Pharmacotherapy for Smoking Cessation

Pharmacotherapy for Smoking Cessation Venita L. Bowie, Pharm.D. Paula Mackrides, DO • Provide Education • Provide Resources • Provide Feedback DEDICATE STAFF • Coordinator • Counselor Promote hospital/clinic smoking cessation policies Insurance Coverage • Tobacco cessation is cost-effective • If services are covered, tobacco cessation increases • Healthy People 2010 policy set a goal of 100% coverage for all tobacco cessation services • Educate patients and providers on coverage for tobacco cessation services Adequate reimbursement for tobacco cessation interventions EVIDENCE BASED • Use of smoking cessation medications as part of smoking cessation is based on solid evidence – Systemic reviews of randomized, controlled trials of smoking cessation aids, including medication, increases the chances of quitting • Cummulative data doesn’t demonstrate an advantage of one smoking cessation aid over another So how do you select? • • • • Patient preference Previous patient experience Contraindications Patient characteristics Chemicals in a cigarette The Food and Drug Administration (FDA) Approved Agents  Nicotine replacement therapy (NRT) include the following forms.       Gum Patch Nasal spray Inhaler Lozenge Oral medications Specific RX Products • • • • • • • Nicoderm CQ (Transdermal) Commit Lozenge (Nicotine Polacrilex) Nicorette Gum (Nicotine Polacrilex) Nicotrol Inhaler Nicotrol Nasal Spray Zyban (Wellbutrin) Chantix (Varenicline) Additional Second-line Agents Not FDA approved  Opioids Antagonists (Naloxone, Naltrexone)  Alpha-2 adrenergic agonist (clonidine)  Tricyclic antidepressants  Nortriptyline, fluoxetine, doxepin, impiramine, paroxetine, sertraline, tryptophan, moclobenide and venlafaxine Additional Second-line Agents Not FDA approved  Mecamylamine  Anxiolytics  Buspirone, doxepin, meprobamate, propranolol, oxprenolol and metoprolol  Other agents  Rimonabant (an endocannabinoid receptor antagonist)  Antibodies that bind to nicotine molecules Nicotine replacement products Nicotine Replacement Therapy Drug □ Nicoderm CQ (Nicotine) Transdermal □ Nicotine (Nicoderm CQ) Transdermal □ Nicotine (Nicoderm CQ) Transdermal Dose 7mg Route Patch Interval Every 24 hours Comments Rotate patch site daily 14 mg (10 cigarettes or less 21 mg (> 10 cigarettes/day) Patch Every 24 hours Every 24 hours Rotate patch site daily Rotate patch site daily (de Patch □ Commit Lozenge*** (Nicotine Polacrilex) 2mg 1 Lozenge every 1 to 2 hours Oral Lozenge Weeks 1 to 6 (every 1 to 2 hrs) Wks 7 to 9: 1 lozenge every 2 to 4 hours. Weeks 10 to 12: 1 lozenge every 4 to 8 hours Nicotine Replacement Therapy □ Nicorette gum (Nicotine Polacrilex) 2 mg and 4mg <25 cigarettes use 2 mg; greater than 25 use 4mg Oral Gum Weeks 1 to 6 1 piece every 1 to 2 hrs Taper after 7 wks 1 piece every 2 to 4 hours □ Nicotrol oral inhaler** (Nicotine) 10 mg/cartridge (4 mg nicotine) inhaler Weeks 1 MAX 16 through 12, cartridges/day use 6 to 16 cartridges daily Max. doses/ hour equals 5 Max dose/day: 40 per day (40 mg, 80 sprays) □ Nicotrol Nasal spray (Nicotine) 10 mg/ml 2_ sprays (One each nostril) Intranasal *1-2 dose per hour Nicotine Replacement Therapy □ Zyban (Wellbutrin) 150 mg PO Daily x 3 days then increase dose to BID BID 6am6pm Maximum dose: 150 mg twice daily Duration: 7-12 weeks □ Zyban (Wellbutrin) 150mg PO □ Chantix (Varenicline) 0.5 mg and 1 mg 0.5 mg once daily for days 1 through 3 0.5 mg and 1 mg 0.5 mg twice daily PO Once daily days 1 through 3 Titrate up after day 3 □ Chantix (Varenicline) PO Days Titrate up 1 4 through 7 mg twice daily day 8 Pharmacotherapy for Smoking Cessation  The Treating Tobacco Use and Dependence guideline panel recommends that all smokers (without contraindications) attempting to quit.  Pharmacotherapy needs to be offered to aid their efforts What are the benefits of pharmacotherapy?  It increases the odds of quitting (1.5 to twofold)  Reduces the withdrawal symptoms  Some patients are provided with some “reward” produced by nicotine in the CNS Nicotine  Nicotine is one of 2 naturally-occurring alkaloids  The second alkaloid is lobeline (less potent)  A potent ganglion and CNS stimulant  Actions are mediated via receptors specific to nicotine  Biphasic actions are dose dependent Nicotine  The cortex via the locus ceruleus is where the stimulating affect occurs  The reward effects: limbic system.  Low doses = stimulating effect  High doses = reward effect Nicotine Similarities  Nicotine is believed to be active similar to the following agents     Opioids Cocaine Methamphetamine Heroin  They all share some physiologic pathways  The release of dopamine Nicotine Similarities  Nicotine, like opioids, and ethanol increases the release of dopamine  Amphetamines increases the release of dopamine through displacement  Cocaine inhibits dopamine reuptake  Heroin modifies the action of dopamine in the nucleus accumbens and in specific areas of the brain Nicotine  CNS stimulation         Tremors Respiratory excitation Convulsions (higher doses) Respiratory failure Euphoria Psychoactive benefits (antidepressant effect) Enhancing task performance Addiction  Other effects include Before Initiating NRT  Instructed patients to stop smoking completely as they begin nicotine cessation therapy.  If a patient is unable to quit smoking by the fourth week of therapy discontinue treatment. Transdermal Patch     Nicoderm, Habitrol, Nicotrol, Prostep Available dose: 11 mg up to 22 mg Dose is dependant on cigarettes per day Length of therapy, dosage strength and duration of wear varies by brand Transdermal Patch  Once applied, an initial increase in serum nicotine level occurs  Steady levels are maintain throughout dosing period  Patches are available in 16 and 24 hour applications  24 hour patches provide better control of cravings and withdrawal Dose  Apply new patch every 24 hrs to non hairy, clean dry skin on the upper body or upper outer arm  > 10 cigarettes/day:  Begin with step 1 (21 mg) for 4-6 wks  Followed by step 2 (14 mg) for 2 wks  Step 3 (7 mg) for 2 wks Dose  < 10 cigarettes/day  Begin with step 2 (14 mg) for 6 wks  Followed by step 3 (7 mg) for 2wks Special Considerations  Patients < 100 pounds, history of cardiovascular disease  Initial dose: 14 mg/day for 4-6 wks followed by 7 mg for 2-4 weeks  Patients on > 600 mg of Cimetidine: decrease to the next lower patch size  Pregnancy Category: D  Cutting the transdermal nicotine patch in half is not recommended Contraindications  Hypersensitivity to nicotine or components  Pregnancy  Patient’s that smoke post myocardial infarction period  Life threatening arrhythmias  Severe or worsening angina pectoris  Non smokers Precautions  Accelerated hypertension  Allergy to adhesive tape  Cardiovascular and peripheral vascular diseases  Severe or worsening angina Adverse Side Effects       Tachycardia Insomnia, abnormal dreams Pruritus, erythema Rhinitis, cough, pharyngitis, and sinusitis Rash Dyspepsia, nausea, xerostomia Drug Interactions  Cytochrome P 450 Effect:  Minor: CYP1A2, 2A6, 2C8/9, 2C19, 2D6, 2E1, 3A4  Weak inhibitor of CYP2A6, and 2E1  Cimetidine increases nicotine concentrations (gum and patch dose effected)  Monitor patients while on patch and bupropion Drug Interactions  Nicotine increases the hemodynamic and AV blocking of adenosine  Clozapine (decreased plasma levels)  Memantine (altered plasma levels of both agents)  Niacin (increased flushing and dizziness) Food Interactions  Lozenge: Acidic foods or beverages decrease absorption of nicotine Commit Lozenge (Nicotine Polacrilex)  Dosage: 2 mg and 4 mg  Patients that smoke their first cigarette within 30 minutes use 4 mg  Week 1-6: One Lozenge every 1-2 hrs  Week 7-9: One lozenge every 2-4 hrs  Weeks 10-12: One lozenge every 4-8 hrs Commit Lozenge  During the first 6 weeks use at least 9 lozenges/day  Do not use more than 1 lozenge/time  Maximum 5 Lozenges q 6hrs (20 per day) Special Instructions  Do not eat or drink 15 minutes before use  Dissolve slowly in mouth over 20 to 30 min  Move lozenge from one side of mouth to the other until completely dissolved  Do not chew or swallow Adverse Side Effects  Tachycardia  Headache (mild),  Nausea, vomiting indigestion, excessive salivation, belching  Mouth or throat soreness, increased appetite or hiccups  Hoarseness Contraindications  Hypersensitivity to nicotine or components  Pregnancy category: D Precautions  Concomitant use of other nicotine products  Concurrent medication for depression or asthma  Uncontrolled high blood pressure  History of Peptic ulcers  Recent MI, Irregular heart beats  Diabetes Nicorette Gum (Nicotine Polacrilex)  Dosages: 2 mg/square, and 4 mg/square  Flavors: mint, orange and original Dose  Heavy smokers: > 25 cigarettes/day  Chew 1 piece 4 mg gum every 1-2hrs for weeks 1-6  Chew 1 piece 4 mg every 2-4 hrs for week 7-9  Chew 1 piece 4 mg every 4-8 hrs for week 1012 Dose  Light smokers: < 25 cigarettes/day  Chew 1 piece 2 mg gum every 1-2hrs for weeks 1-6  Chew 1 piece 2 mg gum every 2-4 hrs for weeks 7-9  Chew 1 piece 2 mg every 4-8 hrs for weeks 10-12 Special Instructions  Do not eat or drink 15 minutes before using  Chew gum slowly until it tingles, then park it between your cheek and gum  When tingles stops repeat process until most of it is gone (approx 30 minutes)  Wrap used pieces in paper before discarding Adverse Side Effects  Tachycardia  Headache (mild)  Nausea, vomiting, indigestion, excessive salivation  Jaw muscle ache, hiccups, hoarseness  Dizziness, nervousness Contraindications  Hypersensitivity to nicotine or components Precautions  Same as the lozenge  Pregnancy Category: C Nicotrol Inhaler  10 mg cartridge (delivers 4 mg nicotine)  1 mouthpiece, 7 storage trays (containing 6 cartridges) Dosage  Usually 6 to 16 cartridges/day up to 12 weeks  Best effect: Inhale by continuous puffing (20 minutes)  Wean gradually over 6 to 12 weeks  Duration of treatment 3 months Special Considerations  Separate mouthpiece, remove and discard used cartridge;  Clean mouthpiece with soap and water and store in plastic case Adverse Side Effects  Throat and mouth irritation  Dizziness Nicotrol Nasal Inhaler      Dosage: 10 mg/ml delivers 0.5 mg/spray 2 sprays (1 in each nostril) 1 to 2 times/hr Max doses: 5 doses per hour Max 40 doses in a 24 hour period Maximum duration: 3 months Special Considerations  Patients should be instructed not to sniff, swallow, or inhale through the nose as the spray is being administered.  Advised to administer the spray with the head tilted back slightly. Questions Oral Medications Zyban (Bupropion)  An antidepressant that is different in structure from tricyclic, (SSRI), and MAOI.  The mechanism of action as an aid to smoking cessation is unknown  Relatively weak inhibitor of the neuronal uptake of serotonin, NE, and dopamine.  The primary MOA is thought to be dopaminergic and or noradrenergic Zyban (Bupropion)  Dose: Smoking Cessation  Initiate 150 mg once daily for 3 days  Increase to 150 mg BID  Initial response: 1 to 2 weeks  Treatment for 7- 12 weeks  Combination treatment of bupropion sustained release and a nicotine transdermal system may be prescribed Pharmacokinetics  Rapidly absorbed  Protein binding 84% (sustained and immediate release)  Liver major site of metabolism  Activity of the metabolites ranges from 20% to 50% potency of parent compound  Renally excreted  Elimination of the active metabolite may be reduced in pts with renal impairment Drug Interactions  Concomitant administration of bupropion and agents that lower seizure threshold should be used with caution  Betamethasone, Budesonide, Danazol, and Dexamethasone (not a complete list)  Increase risk of serotonin syndrome with Zyvox (linezolid) Drug Interactions  Cytochrome P450 substrate effect  Weak inhibitor of: CYP2D6 (however can effect serum levels of some agents)  Minor for: CYP1A2, 2A6, 2C8/9, 2E1, and 3A4  Major for : 2B6 Black Box WARNING  Black box warning pertains to treating patients with depression  Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Contraindications  Seizure disorders  Patients undergoing abrupt discontinuation of alcohol or sedatives  Prior or current diagnosis of bulimia or anorexia  Concomitant MAO inhibitor  Hypersensitivity to bupropion products Precautions  Pregnancy Category: C  Addiction to opiates, cocaine, or stimulants  Diabetes treated with oral hypoglycemics or insulin  Hypertension, myocardial infarction, or unstable heart disease  Medications or treatments that lower the seizure threshold Adverse Side Effects       Dizziness Headache Insomnia Nausea, Xerostomia Pharyngitis Agitation Patient Information  Bupropion can provide beneficial effects with smoking cessation  Must be taken on a regularly scheduled basis  Behavior and lifestyle modifications must be combined Chantix (Varenicline)     Newest agent for smoking cessation Two strengths: 0.5 mg and 1 mg Approved by FDA 5/10/2006 A partial agonist selective for alpha-4beta-2 nicotinic acetylcholine receptor Mechanism of Action  Varenicline binds with high affinity and selectivity at the alpha-4-beta-2 neuronal nicotinic acetylcholine receptors  Efficacy of varenicline is believe to be at the sub-type of the nicotinic receptor  Binding produces its agonist activity Mechanism of Action (continued)  Nicotine is prevented from binding to the alpha-4-beta-2 receptors  Stimulation of the central nervous mesolimbic can not occur  Reinforcement and reward can not occur Pharmacokinetics  Peak plasma concentration: 3-4hrs  Steady state reached in 4 days (following multiple dosing)  Half-life: parent compound 24 hours  Protein binding: 20% or less  Liver metabolism: minimum  92% of the drug is excreted in the urine Contraindications  Hypersensitivity to varenicline tartrate or any component of the formulation  Other specific contraindications have not been determined Precautions  Use caution in renal dysfunction (dose adjustment required)  Altered pharmacokinetics or pharmacodynamics of some drugs including theophylline, warfarin and insulin may occur with smoking cessation  Dose reduction should be considered with intolerable nausea Dose  Recommended starting dose:  1-week titration: 0.5 mg orally once daily on days 1 thru 3, then 0.5 mg twice daily on days 4 thru 7.  Then 1 mg twice daily for 12 weeks (including 1 week titration).  1 mg BID is the recommended dose Dosage Adjustment for Renal Impairment  Mild to moderate renal impairment, no dosage adjustment is required  For severe renal impairment (CrCl < 30 ml/min)  Recommended starting dose is 0.5 milligrams (mg) orally once daily  Patients may be titrated up to 0.5 mg twice daily Special Instructions  Therapy should begin 1 week prior to the date set by patients to stop smoking  Patients that are sensitive to varenicline adverse effects (nausea, headache, insomnia), the dose may be lowered  Educational materials and counseling on smoking cessation should also be provided. Adverse Side Effects  Rash  Abdominal pain, flatulence, and constipation  Nausea (up to 40%), Indigestion, altered taste and increase appetite  Headache, abnormal dreams and insomnia Contraindications  Hypersensitivity to varenicline or any component of the formulation Precautions  Renal dysfunction  During smoking cessation the pharmacokinetics or pharmacodynamics of some drugs including theophylline, warfarin and insulin may be altered  Pregnancy Category: C Efficacy after 12 months Brief Overview Treatment Duration      Zyban: 7 to 12 weeks Nicotine gum: Up to 12 weeks Nicotine Inhaler: Up to 6 months Nicotine nasal inhaler: 3 to 6 months Nicotine patch: 8 weeks (4 wks, then 2 wks, then 2 wks) FDA Approved Agents Efficacy at 12 months      Nicotine patch: 11.1% vs. 5.2 placebo Nicotine nasal spray: no current data Nicotine inhaler: 16.9% vs. 9.1% Nicotine gum: 27.3% vs. 16.5% Bupropion (Zyban): 18.5% vs. 6.6% Efficacy at 12 months with NRT plus Behavioral Intervention  Nicotine patch  Placebo 5.2%  With intervention 11.1%  Nicotine gum  Placebo 16.5%  With intervention 27.3%  Nicotine inhaler  Placebo 9.1%  With intervention 16.9% Efficacy at 12 months with NRT plus Behavioral Intervention  Bupropion  Placebo 13.9%  With intervention 20.0% Combination Therapy  Studies have shown smokers who use combination products greatly increases their chances of remaining smoke-free  Smokers who used a combination of nicotine patch and nasal spray doubled their chances of remaining smoke free for 6 years Summary  Nicotine replacement therapy + behavior therapy increases chances of quitting  Combination therapy greatly increases success rates. Questions??