Varenicline tartrate

Nicotinic acetylcholine receptor partial agonist.1

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

In clinical studies, varenicline therapy increased continuous abstinence rates compared with placebo or active comparator (e.g., bupropion).1 3 4 5 15 16 21 Also reduced urge to smoke.1 3 4 5

In studies in patients with stable, documented cardiovascular disease and patients with mild to moderate COPD, efficacy of varenicline was comparable to that in the general smoking population without these conditions.3 4 15 16

Also evaluated in patients with stable major depressive disorder in a postmarketing study; benefits also observed in this population without evidence of increased neuropsychiatric effects.1 21 (See Neuropsychiatric Symptoms and Suicidality under Cautions.)

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

Contraindications

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

Warnings/Precautions

Neuropsychiatric Symptoms and Suicidality

Serious neuropsychiatric events, 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 during postmarketing experience with varenicline and bupropion (another smoking cessation drug); has occurred in patients with or without psychiatric history.1 10 11 12 13

Additional analyses and studies, including a large randomized controlled study in more than 8000 patients, indicate that risk is lower than previously thought and comparable to nicotine replacement therapy or placebo.1 20 21 22 24 25 26 27 However, there is evidence indicating that patients with a preexisting psychiatric illness (e.g., depression, anxiety disorder, schizophrenia) may be more likely to experience such events.1 24 25

Although risk remains, particularly in individuals with current or past psychiatric illnesses, patients generally do not experience serious consequences (e.g., hospitalization); therefore, benefits of smoking cessation (e.g., reduced risk of developing pulmonary disease, cardiovascular disease, and cancer) continue to outweigh risks of these cessation drugs.24

Monitor 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 Discontinue therapy, reduce dosage, or continue treatment under close monitoring based on severity of symptoms and patient response to smoking cessation therapy.1

Provide ongoing patient monitoring and supportive care until symptoms resolve.1 10

Some neuropsychiatric effects, including unusual and sometimes aggressive behavior directed toward oneself or others, may be worsened by concomitant use of alcohol.1 (See Specific Drugs under Interactions.)

Seizures

Seizures reported, in most cases occurring within first month of therapy.1 Observed in both patients with and without a seizure history.1

Weigh risks versus benefits in patients with a history of seizures or other factors that can lower seizure threshold.1 Discontinue the drug immediately if a seizure occurs during therapy.1 (See Advice to Patients.)

Concomitant Use of Alcohol

Decreased tolerance to alcohol reported during postmarketing experience, sometimes accompanied by unusual, aggressive behavior.1 (See Specific Drugs under Interactions.) In some cases, aggressive behavior resulted in harm to a person or property.1 22 Patients often had no memory or impaired memory of the events.1 22

Patients should reduce their consumption of alcohol until the effects of varenicline on alcohol tolerance are known.1 (See Advice to Patients.)

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.)

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

Somnambulism

Somnambulism, sometimes resulting in harm to self, others, or property, reported.1 (See Advice to Patients.)

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

Discontinue varenicline immediately if such symptoms occur.1 (See Advice to Patients.)

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

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

Available human data insufficient to determine a drug-related risk.1 No major malformations observed in animal reproductive studies, but some evidence of maternal toxicity, developmental toxicity, and decreased fetal weight.1

Smoking during pregnancy is associated with known risks to the mother, fetus, and newborn infant; not known whether smoking cessation with varenicline may reduce these risks.1

Distributed into milk in animals; not known whether distributed into human milk or if drug has any effect on breast-fed infant or on milk production.1 Consider known benefits of breast-feeding along with mother's clinical need for varenicline and any potential adverse effects of the drug or underlying maternal condition on the infant.1

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

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

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

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

• 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 encouraging patients who are motivated to quit but did not succeed with prior varenicline therapy for reasons other than intolerability due to adverse events, or who relapsed after treatment, to make another attempt with varenicline once factors contributing to the failed attempt have been identified and addressed.1 A gradual approach to smoking cessation with varenicline may be considered in patients who are not able or willing to quit abruptly.1 (See Dosage under Dosage and Administration.)

• 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 patients informing clinicians if they have a history of seizures or other factors that can lower seizure threshold.1 Importance of instructing patients to discontinue varenicline and immediately contact a clinician if they experience a seizure while receiving the drug.1

• Importance of advising patients to reduce the amount of alcohol they consume while receiving varenicline until they know whether the drug affects their tolerance to alcohol.1

• 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

• Risk of somnambulism; importance of patients discontinuing varenicline and informing their clinician if they experience such a condition.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.)