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Varenicline (systemic): Drug information

Varenicline (systemic): Drug information
(For additional information see "Varenicline (systemic): Patient drug information" and see "Varenicline (systemic): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • APO-Varenicline;
  • Chantix Continuing Month Pak [DSC];
  • Chantix Starting Month Pak [DSC];
  • Chantix [DSC]
Brand Names: Canada
  • APO-Varenicline;
  • Champix;
  • Champix Starter Pack;
  • TEVA-Varenicline
Pharmacologic Category
  • Partial Nicotine Agonist;
  • Smoking Cessation Aid
Dosing: Adult
Smoking cessation

Smoking cessation: Oral:

Initial:

Days 1 to 3: 0.5 mg once daily.

Days 4 to 7: 0.5 mg twice daily.

Maintenance (day 8 and later): 1 mg twice daily; may consider a temporary or permanent dose reduction if usual dose is not tolerated (Tonstad 2006; manufacturer's labeling).

Duration: Continue maintenance dose for at least 11 weeks (for a total of at least 12 weeks of treatment). May consider extended maintenance therapy based on individual patient risk:benefit; evidence suggests relapse prevention benefits with continuing therapy for up to 1 year (Leone 2020).

Approaches to selecting a tobacco quit date: May either choose a fixed quit date (ie, start varenicline, then quit on day 8) or a flexible quit date (ie, start varenicline, then quit between days 8 to 35). Alternatively, a gradual quit date (ie, start varenicline and reduce smoking 50% by week 4, reduce an additional 50% by week 8, and continue reducing with a goal of complete abstinence by week 12) is acceptable (Hajek 2011; Rigotti 2021; manufacturer's labeling).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Initial: 0.5 mg once daily; maximum maintenance dose: 0.5 mg twice daily

ESRD (receiving hemodialysis): Maximum dose: 0.5 mg once daily

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

(For additional information see "Varenicline (systemic): Pediatric drug information")

Smoking cessation: Adolescents ≥17 years: Note: Efficacy has not been established in patients <17 years of age; a randomized, double-blind, placebo-controlled trial including 216 pediatric patients 12 to 16 years of age showed that varenicline did not improve continuous abstinence rates; use is not recommended in pediatric patients ≤16 years of age. In another double-blind, placebo-controlled trial of 157 adolescents and young adults 14 to 19 years of age (mean age: 19.1 ± 1.5 years), the primary efficacy endpoint of end of treatment (week 12) abstinence was the same in both treatment and placebo groups at 8.9%; significant findings in secondary endpoints were observed, including higher weekly self-reported abstinence rates, and patients who achieved 7-day abstinence reported shorter time to achieve 7 days abstinence (39 days compared to 59 days with placebo) (Gray 2019).

Initial: See "Approaches to selecting a tobacco quit date" for additional information.

Days 1 to 3: Oral: 0.5 mg once daily.

Days 4 to 7: Oral: 0.5 mg twice daily.

Maintenance (≥ Day 8): Oral: 1 mg twice daily for 11 weeks; may consider a temporary or permanent dose reduction if usual dose is not tolerated. If patient successfully quits smoking at the end of the 12 weeks, may continue for another 12 weeks to help maintain success. Patients who are motivated to quit and do not succeed in stopping smoking during prior therapy, or who relapse after treatment, should be encouraged to make another attempt with varenicline once factors contributing to the failed attempt have been identified and addressed.

Approaches to selecting a tobacco quit date: May either choose a fixed quit date (ie, start varenicline, then quit on day 8) or a flexible quit date (ie, start varenicline, then quit between days 8 to 35). Alternatively, a gradual quit date (ie, start varenicline and reduce smoking 50% by week 4, reduce an additional 50% by week 8, and continue reducing with a goal of complete abstinence by week 12) is acceptable.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Adolescents ≥17 years: Patients who cannot tolerate adverse events may require temporary (or permanent) reduction in dose.

Dosing: Kidney Impairment: Pediatric

Adolescents ≥17 years:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Initial: 0.5 mg once daily; maximum maintenance dose: 0.5 mg twice daily.

End-stage renal disease (ESRD) (receiving hemodialysis): Maximum maintenance dose: 0.5 mg once daily.

Dosing: Hepatic Impairment: Pediatric

Adolescents ≥17 years: No dosage adjustment necessary.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Patients who cannot tolerate adverse events may require temporary (or permanent) reduction in dose.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as tartrate:

APO-Varenicline: 0.5 mg

APO-Varenicline: 1 mg [contains fd&c blue #2 aluminum lake]

Chantix: 0.5 mg [DSC]

Chantix: 1 mg [DSC] [contains fd&c blue #2 aluminum lake]

Chantix Continuing Month Pak: 1 mg [DSC] [contains fd&c blue #2 aluminum lake]

Chantix Starting Month Pak: 0.5 mg x 11 & 1 mg x 42 [DSC]

Generic: 0.5 mg, 1 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Miscellaneous, Oral, as tartrate:

Champix Starter Pack: 0.5 mg (11s) and 1 mg (14s) (25 ea)

Generic: 0.5 mg (11s) and 1 mg (14s) (25 ea)

Tablet, Oral, as tartrate:

Champix: 0.5 mg

Champix: 1 mg [contains fd&c blue #2 aluminum lake]

Generic: 0.5 mg, 1 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021928s048lbl.pdf#page=22, must be dispensed with this medication.

Administration: Adult

Oral: Administer after eating and with a full glass of water.

Administration: Pediatric

Oral: Administer after eating and with a full glass of water.

Use: Labeled Indications

Smoking cessation: As an aid to smoking cessation treatment.

Adverse Reactions (Significant): Considerations
Cardiovascular events

A 2011 meta-analysis suggested a potential increased risk of cardiovascular events with varenicline (Ref). However, this has not been observed in several subsequent studies (Ref). To further investigate the potential cardiovascular risk, the FDA requested a 52-week non-treatment extension of the EAGLES Trial, finding no increase in the composite of cardiovascular death, nonfatal acute myocardial infarction, or nonfatal stroke in patients treated with varenicline versus placebo (Ref). While data are inconclusive regarding whether treatment increases the risk of cardiovascular events, the risk appears lower than nicotine replacement therapy (Ref).

Mechanism: Dose-related; related to the pharmacologic action; hypothesized to be due to effects on nicotinic acetylcholine receptors which may impact cardiovascular function (Ref).

Disordered sleep

Abnormal dreams and nightmares have occurred with use. Cases of somnambulism (sleepwalking), involving harmful behavior to self, others, or property have also been reported, which generally resolve with treatment discontinuation (Ref).

Mechanism: Dose-related; related to the pharmacologic action. May also be related to nicotine withdrawal (Ref).

Onset: Varied; reported between 1 day and 1 to 2 months after initiation (Ref).

Nausea

Dose-dependent nausea may occur; both transient and persistent nausea have been reported (Ref).

Mechanism: Dose-related; related to the pharmacologic action; effects on nicotinic acetylcholine receptors (Ref).

Onset: Intermediate; usually begins within first 2 weeks of treatment (Ref).

Risk factors:

• Higher doses (Ref)

Neuropsychiatric effects

Postmarketing cases of serious neuropsychiatric events (including depression, suicidal ideation, and suicidal behavior) have been reported in patients with or without preexisting psychiatric disease; some cases may have been complicated by symptoms of nicotine withdrawal following smoking cessation. Subsequent controlled trials in patients with stable psychiatric disorders or those without psychiatric disorders, however, have not identified significant differences in neuropsychiatric effects for patients taking varenicline, bupropion, nicotine patches, or placebo (Ref). Many postmarketing cases resolved following therapy discontinuation.

Risk factors:

• Comorbid psychiatric illness (Ref)

Seizures

Postmarketing cases of seizures have been reported in patients with or without a history of seizures; however, subsequent observational studies have not shown a definitive association (Ref).

Mechanism: Dose-related; related to the pharmacologic action; possibly due to activation of α4β2 or α7 nicotinic acetylcholine receptors which can increase intracellular calcium levels and thus epileptic activity (Ref).

Onset: Varied; risk greatest within first month of treatment course (Ref).

Risk factors:

• First month of treatment (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Nausea (16% to 40%) (table 1), vomiting (5% to 11%)

Varenicline: Adverse Reaction: Nausea

Drug (Varenicline)

Placebo

Dose

Number of Patients (Varenicline)

Number of Patients (Placebo)

Comments

40%

8%

1 mg twice daily

N/A

N/A

N/A

30%

10%

1 mg twice daily

821

805

N/A

27%

10%

1 mg twice daily

256

269

Patients with major depressive disorder

25%

7%

1 mg twice daily

1,982

1,979

Patients with or without a history of psychiatric disorder

24%

14%

1 mg twice daily

84

43

Patients with stable schizophrenia or schizoaffective disorder

16%

10%

0.5 mg twice daily

129

805

N/A

Nervous system: Abnormal dreams (8% to 13%) (table 2), depressed mood (≤11%), headache (12% to 19%), insomnia (9% to 19%), irritability (11%)

Varenicline: Adverse Reaction: Abnormal dreams

Drug (Varenicline)

Placebo

Dose

Number of Patients (Varenicline)

Number of Patients (Placebo)

Comments

13%

5%

1 mg twice daily

821

805

N/A

12%

5%

1 mg twice daily

1,007

997

Patients with a history of psychiatric disorder

11%

8%

1 mg twice daily

256

269

Patients with major depressive disorder

9%

5%

0.5 mg twice daily

129

805

N/A

8%

4%

1 mg twice daily

975

982

Patients without a history of psychiatric disorder

1% to 10%:

Cardiovascular: Acute myocardial infarction (≤1%), angina pectoris (4%), chest pain (3%), peripheral edema (2%)

Dermatologic: Skin rash (3%)

Endocrine & metabolic: Menstrual disease, weight gain

Gastrointestinal: Abdominal pain (7%), anorexia (≤2%), constipation (5% to 8%), decreased appetite (≤2%), diarrhea (6%), dysgeusia (5% to 8%), dyspepsia (5%), flatulence (6% to 9%), gastroesophageal reflux disease (1%), increased appetite (3% to 4%), toothache, xerostomia (6%)

Hepatic: Abnormal hepatic function tests

Nervous system: Agitation (5% to 7%), anxiety (8%), disturbance in attention, dizziness, drowsiness (3%), emotional disturbance (5%), fatigue (≤7%), hostility (2% to 3%), lethargy (1% to 2%), malaise (≤7%), nightmares (1% to 2%) (table 3), sleep disorder (2% to 5% (table 4)), tension (4%)

Varenicline: Adverse Reaction: Nightmares

Drug (Varenicline)

Placebo

Dose

Number of Patients (Varenicline)

Number of Patients (Placebo)

2%

0%

0.5 mg twice daily

129

805

1%

0%

1 mg twice daily

821

805

Varenicline: Adverse Reaction: Sleep Disorder

Drug (Varenicline)

Placebo

Dose

Number of Patients (Varenicline)

Number of Patients (Placebo)

Comments

5%

3%

1 mg twice daily

821

805

N/A

3%

2%

1 mg twice daily

975

982

Patients without a history of psychiatric disorder

3%

2%

1 mg twice daily

1,007

997

Patients with a history of psychiatric disorder

2%

3%

0.5 mg twice daily

129

805

N/A

Neuromuscular & skeletal: Arthralgia, asthenia (≤7%), back pain, myalgia

Respiratory: Dyspnea (2%), respiratory system disorder, rhinorrhea (≤1%), upper respiratory tract infection (5% to 7%)

<1%:

Cardiovascular: Acute coronary syndrome, atrial fibrillation, bradycardia, cardiac arrhythmia, cardiac flutter, cerebrovascular accident, chest discomfort, coronary artery disease, ECG abnormality, edema, flushing, ophthalmic vascular disease, palpitations, pulmonary embolism, syncope, tachycardia, thrombosis, transient ischemic attacks, ventricular premature contractions

Dermatologic: Acne vulgaris, eczema, erythema of skin, hyperhidrosis, psoriasis, skin photosensitivity, urticaria, xeroderma

Endocrine & metabolic: Decreased libido, diabetes mellitus, hyperlipidemia, hypoglycemia, hypokalemia, thyroid disease

Gastrointestinal: Acute pancreatitis, dysphagia, enterocolitis, eructation, esophagitis, gallbladder disease, gastric ulcer, gastritis, gastrointestinal hemorrhage, intestinal obstruction, oral mucosa ulcer

Genitourinary: Abnormal urine test finding, erectile dysfunction, nocturia, pollakiuria, sexual difficulty, urethral disease, urinary retention, urine abnormality

Hematologic & oncologic: Anemia, leukocytosis, lymphadenopathy, splenomegaly, thrombocytopenia

Nervous system: Abnormal sensory symptoms, abnormality in thinking, altered sense of smell, amnesia, balance impairment, Bell's palsy, bradyphrenia, chills, decreased mental acuity, difficulty thinking, disorientation, dissociative disorder, dysarthria, emotional lability, euphoria, migraine, psychomotor agitation, psychomotor impairment, restless leg syndrome, seizure, vertigo

Neuromuscular & skeletal: Arthritis, elevation in serum levels of skeletal-muscle enzymes, multiple sclerosis, muscle cramps, musculoskeletal pain, myositis, osteoporosis, tremor

Ophthalmic: Blurred vision, cataract (subcapsular), conjunctivitis, eye irritation, eye pain, night blindness, nystagmus disorder, photophobia, transient blindness, visual field defect, vitreous opacity, xerophthalmia

Otic: Deafness, Meniere's disease, tinnitus

Renal: Acute kidney injury, nephrolithiasis, polyuria

Respiratory: Allergic rhinitis, asthma, cor pulmonale, epistaxis, flu-like symptoms, pleurisy, upper respiratory tract inflammation

Miscellaneous: Fever

Postmarketing:

Dermatologic: Erythema multiforme, Stevens-Johnson syndrome

Endocrine & metabolic: Hyperglycemia

Hypersensitivity: Angioedema (Seak 2019)

Nervous system: Aggressive behavior, behavioral changes, delusion, depression (Anthenelli 2016), hallucination, homicidal ideation, lack of concentration, loss of consciousness, mania, panic, paranoid ideation, psychosis, somnambulism (Savage 2015, Thomas 2015), suicidal behavior (Anthenelli 2016), suicidal ideation (Anthenelli 2016)

Miscellaneous: Accidental injury (Molero 2015)

Contraindications

Serious hypersensitivity reactions or skin reactions to varenicline or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking varenicline.

• Hypersensitivity reactions: Postmarketing reports of hypersensitivity reactions (including angioedema) and rare cases of serious skin reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported. Patients should be instructed to discontinue use and contact health care provider if signs/symptoms occur.

• Nausea: Dose-dependent nausea may occur; both transient and persistent nausea has been reported. Dosage reduction may be considered for intolerable nausea.

• Neuropsychiatric effects: Postmarketing cases of serious neuropsychiatric events (including depression, suicidal thoughts, and suicide) have been reported in patients with or without preexisting psychiatric disease; some cases may have been complicated by symptoms of nicotine withdrawal following smoking cessation. Subsequent controlled trials in patients with or without psychiatric disorders, however, have not identified significant differences in neuropsychiatric effects for patients taking varenicline, bupropion, nicotine patches, or placebo (Anthenelli 2013; Anthenelli 2016; Gibbons 2013; Thomas 2015). Monitor all patients for behavioral changes and psychiatric symptoms (eg, agitation, depression, suicidal behavior, suicidal ideation); inform patients to discontinue treatment and contact their health care provider immediately if they experience any behavioral and/or mood changes. Of postmarketing cases, many resolved following therapy discontinuation.

• Somnambulism: Cases of somnambulism, involving harmful behavior to self, others, or property, have been reported. Discontinue treatment if somnambulism occurs.

Disease-related concerns:

• Cardiovascular events: Treatment may increase risk of cardiovascular events; however, the risk appears lower than nicotine replacement therapy (Benowitz 2018; Carney 2020; Sterling 2016; Ware 2013). Patients should be instructed to contact their health care provider if cardiovascular symptoms occur.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required with severe impairment.

• Seizures: Seizures have been reported in patients with or without a history of seizures. Seizures generally occurred within the first month of therapy. Consider the risks against the benefits before initiating in patients with a history of seizures or other factors that can lower the seizure threshold; discontinue use if seizures occur during therapy.

Warnings: Additional Pediatric Considerations

Varenicline has not demonstrated efficacy in patients ≤16 years; the manufacturer conducted a randomized, double-blind, placebo-controlled trial including 216 pediatric patients 12 to 16 years of age as part of the Pediatric Research Equity Act which showed that varenicline did not increase smoking abstinence rates compared to placebo in this age group (FDA 2019).

Metabolism/Transport Effects

Substrate of OCT2

Drug Interactions

Alcohol (Ethyl): Varenicline (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). Specifically, alcohol tolerance may be decreased and the risk for neuropsychiatric adverse effects may be increased. Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of OCT2 Substrates. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of fexinidazole with OCT2 substrates when possible. If combined, monitor for increased OCT2 substrate toxicities. Risk D: Consider therapy modification

Nicotine: Varenicline (Systemic) may enhance the adverse/toxic effect of Nicotine. Risk C: Monitor therapy

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification

Pregnancy Considerations

The incidence of adverse pregnancy outcomes following maternal use of varenicline is not greater in comparison to pregnancy outcomes of pregnant patients who smoke (Pedersen 2020; Tran 2020; Turner 2019).

Varenicline is approved for use as an aid to smoking cessation. Adverse pregnancy outcomes are associated with maternal cigarette smoking (refer to Nicotine monograph for details). All pregnant patients should be screened for nicotine use, regardless of form (cigarettes, e-cigarettes, hookahs, snus, vaping products, as well as lozenges, patches, and gum). Cessation of intake is recommended, and interventions should be individualized (ACOG 2020). The benefit of tobacco smoking cessation for pregnant patients is well documented; behavioral interventions are effective and recommended. Information related to pharmacotherapy interventions in pregnancy is limited and insufficient to make specific recommendations (USPSTF [Krist 2021]). When behavioral counseling is insufficient, the severity of maternal tobacco dependance should be considered along with the known risks of smoking and possible risks of the pharmacologic intervention (ACOG 2020; USPSTF [Krist 2021]). The efficacy of varenicline as an aid to smoking cessation in pregnancy has not been established (Claire 2020; USPSTF [Krist 2021]).

Breastfeeding Considerations

It is not known if varenicline is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants exposed via breast milk should be monitored for seizures or excessive vomiting.

Dietary Considerations

Take after eating and with a full glass of water to decrease gastric upset.

Monitoring Parameters

Monitor for behavioral changes and psychiatric symptoms (eg, agitation, depression, suicidal behavior, suicidal ideation).

Mechanism of Action

Partial neuronal α4 β2 nicotinic receptor agonist; prevents nicotine stimulation of mesolimbic dopamine system associated with nicotine addiction. Also binds to 5-HT3 receptor (significance not determined) with moderate affinity. Varenicline stimulates dopamine activity but to a much smaller degree than nicotine does, resulting in decreased craving and withdrawal symptoms.

Pharmacokinetics

Absorption: Well absorbed; unaffected by food

Protein binding: ≤20%

Metabolism: Minimal (<10% of clearance is through metabolism)

Bioavailability: ~90%

Half-life elimination: ~24 hours

Time to peak, plasma: ~3 to 4 hours

Excretion: Urine (92% as unchanged drug)

Pharmacokinetics: Additional Considerations

Renal function impairment:

Moderate renal impairment (CrCl ≥30 to ≤50 mL/minute): Drug exposure increased 1.5-fold

Severe renal impairment (CrCl <30 mL/minute): Drug exposure increased 2.1-fold

ESRD requiring hemodialysis: Drug exposure increased 2.7-fold

Pricing: US

Tablets (Varenicline Tartrate Oral)

0.5 mg (per each): $8.79

1 mg (per each): $8.79

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Champix (AE, AR, AT, AU, BE, BG, BH, BR, BZ, CH, CL, CN, CO, CY, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, IN, IS, IT, JO, JP, KR, KW, LB, LT, LU, LV, MT, MX, MY, NL, NO, NZ, PE, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, UA, UY, VE, VN, ZW);
  • Varni (BD)


For country abbreviations used in Lexicomp (show table)

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