Varenicline tartrate

Pronunciation

Class: Autonomic Drugs, Miscellaneous
Chemical Name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1)
Molecular Formula: C13H13N3•C4H6O6
CAS Number: 375815-87-5
Brands: Chantix

Warning(s)

  • Neuropsychiatric Symptoms and Suicide Risk
  • Serious neuropsychiatric symptoms (e.g., depression, suicidal ideation, suicide attempt, completed suicide) have been reported in patients receiving varenicline for smoking cessation.1 10 11 12 13 (See Neuropsychiatric Symptoms and Suicidality under Cautions.)

  • Such effects have occurred in patients with or without psychiatric illnesses.1 10 11 12 13 Safety and efficacy of varenicline not established in patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, major depressive disorder); such patients may experience recurrence or worsening of symptoms during varenicline therapy.1 10 12

  • Depressed mood may be a symptom of nicotine withdrawal; however, some symptoms occurred in varenicline-treated patients who continued to smoke.1

  • Most symptoms occurred during varenicline therapy, but some were reported following discontinuance of drug.1 10 13

  • Monitor all patients receiving varenicline for neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, and suicide-related events (including ideation, behavior, and attempted suicide).1 10 12

  • Patient should discontinue varenicline and immediately contact clinician if agitation, hostility, depressed mood, or changes in thinking or behavior not typical for the patient occur, or if patient develops suicidal ideation or behavior.1 10 11 13

  • Symptoms resolved upon drug discontinuance in many cases, but persisted in some.1 10 12 Provide ongoing patient monitoring and supportive care until symptoms resolve.1 10

  • Weigh risks of varenicline therapy against benefits of its use for smoking cessation.1 10 13

REMS:

FDA approved a REMS for varenicline tartrate to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of varenicline tartrate and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Nicotinic acetylcholine receptor partial agonist.1

Uses for Varenicline tartrate

Smoking Cessation

Adjunct in the cessation of cigarette smoking.1 3 4 5 8

USPHS guideline for the treatment of tobacco use and dependence recommends varenicline as one of several first-line drugs that may reliably increase long-term smoking abstinence rates.152 For additional information, consult the most current USPHS Clinical Practice Guideline available at

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Urge to smoke was less severe in individuals receiving varenicline than in those receiving placebo.1 3 4 5

Efficacy of varenicline in studies in patients with stable, documented cardiovascular disease (other than hypertension) and in patients with mild to moderate COPD was comparable to its efficacy in the general smoking population without these conditions.3 4 15 16

Efficacy and safety of varenicline given in conjunction with other smoking cessation therapies (e.g., bupropion, nicotine replacement therapy) have not been established.1

Varenicline tartrate Dosage and Administration

Administration

Oral Administration

Administer tablets orally after eating, with a full glass of water.1 3 4 5

Dosage

Available as varenicline tartrate; dosage expressed in terms of varenicline.1

Adults

Smoking Cessation
Oral

0.5 mg once daily on days 1–3, followed by 0.5 mg twice daily on days 4–7, and then 1 mg twice daily from day 8 through the end of 12 weeks of treatment.1 Initiate 1 week before the target smoking cessation date.1 Alternatively, patients may begin treatment with varenicline and then quit smoking between days 8 and 35 of treatment.1

Titrate dosage during the initial week of treatment to reduce the incidence of drug-related nausea.1 Dosage may be reduced temporarily or permanently in patients who experience intolerable adverse effects.1

In patients who have successfully stopped smoking by the end of 12 weeks of initial treatment, consider an additional 12 weeks of therapy to increase the likelihood of long-term abstinence.1

Patients unable to quit smoking during 12 weeks of treatment or those who have relapsed after varenicline therapy should make another attempt to quit smoking once factors responsible for such failure have been identified and addressed.1

Prescribing Limits

Adults

Oral

1 mg twice daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.1

Renal Impairment

Mild to moderate renal impairment: No dosage adjustment needed.1

Severe renal impairment (Clcr <30 mL/minute): Initially administer 0.5 mg once daily; titrate dosage as needed to a maximum of 0.5 mg twice daily.1

Patients with end-stage renal disease undergoing hemodialysis: Maximum of 0.5 mg once daily.1

Geriatric Patients

Dosage adjustment not needed; select dosage carefully and monitor renal function.1 (See Geriatric Use under Cautions.)

Cautions for Varenicline tartrate

Contraindications

  • Known history of serious hypersensitivity reactions or skin reactions to varenicline.1

Warnings/Precautions

Warnings

Neuropsychiatric Symptoms and Suicidality

Serious neuropsychiatric symptoms, including changes in mood (e.g., depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, and suicidality (e.g., suicidal ideation, attempted and completed suicides), reported.1 10 11 12 13 (See Neuropsychiatric Symptoms and Suicide Risk in Boxed Warning.)

While some patients who stopped smoking have experienced these symptoms as a result of nicotine withdrawal, others who had not yet discontinued smoking also experienced such symptoms.1

Monitor all patients for neuropsychiatric symptoms or for worsening of preexisting psychiatric conditions.1 10 12 Discontinue varenicline in patients who develop agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient or who develop suicidal ideation or suicidal behavior.1 10 11 13

Symptoms resolved after varenicline discontinuance in many cases but persisted in some despite discontinuance.1 10 12 Provide ongoing patient monitoring and supportive care until symptoms resolve.1 10

Risk of worsening preexisting psychiatric illness in patients receiving varenicline.1 10 11 12 13 Nicotine withdrawal also has been associated with exacerbation of underlying psychiatric illness.1 Data are limited in patients with schizophrenia or schizoaffective disorders;1 20 safety and efficacy of varenicline in patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, major depressive disorder) are not established.1

Discuss risk of developing serious neuropsychiatric effects with patients prior to use of varenicline.1 10 (See Advice to Patients.) Weigh such risks against health benefits of smoking cessation (e.g., reduction in the risk of developing pulmonary disease, cardiovascular disease, or certain types of cancer).1 10 13

Other Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including angioedema, reported.1 Manifestations included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (pharynx and larynx).1 Life-threatening angioedema requiring emergent medical attention because of respiratory compromise infrequently reported.1

Instruct patients to discontinue varenicline and immediately seek medical attention if such symptoms occur.1

Dermatologic Effects

Serious dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, reported; potentially life-threatening.1 Instruct patients to discontinue varenicline and immediately contact healthcare provider at first appearance of rash with mucosal lesions or any signs of hypersensitivity.1

Cardiovascular Effects

In patients with stable cardiovascular disease who had received varenicline, certain cardiovascular events (i.e., angina pectoris, nonfatal MI, nonfatal stroke, need for coronary revascularization, hospitalization for angina pectoris, TIA, new diagnosis of peripheral vascular disease, hospital admission for a peripheral vascular disease procedure) reported.1 18 A meta-analysis revealed that major adverse cardiac events (cardiovascular death, nonfatal MI, nonfatal stroke) occurred more frequently during treatment and the 30 days after treatment in patients receiving varenicline when compared with patients receiving placebo, while overall and cardiovascular mortality was lower with varenicline.1 19 Results were not statistically significant but were consistent; power was limited due to low event rates.1 19

Not studied in patients with unstable cardiovascular disease or in patients having experienced a cardiovascular event during the 2 months prior to screening.1

Weigh risks against benefits of varenicline use in smokers with cardiovascular disease.1 17 Smoking is an independent and major risk factor for cardiovascular disease, and cessation is of particular importance in this patient population.1 17

Advise patients to notify a healthcare provider if experiencing new or worsening symptoms of cardiovascular disease.1 18

Accidental Injury

Traffic accidents, near-miss incidents in traffic, or other accidental injuries reported.1 In some cases, somnolence, dizziness, loss of consciousness or difficulty concentrating was reported.1 (See Advice to Patients.)

Nausea

Nausea is most commonly reported adverse effect; usually mild or moderate, dose related, and often transient (although may persist for several months).1 3 4 8

Initial titration of varenicline dosage reduces incidence of nausea (see Dosage under Dosage and Administration).1 Consider dosage reduction in patients experiencing intolerable nausea.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in animals; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 (See Special Populations under Pharmacokinetics.)

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Select dosage cautiously because of age-related decreases in renal function.1 May be useful to monitor renal function in geriatric patients.1

Renal Impairment

Exposure to the drug was increased in patients with moderate to severe renal impairment and in patients with end-stage renal disease undergoing hemodialysis.1

Dosage adjustment recommended for patients with severe renal impairment or end-stage renal disease undergoing hemodialysis.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, abnormal (vivid, unusual, strange) dreams, constipation, flatulence, vomiting.1

Interactions for Varenicline tartrate

Physiologic changes resulting from smoking cessation (with or without varenicline) may alter the pharmacokinetics or pharmacodynamics of some drugs (e.g., insulin, theophylline, warfarin); dosage adjustment may be required.1

Varenicline does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 in vitro; does not induce CYP isoenzymes 1A2 or 3A4 in vitro.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely with drugs metabolized by or affecting CYP isoenzymes.1

Drugs Eliminated by Renal Secretion

Clinically important pharmacokinetic interaction requiring dosage reduction of varenicline unlikely.1

Organic Cation Transporter Inhibitors

Potential pharmacokinetic interaction (increased plasma concentration of varenicline as a result of a reduction in renal clearance).1 Concomitant use with OCT2 inhibitors may not necessitate varenicline dosage adjustment; increased systemic exposure to varenicline is not expected to be clinically important.1

Specific Drugs

Drug

Interaction

Comments

Bupropion

Pharmacokinetic interaction unlikely1

Safety of combined use not established1

Cimetidine

Possible increased plasma concentration of varenicline secondary to a reduction in renal clearance1

Interaction not expected to be clinically important;1 dosage adjustment may not be necessary1

Digoxin

Pharmacokinetic interaction unlikely1

Metformin

Pharmacokinetic interaction unlikely1

Nicotine

Pharmacokinetic interaction unlikely;1 increased incidence of adverse effects (nausea, headache, vomiting, dizziness, dyspepsia, fatigue) and increased rate of discontinuance of combination (varenicline and transdermal nicotine replacement) therapy compared with those receiving transdermal nicotine and placebo1

Safety and efficacy of varenicline in combination with other smoking cessation therapies not established1

Warfarin

Pharmacokinetic interaction unlikely;1 warfarin pharmacokinetics may be affected by smoking cessation1

Varenicline tartrate Pharmacokinetics

Absorption

Bioavailability

Almost completely absorbed following oral administration; approximately 90% bioavailable.1 Time of dosing does not appear to affect oral bioavailability.1

Peak plasma concentration usually attained within 3–4 hours.1

Food

Food does not appear to affect oral bioavailability.1

Distribution

Plasma Protein Binding

≤20%; independent of age and renal function.1

Elimination

Metabolism

Undergoes limited biotransformation.1

Elimination Route

Excreted in urine principally (92%) as unchanged drug.1

Half-life

24 hours.1

Special Populations

No evidence of gender-, age-, race-, smoking status-, or concomitant drug-related pharmacokinetic differences.1

In pediatric patients 12–17 years of age, systemic exposure (assessed by AUC and renal clearance) in those weighing >55 kg was comparable to that in adults over dosage range of 0.5–2 mg daily; however, in those weighing ≤55 kg, steady-state exposure at a dosage of 0.5 mg twice daily was approximately 40% higher compared with that in adults.1

In individuals with moderate (Clcr ≤50 mL/minute) to severe (Clcr <30 mL/minute) renal impairment or end-stage renal disease undergoing hemodialysis, exposure to varenicline was increased. 1 (See Renal Impairment under Dosage and Administration.) Pharmacokinetics unchanged in individuals with mild renal impairment (estimated Clcr >50 mL/minute up to 80 mL/minute).1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Binds with high affinity and selectivity to α4β2 nicotinic acetylcholine receptors located in the brain to stimulate receptor-mediated activity, but at a substantially lower level than nicotine.1 6

  • Stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation.1 4 6

  • Blocks the ability of nicotine to activate α4β2 receptors by preventing nicotine-induced stimulation of the mesolimbic dopaminergic system and thus reducing the reinforcement and reward effects of cigarette smoking.1 6

Advice to Patients

  • A medication guide must be dispensed with every prescription for the drug.14 Patients should be instructed to read the medication guide before initiation of varenicline therapy and every time the prescription is refilled since the information may have been revised.1

  • Importance of providing educational materials and counseling to support patient’s attempt to quit smoking.1

  • Advise patients to set a date to quit smoking and to start varenicline therapy 1 week prior to the quit date.1 Alternatively, patients may begin treatment with varenicline and then quit smoking between days 8 and 35 of treatment.1 Importance of encouraging patients to continue to attempt to quit smoking if they have early lapses after the set quit date.1

  • Importance of taking varenicline after eating and with a full glass of water.1

  • Advise patients to take the drug exactly as prescribed by clinician.1 Importance of instructing patients how to titrate varenicline dosage, starting with a dosage of 0.5 mg daily.1 (See Smoking Cessation under Dosage and Administration.)

  • Advise patients that nausea or insomnia (usually transient) may occur; advise patient to notify clinician if these adverse effects persist.1 Consideration of dosage reduction may be necessary.1

  • Importance of informing patients that quitting smoking, with or without use of varenicline, may be associated with symptoms of nicotine withdrawal (e.g., depression, agitation, hostility, urge to smoke, difficulty sleeping, irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite, weight gain) or exacerbation of preexisting psychiatric illness.1 10 13

  • Importance of advising patients and their caregivers that changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide, have been reported in patients attempting to quit smoking while receiving varenicline.1 10 11 12 13 Importance of advising patients to discontinue varenicline and notify a clinician if they or their caregivers observe agitation, depressed mood, or changes in behavior or thinking that are not typical for the patients, or if the patient develops suicidal ideation or suicidal behavior.1 10 11 13 Importance of informing clinicians of preexisting psychiatric illness.1

  • Risk of angioedema or serious skin reactions.1 Importance of immediately discontinuing varenicline and contacting a clinician at first sign of rash with mucosal lesions (e.g., peeling skin, mouth blisters) or other skin reactions or symptoms of angioedema (e.g., swelling of the face, mouth [lips, gums, tongue], throat).1

  • Risk of cardiovascular events.1 Importance of informing clinicians of symptoms of new or worsening heart disease;1 importance of seeking immediate medical attention if experiencing signs and symptoms of MI (e.g., chest discomfort that lasts more than few minutes or recurs; pain or discomfort in arm(s), back, neck, jaw, or stomach; shortness of breath; sweating; nausea; vomiting; feeling lightheaded in association with chest discomfort).1

  • Importance of informing clinicians about development of symptoms associated with previous attempts to quit smoking (with or without varenicline).1

  • Importance of informing patients that they may experience vivid, unusual, or strange dreams during varenicline treatment.1

  • Somnolence, dizziness, or difficulty concentrating reported.1 Importance of advising patients to use caution while driving, operating machinery, or engaging in other potentially hazardous activities until the effects of varenicline on the individual are known.1

  • Importance of informing patients that some medications may require dosage adjustment due to effects of smoking cessation.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise such women of risks of smoking to a pregnant woman and the developing fetus, risks and benefits of using varenicline to aid in smoking cessation during pregnancy and breast-feeding, and benefits of smoking cessation with or without varenicline.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., depression or other psychiatric illness, renal disease).1 Some concomitantly administered drugs may require dosage adjustment due to effects of smoking cessation.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Varenicline Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

11 Tablets, film-coated, Varenicline Tartrate 0.5 mg (of varenicline) (Chantix)

42 Tablets, film-coated, Varenicline Tartrate 1 mg (of varenicline) (Chantix)

Chantix Pack (available as dose/cards for first month of therapy)

Pfizer

Tablets, film-coated

0.5 mg (of varenicline)

Chantix

Pfizer

1 mg (of varenicline)

Chantix (available as 4 cards of 14 tablets and regular packaging)

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Chantix 0.5MG Tablets (PFIZER U.S.): 56/$177.65 or 168/$499.17

Chantix 1MG Tablets (PFIZER U.S.): 56/$179.00 or 168/$506.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 28, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer Labs. Chantix (varenicline) tablets prescribing information. New York, NY; 2013 Feb.

2. Kuehn BM. FDA speeds smoking cessation drug review. JAMA. 2006; 295:614. [PubMed 16467225]

3. Jorenby DE, Hays JT, Rigotti NA et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006; 296:56-63. [PubMed 16820547]

4. Gonzales D, Rennard SI, Nides M et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006; 296:47-55. [PubMed 16820546]

5. Tonstad S, Tonnesen P, Hajek P et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006; 296:64-71. [PubMed 16820548]

6. Coe JW, Brooks PR, Vetelino MG et al. Varenicline: an α4β2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005; 48:3474-7. [PubMed 15887955]

8. Klesges RC, Johnson KC, Somes G. Varenicline for smoking cessation: definite promise, but not panacea. JAMA. 2006; 296:94-5. [PubMed 16820552]

9. Pifzer Inc., Morris Plains, NJ: Personal communication.

10. Food and Drug Administration. FDA Alert: Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Rockville, MD; 2009 Jul 1. From the FDA web site. Accessed 2009 Sep 24.

11. Food and Drug Administration. FDA MedWatch alert: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Rockville, MD; 2009 Jul 1. From the FDA web site. Accessed 2009 Sep 25.

12. Pollock M, Lee JH. The smoking cessation aids varenicline (marketed as Chantix) and bupropion (marketed as Zyban and generics): suicidal ideation and behavior. Drug Safety Newsletter. 2009; 2:1–4. From the FDA web site. Accessed 2009 Sep 25.

13. Food and Drug Administration. Public Health Advisory: FDA requires new boxed warnings for the smoking cessation drugs Chantix and Zyban. Rockville, MD; 2009 Jul 1. From the FDA web site. Accessed 2009 Sep 25.

14. NDA 21-928 Chantix (varenicline) tablets nicotinic receptor partial agonist aid to smoking cessation risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2011 Jul 28.

15. Rigotti NA, Pipe AL, Benowitz NL et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010; 121:221-9. [PubMed 20048210]

16. Tashkin DP, Rennard S, Hays JT et al. Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial. Chest. 2011; 139:591-9. [PubMed 20864613]

17. Food and Drug Administration. FDA Drug Safety Communication: Chantix (varenicline) drug label now contains updated efficacy and safety information. Rockville, MD; 2011 Jul 22. From the FDA web site. Accessed 2011 Aug 8.

18. Food and Drug Administration. FDA Drug Safety Communication: Chantix (varenicline) may increase the risk os certain cardiovascular adverse events in patients with cardiovascular disease. Rockville, MD; 2011 Jun 16. From the FDA web site. Accessed 2011 Aug 8.

19. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of cardiovascular adverse events. Rockville, MD; 2012 Dec 12. From the FDA web site. Accessed 2013 Apr 10.

20. Williams JM, Anthenelli RM, Morris CD et al. A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012; 73:654-60. [PubMed 22697191]

152. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services, Public Health Service. 2008 May.

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