plasma levels of nicotine achieved with standard doses of NRT are generally lower than are those attained with smoking. As a result, conventionally dosed NRT might deliver subtherapeutic nicotine levels for some individuals, and in particular, for moderate-to-heavy smokers. Dual NRT regimens, which typically consist of a long-acting agent (ie, nicotine patch combined with a short-acting formulation (ie, gum, lozenge, inhaler, or nasal spray, are recognized as viable, first-line treatment approaches. 6,38 The long-acting NRT delivers nicotine at a constant level, preventing the onset of withdrawal symptoms, while short-acting NRTs deliver nicotine more rapidly and are titrated by the patient as needed to control withdrawal symptoms during cravings (eg, after meals, during times of stress, or when around other smokers. Evidence suggests that patients who use combination NRT are 1.3 to 1.6 times more likely to remain abstinent when compared with patients who use single-agent NRT (Table 3. 27,28 Given these improved quit rates, clinicians should consider combination NRT as a preferred treatment approach relative to NRT monotherapy. The evidence in support of other combination regimens is less compelling but might be considered for patients who have been unsuccessful using first-line approaches. Pooled results from 12 studies of bupropion SR in combi- Table 3. Medications for Smoking Cessation: Treatment Comparison Meta-Analysis 27,30 Medication vs Placebo Odds Ratio 1 of Quitting (95% CI Nicotine gum vs placebo 1.7 ( Bupropion SR vs placebo 1.9 ( Nicotine patch vs placebo 1.9 ( Other NRT 2 vs placebo 2.0 ( Combination NRT vs placebo 2.7 ( Varenicline vs placebo 2.9 ( The odds ratio represents the likelihood that quitting smoking will occur with use of the medication over the likelihood of quitting with no medication (placebo. 2 Includes nicotine inhaler, lozenge, and nasal spray Abbreviations: NRT, nicotine replacement therapy; SR, sustained-release 8

8 nation with NRT (primarily patch or lozenge yielded quit rates that were 1.2-fold higher than those attained with NRT alone; however, the results were highly variable, with most studies finding no significant additional benefit with the combination. 29 Research using varenicline in combination with other first-line agents also is limited. To date, controlled trials comparing varenicline plus the nicotine patch versus varenicline alone have generated conflicting results, with two studies demonstrating no benefit from combination therapy 65,66 and a third finding significant improvements in quit rates at 6 months. 67 Similarly, controlled trials of varenicline combined with bupropion SR compared to varenicline alone have yielded mixed results, and further investigation is needed. Additionally, although varenicline in combination with bupropion SR or NRT appears to be reasonably well tolerated, the efficacy and long-term safety of these combinations has yet to be demonstrated. Because subgroup analyses in some trials suggested that varenicline/nrt 66 or varenicline/bupropion SR may be more effective than varenicline alone primarily in patients with high levels of nicotine dependence, clinicians should use these combinations only among patients who have been unable to quit while using first-line regimens. Other Treatment Approaches Among individuals who 1 report persistent withdrawal symptoms during treatment, 2 have relapsed shortly after medication discontinuation, or 3 are interested in long-term therapy, extended use of medications might be beneficial. 6 However it should be noted that randomized, controlled trials evaluating extended treatment with NRT, bupropion SR, or varenicline to prevent relapse are limited. 71 Evidence to date suggests longer treatment courses (6-12 months with varenicline might prevent relapse, 30 but extended duration therapy with bupropion is unlikely to be beneficial. 71 Extended use of NRT requires further study. 71 Given the established efficacy of bupropion SR and varenicline, both of which are started before patients quit smoking, a similar approach has been investigated to enhance quit rates with NRT use. In contrast to standard NRT dosing, for which it is recommend to initiate treatment on the quit date, pre-quit NRT (also known as nicotine preloading is initiated 2-4 weeks before the patient quits smoking. In theory, pre-quit use of NRT might improve success rates through multiple mechanisms, including 1 a reduction in cigarettes smoked and thus a reduced dependence on nicotine obtained from tobacco smoke; 2 attenuation of the reward and pleasure associated with smoking; and 3 increased confidence in and experience with NRT formulations prior to complete cessation. A pooled analysis of 8 clinical trials (6 patch and 2 gum found a significant increase in quit rates among participants using NRT before the quit date, compared with those using standard NRT dosing regimens. 28 Among the NRT formulations studied, pre-quit use of the nicotine patch appears to be more effective than short-acting NRT formulations, but a statistically significant improvement in quit rates has been observed in only one trial. 28,72 The use of NRT prior to quitting smoking does not appear to increase adverse effects. 72 Other treatment approaches, including a high-dose (eg, 42 mg nicotine patch, 28 and high-dose varenicline (5 mg/ day 73 have yielded small benefits but inconclusive results with respect to long-term abstinence rates, and further investigation is needed. The use of high dose varenicline, has resulted in significantly increased adverse effects of nausea and vomiting. 73 Although electronic nicotine delivery systems (eg, e- cigarettes might be effective aids for cessation, currently these products are not recommended due to insufficient efficacy and safety data. 38 Until more convincing evidence is available, proven treatments (ie, FDA-approved medications, behavioral counseling should be recommended as first-line for patients who are ready to quit. 74 Summary Healthcare providers are ideally positioned to identify tobacco users and assist them with quitting. By applying the 5 A s and combining drug therapy with counseling, clinicians can significantly reduce the public health burden of smoking. When time, logistics, or lack of expertise are not conducive to providing comprehensive counseling, the busy clinician can have an important impact on the health of patients by implementing brief interventions: ask all patients about tobacco use, advise tobacco users to quit, and refer patients who are ready to quit to other resources for further assistance. Chief Editor: Terry M. Baker, PharmD; Managing Editor: Tracy Farnen, PharmD; Associate Editors: James Chan,PharmD, PhD, Cherie Dillon, PharmD, Ron Finley, RPh, Angie Graham, PharmD, Julio R. Lopez, PharmD, FCSHP, Pamela Mausner, MD, Candy Tsourounis, PharmD; Senior Editorial Advisor: Gerard Hatheway, PharmD, PhD; Editorial Advisors: Helen Berlie, Pharm.D., CDE; Belinda M. Danielson, RPh, Christopher M. DeSoto, PharmD; Cynthia Chan Huang, PharmD; Fred S. Mayer, RPh, MPH, Fred Plageman, PharmD; Continuing Education Coordinator: Ashrani Chandra 9

9 References 1. U.S. Public Health Service. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Service. U.S. Department of Health, Education, and Welfare. Public Health Service. Centers for Disease Control. PHS Publication No Centers for Disease Control and Prevention. Current cigarette smoking among adults United States, MMWR 2016;65: U.S. Department of Health and Human Services. The Health Consequences of Smoking 50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Campaign for Tobacco-Free Kids. State Cigarette Excise Tax Rates & Rankings. Available at (accessed September 12, Babb S, Malarcher A, Schauer G, et al. Quitting Smoking Among Adults US MMWR 2017;65: Fiore MC, Jaén CR, Baker TB, et al. 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The FTC cigarette test method for determining tar, nicotine and carbon monoxide yields for US cigarettes NCI smoking and tobacco control Monograph No 7. NIH Publication No Bethesda, MD: US National Institutes of Health, National Cancer Institute, 1996: Benowitz NL. Clinical pharmacology of inhaled drugs of abuse: implications in understanding nicotine dependence. NIDA Res Monogr 1990;99: Benowitz NL. Nicotine addiction. N Engl J Med 2010;362: Hughes JR. Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res 2007;9: Benowitz NL. Cigarette smoking and nicotine addiction. Med Clin North Am 1992;76: University of California, San Francisco. Rx for Change: Clinician-Assisted Tobacco Cessation. San Francisco, CA: Regents of the University of California; Available at: (accessed September 12, Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007;64(18: Stead LF, Hartmann-Boyce J, Perera R, et al. Telephone counselling for smoking cessation. Cochrane Database Syst Rev 2013;8:CD Corelli RL, Fenlon CM, Kroon LA, et al. Evaluation of a train-the-trainer program for tobacco cessation. Am J Pharm Educ 2007;71: Adams AJ, Hudmon KS. Pharmacist prescriptive authority for smoking cessation medications in the United States Manuscript submitted for publication; currently under review. 19. State of Arizona. Senate Bill First Regular Session, Available at: (accessed September 12, California State Board of Pharmacy Protocol for Pharmacists Furnishing Nicotine Replacement Products. Available at: regs/1746_2_pt.pdf (accessed September 12, State of Colorado Department of Regulatory Agencies. Colorado State Board of Pharmacy Approved Statewide Protocol for Dispensing Tobacco Cessation Products. Available at: view (accessed September 12, First Regular Session of the 120th Indiana General Assembly (2017. House Enrolled Act No Available at: HB ENRS.pdf (accessed September 12, th Maine Legislature. Public Law, Chapter 185. An Act Relating to the Provision of Nicotine Replacement Products by Pharmacists. Available at: mainelegislature.org/legis/bills/bills_128th/chapters/public185.asp (accessed September 12, New Mexico Regulation and Licensing Department. Protocol for Pharmacist Prescribing for Tobacco Cessation. Available at: (accessed September 12, Oregon Board of Pharmacy State Drug Therapy Management Protocols. Available at: OBOPCurrent_Laws_Rules.pdf. (accessed September 12, Idaho State Legislature. House Bill 4, 2017 Session. Available at: idaho.gov/wp-content/uploads/sessioninfo/2017/legislation/h0004.pdf (accessed September 12, Cahill K, Stevens S, Perera R, et al. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013;5:CD Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2012;11:CD Hughes JR, Stead LF, Hartmann-Boyce J, et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2014;1:CD Cahill K, Lindson-Hawley N, Thomas KH, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2016;5:CD Benowitz NL, Burbank AD. Cardiovascular toxicity of nicotine: implications for electronic cigarette use. Trends Cardiovasc Med 2016;26: Mills EJ, Thorlund K, Eapen S, et al. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation 2014;129: Working Group for the Study of Transdermal Nicotine in Patients with Coronary Artery Disease. Nicotine replacement therapy for patients with coronary artery disease. Arch Intern Med 1994;154: Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996;335: Erratum in: N Engl J Med 2007;356: Tzivoni D, Keren A, Meyler S, et al. Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking. Cardiovasc Drugs Ther 1998;12: Benowitz NL, Dempsey DA. Pharmacotherapy for smoking cessation during pregnancy. Nicotine Tob Res 2004;6 Suppl 2:S Coleman T, Chamberlain C, Davey MA, et al. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2015;12:CD Patnode CD, Henderson JT, Thompson JH, et al. Behavioral counseling and pharmacotherapy interventions for tobacco cessation in adults, including pregnant women: a review of reviews for the U.S. Preventive Services Task Force. Ann Intern Med 2015;163: Committee Opinion No Smoking cessation during pregnancy (reaffirmed Obstet Gynecol 2010;116: Tomar SL, Henningfield JE. Review of the evidence that ph is a determinant of nicotine dosage from oral use of smokeless tobacco. Tob Control 1997;6: Choi JH, Dresler CM, Norton MR, et al. Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 2003;5: Kotlyar M, Mendoza-Baumgart MI, Li Z, et al. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tobacco Control 2007;16: Palmer KJ, Buckley MM, Faulds D. Transdermal nicotine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an aid to smoking cessation. Drugs 1992;44: Nicotrol NS (nicotine nasal spray prescribing information. New York, NY: Pharmacia & Upjohn Co.; July Schneider NG, Lunell E, Olmstead RE, et al. Clinical pharmacokinetics of nasal nicotine delivery. A review and comparison to other nicotine systems. Clin Pharmacokinet 1996;31: Benowitz NL, Zevin S, Jacob P 3rd. Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking. Br J Clin Pharmacol 1997;43: Nicotrol Inhaler (nicotine inhalation system prescribing information. New York, NY: Pharmacia & Upjohn; December Schneider NG, Olmstead RE, Franzon MA, et al. The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 2001;40: Zyban (bupropion sustained release prescribing information. Research Triangle Park, NC: GlaxoSmithKline; May Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337: Swan GE, McAfee T, Curry SJ, et al. Effectiveness of bupropion sustained release for smoking cessation in a health care setting: a randomized trial. Arch Intern Med 2003;163: Zyban (bupropion sustained release prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Available at: drugsatfda_docs/label/2009/020711s032s033lbl.pdf (accessed September 18, Food and Drug Administration (FDA. FDA requires new boxed warnings for the smoking cessation drugs Chantix and Zyban. Archived content; last updated August 16, Available at: ucm htm (accessed September 12,

10 54. Food and Drug Administration (FDA. FDA revises description of mental health side effects of the stop-smoking medicines Chantix (varenicline and Zyban (bupropion to reflect clinical trial findings. FDA Drug Safety Communication; December 16, Available at: (accessed September 18, Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES: a double-blind, randomised, placebo-controlled clinical trial. Lancet 2016;387: Chantix (varenicline prescribing information. New York, NY: Pfizer Labs; December Foulds J. The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. Int J Clin Pract 2006;60: Sterling LH, Windle SB, Filion KB, et al. Varenicline and adverse cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2016;5:e Pfizer Inc. A phase 4, non-treatment follow-up for cardiac assessments following use of msoking cessation treatments in subjects with and without a history of psychiatric disorders. Public disclosure synopsis, protocol A ; October 13, Available at: trials/csr synopsis/a Public Disclosure Synopsis.docx_.pdf (accessed September 14, Nicorette (nicotine polacrilex gum product label. Moon Township, PA: GlaxoSmithKline Consumer Healthcare; Available at: drugsatfda_docs/label/2012/018612s061_020066s042lbl.pdf (accessed September 23, Nicorette (nicotine polacrilex lozenge product label. Moon Township, PA: GlaxoSmithKline Consumer Healthcare; Available at: drugsatfda_docs/label/2013/021330orig1s016lbl.pdf (accessed September 23, Nicorette mini (nicotine polacrilex lozenge product label. Moon Township, PA: GlaxoSmithKline Consumer Healthcare; Available at: fda.gov/drugsatfda_docs/label/2013/022360orig1s007lbl.pdf (accessed September 23, NicoDerm CQ (nicotine patch product label. Moon Township, PA: GlaxoSmith- Kline Consumer Healthcare; Available at: drugsatfda_docs/label/2015/020165orig1s035lbl.pdf (accessed September 25, Nicotine transdermal system product label. Princeton, NJ: Dr. Reddy's Laboratories; Available at: cfm?setid=e2391b29-9bac-fc09-f2a5-a3370bc4e2c3&type=display (accessed September 23, Hajek P, Smith KM, Dhanji AR, et al. Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial. BMC Med 2013;11: Ramon JM, Morchon S, Baena A, et al. Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation. BMC Med 2014;12: Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA 2014;312: Rose JE, Behm FM. Combination treatment with varenicline and bupropion in an adaptive smoking cessation paradigm. Am J Psychiatry 2014;171: Rose JE, Behm FM. Combination varenicline/bupropion treatment benefits highly dependent smokers in an adaptive smoking cessation paradigm. Nicotine Tob Res 2017;19: Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA 2014;311: Hajek P, Stead LF, West R, et al. Relapse prevention interventions for smoking cessation. Cochrane Database Syst Rev 2013;8:CD Rose JE, Herskovic JE, Behm FM, et al. Precessation treatment with nicotine patch significantly increases abstinence rates relative to conventional treatment. Nicotine Tob Res 2009;11: Hajek P, McRobbie H, Myers Smith K, et al. Increasing varenicline dose in smokers who do not respond to the standard dosage: a randomized clinical trial. JAMA Intern Med 2015;175: Erratum in: JAMA Intern Med 2016;176: Siu AL; US Preventive Services Task Force. Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2015;163:

11 Patient Connection December 2017 Nicotine Gum (Nicorette, generic and Nicotine Lozenge (Nicorette, Nicorette Mini, generic Avoid food and acidic beverages (coffee, juices, wine, soft drinks 15 minutes before and while chewing the gum or using the lozenge. Chew the gum slowly. At the first sign of a tingling sensation (usually requires chews, park the gum between the cheek and gums. Chew again when the tingle fades. Repeat until the tingle does not return despite continued chewing, generally about 30 minutes. Chewing the gum too rapidly can lead to increased release of nicotine and side effects (eg, nausea, throat irritation, light-headedness, and hiccups. Place the lozenge in the mouth and allow it to dissolve slowly (20-30 minutes. As the nicotine is released, a warm, tingling sensation might be felt. To decrease the risk of mouth irritation, rotate the lozenge to different areas of the mouth during use. To minimize withdrawal symptoms, use the nicotine gum or lozenge on a fixed schedule (1 every 1-2 hours, initially rather than as needed. Follow recommendations for gradual dose reductions; most people can stop using the gum or lozenge after 12 weeks of treatment. Do not chew more than 24 pieces of gum per day. Do not use more than 5 lozenges in 6 hours or more than 20 lozenges per day. The nicotine gum is stickier than ordinary chewing gum and is more likely to stick to fillings, bridges, dentures, crowns, and braces. If excessive sticking or damage to dental work occurs, stop using the gum and consult your dentist and your prescriber. Patients who use more than 1 lozenge at a time, continuously use lozenges, or chew or swallow them are more likely to experience side effects such as nausea, throat irritation, light-headedness, hiccups, and heartburn. Have at least 1 full sleeve of nicotine gum or lozenges (12 pieces readily available. Keep them in the same place where you kept your cigarettes (eg, shirt pocket, purse, desk. Transdermal Nicotine Patch (NicoDerm CQ, generic At about the same time each day, apply the patch to a clean, dry, hairless, low-friction area of the skin, generally between the neck and waist. Press firmly on the patch with the palm of the hand for 10 seconds. After removing the patch, fold it so the halves stick together and dispose of it in the trash. Wash hands after applying or removing the patch. Water will not harm patches that are applied correctly. You may shower, bathe, or swim with the patch on. If the patch comes off for any reason, replace it with a new patch. Do not cut patches in half or in smaller pieces to adjust the nicotine dosage. Nicotine can rapidly evaporate from the cut edges, and the patch might be less effective. Mild skin irritation (itching, burning, and redness commonly occurs at the patch application site; this typically disappears in a day or two. These reactions are generally caused by the patch adhesives. To decrease the chances for skin reactions, rotate application sites each day; do not use the same site again for at least 1 week. If needed, skin irritation can be treated with nonprescription hydrocortisone cream. If the skin remains red for more than 4 days or if swelling or a rash appears, notify your healthcare provider. If you experience vivid dreams or other sleep problems, consider removing the patch at bedtime. Nicotine Nasal Spray (Nicotrol NS Before the first use, squirt ( prime the pump into a tissue until a fine spray is seen (6-8 pumps. If the pump is not used within 24 hours, prime 1-2 times into a tissue. Each bottle contains about 100 doses (200 sprays. Avoid excessive priming, which can reduce the amount of medicine for use. Blow the nose, tilt the head back slightly, and insert tip of bottle as far into nose as is comfortable. Breathe in through the mouth and press the bottom of the bottle to spray. After spraying the medication, do not sniff or inhale through the nose, because this increases the irritant effects of the spray. Repeat with the other nostril. If the nose runs, sniff gently; have a tissue available to catch any excess. Wait 2-3 minutes before blowing the nose. Do not use more than 5 times per hour or 40 times per day. To avoid withdrawal symptoms, initially use at least 8 doses per day (1 dose every 1-2 hours. After 6-8 weeks, gradually decrease the dose over an additional 4-6 weeks. During the first week of use, most people will have a hot, peppery feeling in the back of the throat or nose, runny nose, sneezing, coughing, or watery eyes. Because these side effects subside over time, patients should be advised not to stop using the medication. However, for combination therapy, where short-acting NRT is used as needed, tolerance to these side effects might not develop. 12

12 Resources for More Information Nicotine Oral Inhaler (Nicotrol Inhaler Because nicotine in the inhaler is absorbed through the lining of the mouth, food and acidic beverages (coffee, juices, wine, soft drinks should be avoided 15 minutes before and while using the inhaler. To open, align the marks on the mouthpiece and pull to separate. Insert the nicotine cartridge into the bottom half of the mouthpiece, and push down firmly until it pops into place. Line up the markings and push the 2 pieces tightly together. Twist so that the marks do not line up in order to lock and secure the mouthpiece during use. Inhale into back of throat or puff in short breaths, as if lighting a pipe, to decrease the likelihood of throat irritation. Nicotine in the cartridges is depleted after about 20 minutes of active puffing. The inhaler can be used for a few minutes, put down, and used again later. Once opened, each cartridge (whether fully used or not should be thrown away after 24 hours. To decrease withdrawal symptoms, initially use at least 6 cartridges (maximum of 16 per day for 3-12 weeks; gradually decrease the dose over an additional 6-12 weeks. Do not use more than 6 months. The release of nicotine from the inhaler is decreased at temperatures below 59 o F. In cold conditions, store the inhaler and cartridges in a warm place (eg, inside a pocket, not exceeding 77 o F. Bupropion SR (Zyban, generic Begin by taking one tablet (150 mg once a day for 3 days; if tolerated, increase to 150 mg twice a day (at least 8 hours apart on day 4. If insomnia is experienced, avoid taking the second dose close to bedtime, but ensure that no less than 8 hours has passed since the prior dose. Continue smoking until the quit date, which should be during the 2 nd week of bupropion SR treatment. About 1 in 1,000 patients have seizures. Discuss your seizure risk with your provider before starting bupropion SR. Excessive drinking of alcohol (or suddenly stopping alcohol use increases the risk of having a seizure. Some people have experienced changes in behavior or moods while using bupropion to help them quit smoking. If you, your family or friends/co-workers notice agitation, hostility, depression or changes in behavior, thinking, or mood that are not typical for you, stop taking bupropion and call your healthcare provider right away. Clinical Practice Guideline for Treating Tobacco Use and Dependence U.S. Department of Health and Human Services, Public Health Service. Consumer and clinician resources Centers for Disease Control and Prevention Smoking & Tobacco Use American Cancer Society Guide to Quitting Smoking tingsmoking/index American Heart Association Getting Healthy Quit Smoking Smoking_UCM_001085_SubHomePage.jsp American Lung Association Stop Smoking Campaign for Tobacco-Free Kids Truth Initiative Tobacco Quitline (telephone counseling 1-(800 QUIT-NOW Rx for Change: Clinician-Assisted Tobacco Cessation National Alliance of State Pharmacy Associations Updates on pharmacists authorization to prescribe cessation therapy co-cessation-therapy-in-more-states/ Varenicline (Chantix Begin by taking one white tablet (0.5 mg once a day for 3 days. Increase to 0.5 mg twice a day on days 4 through 7, then increase to one blue tablet (1 mg twice a day. If insomnia is experienced, avoid taking the second dose close to bedtime. Continue smoking until the quit date, which should be 1 week after starting varenicline treatment. Continue taking the medication for a total of 12 weeks. The most common side effect is nausea. Taking the medication after eating and with a full (8 ounces glass of water helps to decrease this problem. Less common, but serious side effects include mood changes, anxiety and seizures. Notify your provider immediately if these occur while taking varenicline. Avoid alcohol with varenicline. Lower tolerance to alcohol (eg., increased drunkenness and loss of memory while drinking alcohol may occur. 13

13 Test Questions Questions are based on information provided in the text, tables, and Patient Connection page. To receive CE credit, take the test online at or write your answers on the Credit Request form and mail it to The Rx Consultant, P.O. Box 1516, Martinez, CA 94553, or FAX it to ACPE Universal program # H01-P 1. How long after quitting will nicotine withdrawal symptoms generally subside (for most patients? a hours c. 2-4 weeks b days d. 2-4 months 2. How long does it take for inhaled nicotine to reach the brain? a. < 5 seconds c minutes b. 1-2 hours d seconds 3. Which of the following is not a component of the The 5 A s for tobacco cessation intervention? a. Ask: ask patients about their tobacco use b. Aware: make patients aware of health consequences of smoking c. Assess: assess patient s readiness to quit d. Arrange: arrange follow-up care 4. What toll-free telephone number should you encourage smokers to call? a JUST QUIT c NO SMOKE b QUIT NOW d STOP NOW 5. It is important to identify patients who smoke in order to screen for potential drug interactions. Tobacco smoking increases the clearance of which of the following medications? a. Olanzapine c. Sertraline b. Oxycodone d. Bupropion 6. Which of the following is more likely to occur in a woman who smokes and takes hormonal contraceptives compared with a woman who takes them and does not smoke? a. Gastrointestinal ulcers c. Bone fractures b. Migraine headaches d. Thromboembolism 7. A 60-year-old man, who had been smoking about 1 pack per day, started using the 21 mg nicotine patch 4 days ago. He is still experiencing situational urges to smoke, especially after meals. What would be the most appropriate adjustment to medication therapy? a. No adjustment. The urges to smoke should lessen within a week. b. Increase the nicotine patch to 42 mg (21 mg x 2 patches daily. c. Add a short-acting NRT (eg, gum or lozenge as needed for cravings. d. Add an e-cigarette as needed for situational cravings. 8. Which of the following requires a dosage adjustment for patients with liver impairment? a. Varenicline c. Bupropion SR b. Nicotine lozenge d. a and c Release Date: November 22, 2017 Expiration Date: November 22, 2020 Target audience: pharmacists and nurses Upon successful completion (70% of the test and evaluation for this knowledge-based CE activity, 2 hours of continuing education credit will be awarded to subscribers. If you are not a subscriber and would like credit for this issue, include a check for $10.00 with your Credit Request. The Rx Consultant is a publication of Continuing Education Network, Inc. P A E C CA BRN 9. MK is a 50-year-old woman interested in using the nicotine patch for her upcoming quit attempt. She has been smoking for 20 years (1 to 1½ packs of cigarettes daily. Her other medical problems include type 2 diabetes and hypertension. Which of the following doses is most appropriate for the initial 4 to 6 weeks of treatment? a. 21 mg daily c. 7 mg daily b. 42 mg daily d. 14 mg daily 10. A patient who has been using nicotine gum begins experiencing lightheadedness, nausea, and throat irritation. What is a probable cause? a. Improper chewing technique that leads to rapid nicotine release b. Smoking while using the gum c. Storing the gum in a humid area which causes the nicotine to be more available when chewed d. Increased caffeine intake 11. A 69-year-old man has been filling prescriptions at your pharmacy for the last 5 years. He currently takes metformin and atorvastatin daily. He has a new prescription for metoprolol XL and shares with you that he had a heart attack 1 week ago. He is a known smoker. After counseling him about metoprolol, which of the following regarding his smoking is appropriate to say? a. "You need to quit smoking. Do you want to have another heart attack? b. Since you just had a heart attack you need to start taking Chantix because you can't take nicotine replacement products. Can I call your doctor for a prescription for Chantix? c. I m very concerned that you smoke, because you ve recently had a heart attack. If it s OK with you, I d like to talk with you about quitting smoking. d. "None of the quit-smoking medications are safe to use after a heart attack so you'll need to try and quit cold turkey." 12. A 65-year-old woman was admitted to the hospital for an asthma exacerbation. Upon talking to her, she indicates that she is ready to quit now. When asking about her tobacco use, you learn that she smokes approximately one pack per day and has her first cigarette of the day within 10 minutes of waking up. Her medical problems include psoriasis, seasonal allergies, and TMJ. She likes the idea of using a nicotine replacement product. Which of the following nicotine replacement regimens is most appropriate to start? a. Nicotine gum 2 mg, 1 piece every 1-2 hours b. Nicotine gum 4 mg, 1 piece every 1-2 hours c. Nicotine lozenge, 4 mg, 1 piece every 1-2 hours d. Nicotine lozenge 2 mg, 1 piece every 1-2 hours Continuing Education Network, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Continuing Education Network, Inc. is approved by the California Board of Registered Nursing, Provider Number CEP Programs approved by CA BRN are accepted by most State Boards of Nursing. 2 Hours CE To begin a subscription, contact The Rx Consultant office. The yearly subscription rate of $127 includes issues, Quick Reference cards, Rx News Connection, and 50+ hours of CE. Direct inquiries to: The Rx Consultant, P.O. Box 1516, Martinez, CA Toll Free Number FAX Copyright 2017, Continuing Education Network, Inc. 14

14 DRUG INTERACTIONS WITH TOBACCO SMOKE 14 Many interactions between tobacco smoke and medications have been identified. In most cases it is the tobacco smoke not the nicotine that causes these drug interactions. Tobacco smoke interacts with medications through pharmacokinetic (PK and pharmacodynamic (PD mechanisms. PK interactions affect the absorption, distribution, metabolism, or elimination of other drugs, potentially causing an altered response to those drugs. Most PK interactions with smoking result from induction of hepatic cytochrome P450 enzymes (primarily CYP1A2. Smokers may require higher doses of medications that are CYP1A2 substrates. Upon cessation, dose reductions might be needed. PD interactions alter the expected response or actions of other drugs. The amount of tobacco smoking needed to have an effect has not been established, and the assumption is that any smoker is susceptible to the same degree of interaction. The most clinically significant interactions appear in the shaded rows. DRUG/CLASS MECHANISM OF INTERACTION AND EFFECTS Pharmacokinetic Interactions Alprazolam (Xanax Conflicting data on significance, but possible â plasma concentrations (up to 50%; â halflife (35%. á Metabolism (induction of CYP1A2. Manufacturer recommends using with caution in Bendamustine (Treanda smokers due to likely â bendamustine concentrations, with á concentrations of 2 active metabolites. á Metabolism (induction of CYP1A2; á clearance (56%. Caffeine Caffeine levels likely á after cessation. Cilostazol (Pletal â Plasma concentrations (by 20%. Chlorpromazine â Area under the curve (AUC (36%; â plasma concentrations (by 24%. (Thorazine á Levels upon cessation have been reported causing sedation and hypotension. á Metabolism (induction of CYP1A2 of clopidogrel to its active metabolite. Clopidogrel s effects are enhanced in smokers ( 10 cigarettes/day; while improved clinical Clopidogrel (Plavix outcomes have been shown (smokers paradox; may be dependent on CYP1A2 genotype; might also á risk of bleeding. Tobacco cessation should still be recommended in the at-risk populations needing clopidogrel. á Metabolism (induction of CYP1A2; â plasma concentrations (by 18%. Clozapine (Clozaril á Levels upon cessation may occur; closely monitor drug levels and reduce dose as required to avoid toxicity. Duloxetine (Cymbalta â Area under the curve (AUC (33%. Dosage modifications not routinely recommended. Erlotinib (Tarceva á Clearance (24%; â trough plasma concentrations (2-fold. Flecainide (Tambocor á Clearance (61%; â trough plasma concentrations (25%. Smokers may need á dosages. á Metabolism (induction of CYP1A2; á clearance (24%; â AUC (31%; â Cmax (32% Fluvoxamine (Luvox and Css (39%. Dosage modifications not routinely recommended but smokers may need á dosages. Haloperidol (Haldol á Clearance (44%; â plasma concentrations (by 70%; data are inconsistent therefore clinical significance is unclear. Possible â insulin absorption secondary to peripheral vasoconstriction. Insulin, subcutaneous Smoking is reported to cause insulin resistance. PK & PD interactions likely not clinically significant, but smokers may need á dosages. á Clearance (18%; â plasma concentrations of active metabolite, SN-38 (~40%; via Irinotecan (Camptosar induction of glucuronidation; â systemic exposure resulting in lower hematologic toxicity and may reduce efficacy. Smokers may need á dosages. á Metabolism (induction of CYP1A2 [minor pathway for methadone]. Methadone á Levels upon smoking cessation have been reported causing sedation, confusion and labored breathing which required dosage â. Carefully monitor response upon cessation. Mexiletine (Mexitil á Clearance (25%; â half-life (36%. Nintedanib (OFEV Decreased exposure (21% in smokers. No dose adjustment recommended; however, avoid smoking during treatment. i Copyright The Regents of the University of California. All rights reserved.