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VARENICLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Varenicline tartrate is a partial agonist of alpha-4-beta-2 nicotinic acetylcholine receptor types.

Specific Substances

    1) Vareniclina
    2) Vareniclinum
    3) Varenicline, Tartrate de
    4) Vareniclini Tartras
    5) 7,8,9,10-tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline
    6) 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1)
    7) CAS 249296-44-4 (varenicline)
    8) CAS 375815-87-5 (varenicline tartrate)
    1.2.1) MOLECULAR FORMULA
    1) C13-H13-N3 (varenicline)
    2) C13-H13-N3,C4-H6-O6 (varenicline tartrate)

Available Forms Sources

    A) FORMS
    1) Varenicline tartrate is available in the US as 0.5 mg capsular biconvex, white to off-white, film-coated tablets and 1 mg capsular biconvex, light blue film-coated tablets (Prod Info CHANTIX(R) oral tablets, 2014).
    B) USES
    1) Varenicline tartrate is used as an aid to smoking cessation treatment (Prod Info CHANTIX(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Varenicline is used as an aid for smoking cessation.
    B) PHARMACOLOGY: Varenicline tartrate is a partial agonist of alpha-4-beta-2 nicotinic acetylcholine receptor subtypes. Its binding can produce agonist activity at a subtype of the nicotinic receptor, but at a significantly lower level than nicotine. Varenicline also prevents nicotine binding to alpha-4-beta-2 receptors, which prevents stimulation of the central nervous mesolimbic dopamine system (ie, the mechanism responsible for the reinforcement and reward experience associated with smoking).
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Mild to moderate nausea (in up to 52%), insomnia (in up to 35%), headache (in up to 34%), and abnormal dreams (in up to 15%) are the most common adverse effects reported following varenicline use. Other adverse effects have included: abdominal pain, constipation, dry mouth, dyspepsia, flatulence, vomiting, anorexia, dysgeusia, increased appetite, gastroesophageal reflux disease, rash, somnolence, lethargy, nightmares, rhinorrhea and dyspnea. A manic episode and exacerbation of schizophrenia have been reported in patients several days after the initiation of varenicline. Based on postmarketing experience, serious neuropsychiatric events, including depression, suicidal ideation, suicide attempt, have been reported in some patients following the therapeutic use of varenicline.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Transient tachycardia and vomiting have been reported. Agitation and confusion have also been observed in a limited number of patients (adults and children) following exposure to varenicline. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.
    0.2.20) REPRODUCTIVE
    A) US FDA Category C. Adequate and well-controlled studies with varenicline in pregnant women are lacking. Until further data are available, varenicline should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of varenicline in humans.

Laboratory Monitoring

    A) Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea.
    B) Monitor neuro status as indicated.
    C) Monitor patients for psychiatric disturbances (eg, agitation, confusion) following exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea. Monitor neuro status as indicated. Monitor patients for psychiatric disturbances (eg, agitation, confusion) following exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. If significant agitation occurs, large doses of benzodiazepines may be required. Seizure activity has developed infrequently with use. Initially, treat with benzodiazepines (eg, diazepam, lorazepam). If seizures persist or recur, consider phenobarbital or propofol.
    C) DECONTAMINATION
    1) PREHOSPITAL: Severe toxicity is not anticipated. Vomiting may develop shortly after a significant inadvertent or intentional exposure. Prehospital decontamination should be avoided if vomiting is present.
    2) HOSPITAL: Consider activated charcoal following a recent, large ingestion or if more toxic coingestants are involved and the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a mild or moderate exposure. During postmarketing experience, there have been infrequent reports of life-threatening angioedema. Ensure adequate ventilation and airway support as needed.
    E) ANTIDOTE
    1) There is no specific antidote for varenicline overdose.
    F) ENHANCED ELIMINATION
    1) Although there is no experience with dialysis following overdose, dialysis was found to be effective in removing varenicline in patients with end-stage renal disease who were receiving 0.5 mg daily.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a minor unintentional exposure (1.5 mg or less) who are asymptomatic or have mild symptoms (eg, gastrointestinal) can likely be managed at home.
    2) OBSERVATION CRITERIA: Mild to moderately symptomatic patients should be sent to a health care facility for evaluation and treatment as necessary. Neuropsychiatric events (eg, agitation, confusion) have been observed in some patients (adults and children) following inadvertent exposure to varenicline.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison control center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PHARMACOKINETICS
    1) Tmax: 3 to 4 hours after oral administration. Plasma protein binding is low (less than or equal to 20%). The elimination half-life is approximately 24 hours. Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine.
    I) PITFALLS
    1) Failure to obtain an adequate history of exposure.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that can cause gastrointestinal or neurologic disorders.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Transient tachycardia and vomiting, and mild hypertension developed in an adolescent who ingested 15 mg. Another teenager ingested 10 mg and developed agitation, vomiting, tachycardia and tachypnea; symptoms resolved completely with supportive care. Varenicline was associated with the death of a 37-year-old man following an estimated ingestion of 83 mg.
    B) THERAPEUTIC DOSE: ADULT: The maximum total daily therapeutic dose is 2 mg. In clinical trials, a daily dose of 3 mg twice daily produced minimal increases in the incidence of common side effects. PEDIATRIC: The safety and efficacy of varenicline have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Varenicline is used as an aid for smoking cessation.
    B) PHARMACOLOGY: Varenicline tartrate is a partial agonist of alpha-4-beta-2 nicotinic acetylcholine receptor subtypes. Its binding can produce agonist activity at a subtype of the nicotinic receptor, but at a significantly lower level than nicotine. Varenicline also prevents nicotine binding to alpha-4-beta-2 receptors, which prevents stimulation of the central nervous mesolimbic dopamine system (ie, the mechanism responsible for the reinforcement and reward experience associated with smoking).
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Mild to moderate nausea (in up to 52%), insomnia (in up to 35%), headache (in up to 34%), and abnormal dreams (in up to 15%) are the most common adverse effects reported following varenicline use. Other adverse effects have included: abdominal pain, constipation, dry mouth, dyspepsia, flatulence, vomiting, anorexia, dysgeusia, increased appetite, gastroesophageal reflux disease, rash, somnolence, lethargy, nightmares, rhinorrhea and dyspnea. A manic episode and exacerbation of schizophrenia have been reported in patients several days after the initiation of varenicline. Based on postmarketing experience, serious neuropsychiatric events, including depression, suicidal ideation, suicide attempt, have been reported in some patients following the therapeutic use of varenicline.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Transient tachycardia and vomiting have been reported. Agitation and confusion have also been observed in a limited number of patients (adults and children) following exposure to varenicline. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported in a limited number of cases following intentional exposure to varenicline (Kreshak et al, 2009; Hedlund et al, 2009).
    b) A 16-year-old girl ingested 15 mg varenicline and developed tachycardia (heart rate, 129 bpm), mild hypertension (135/90 mm Hg) and one episode of vomiting; pulse and blood pressure were normal 4 hours later (Hedlund et al, 2009).
    B) ATRIAL FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) In a clinical trial, one patient developed atrial fibrillation on day 84 after initiation of drug, which was attributed to varenicline (Gonzales et al, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASAL DISCHARGE
    1) WITH THERAPEUTIC USE
    a) Rhinorrhea has been reported in 1% of patients taking varenicline compared to no reports in placebo-treated patients (Prod Info CHANTIX(R) oral tablets, 2014a).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported in 2% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 1% of patients (n=821) treated with 1 mg orally twice daily compared to 1% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with varenicline therapy (Kreshak et al, 2009).
    b) Headache was reported in 19% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 15% of patients (n=821) treated with 1 mg orally twice daily compared to 13% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 18% (n=821) and 19% (n=129) of patients treated with varenicline 1 mg or 0.5 mg orally twice daily, respectively, compared to 13% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported infrequently during clinical trials and in postmarketing experience. In some patients, there was no history of seizure disorder. In most cases, the seizure activity usually occurred during the first month of therapy (Prod Info CHANTIX(R) oral tablets, 2014a).
    D) DREAM DISORDER
    1) WITH THERAPEUTIC USE
    a) Abnormal dreams occurred at approximately a 2-fold higher rate in patients treated with varenicline compared to placebo-treated patients (9% to 13% vs 5%, respectively) (Prod Info CHANTIX(R) oral tablets, 2014a).
    b) Patients treated with varenicline reported experiencing nightmares; whereas, placebo-treated patients (n=805) did not report any nightmares. Nightmares occurred in 2% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 1% of patients (n=821) treated with 1 mg orally twice daily (Prod Info CHANTIX(R) oral tablets, 2014a).
    E) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence has been reported in 3% of patients (n=129) treated with varenicline 0.5 mg twice daily and 3% of patients (n=821) treated with 1 mg orally twice daily compared to 2% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    b) Patients treated with varenicline for smoking cessation reported lethargy (1% to 2%); whereas, placebo-treated patients did not develop lethargy (Prod Info CHANTIX(R) oral tablets, 2014a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) The most common adverse effects reported in clinical trials were gastrointestinal adverse effects. Nausea was the most common adverse effect associated with varenicline administration. It was mild to moderate in severity, usually transient, and dose-dependent. Other common gastrointestinal adverse effects include: abdominal pain, constipation, dry mouth, dyspepsia and flatulence. Less frequently reported gastrointestinal complaints include: vomiting, anorexia, dysgeusia, increased appetite and gastroesophageal reflux disease. There have been rare reports of gastric ulcer, intestinal obstruction and acute pancreatitis (Prod Info CHANTIX(R) oral tablets, 2014a).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a two year retrospective, descriptive study conducted by the California Poison Control System, mild gastrointestinal symptoms (ie, nausea, abdominal pain, vomiting) were the most commonly reported adverse events following inadvertent exposure in pediatric patients and among adults with a minor exposure (i.e., an extra dose of varenicline) (Kreshak et al, 2009).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was the most common adverse effect reported in patients treated with varenicline in clinical trials and was generally mild to moderate in severity. The incidence of nausea was dose-related and occurred in 16% of patients (n=129) treated with 0.5 mg orally twice daily and in 30% of patients (n=821) treated with 1 mg orally twice daily compared to 10% of placebo-treated patients (n=805). In a one-year study, the incidence of nausea was reported in 40% of patients (n=821) treated with varenicline 1 mg orally twice daily compared to 8% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a). Other trials showed a rate of as high as 52% (Nides et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) Nausea developed in two patients following minor (ie, an "extra dose" of varenicline; median dose: 1.5 mg) inadvertent exposures to varenicline. They were managed successfully at home (Kreshak et al, 2009).
    C) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting was reported at a lower incidence than placebo at a dose of varenicline 0.5 mg (n=129) orally twice daily (1% vs 2%, respectively); however, at a dose of 1 mg (n=821) orally twice daily, the incidence of vomiting was 5% compared 2% of placebo-treated pateitns (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    2) WITH POISONING/EXPOSURE
    a) Vomiting has been reported in a limited number of cases following intentional exposure to varenicline (Kreshak et al, 2009; Hedlund et al, 2009).
    b) A 16-year-old girl ingested 15 mg varenicline and developed tachycardia, mild hypertension, and one episode of vomiting; pulse and blood pressure were normal 4 hours later (Hedlund et al, 2009).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In patients treated for smoking cessation, abdominal pain was reported in 5% of patients treated with varenicline 0.5 mg (n=129) orally twice daily compared to 5% of placebo-treated patients. Abdominal pain, including discomfort, tenderness, or distension was reported in 7% of patients treated with 1 mg (n=821) orally twice daily compared to 5% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence occurred 2 to 3 times more frequently in patients treated with varenicline 1 mg (n=821) or 0.5 mg (n=129) orally twice daily compared to placebo-treated patients (6% to 9% vs 3%, respectively) (Prod Info CHANTIX(R) oral tablets, 2014a).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) The incidence of dyspepsia reported in clinical trials was 5% for the treatment groups (0.5 mg (n=129) and 1 mg (n=821)) compared to 3% of the placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    G) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 5% (n=129) and 8% (n=821) of patients taking varenicline 0.5 mg or 1 mg orally twice daily, respectively, compared to 3% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    H) GASTROESOPHAGEAL REFLUX DISEASE
    1) WITH THERAPEUTIC USE
    a) Gastroesophageal reflux disease (GERD) has been reported in 1% of all patients treated with varenicline (0.5 mg (n=129) and 1 mg (n=821)) compared to no reports in placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    I) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth was reported in 4% (n=129) and 6% (n=821) of patients treated with varenicline 0.5 mg or 1 mg orally twice daily, respectively, compared to 4% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    J) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) During clinical trials, decreased appetite was reported with varenicline administration. Anorexia was reported in 1% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 2% of patients (n=821) treated with 1 mg orally twice daily compared to 1% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    K) INCREASED APPETITE
    1) WITH THERAPEUTIC USE
    a) Appetite was increased in 4% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 3% of patients (n=821) treated with 1 mg orally twice daily compared to 2% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).
    L) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) Dysgeusia occurred in 8% of patients (n=129) treated with varenicline 0.5 mg orally twice daily and 5% of patients (n=821) treated with 1 mg orally twice daily compared to 4% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash was reported in 1% (n=129) and 3% (n=821) of patients taking varenicline 0.5 mg or 1 mg orally twice daily, respectively, compared to 2% of placebo-treated patients (n=805) (Prod Info CHANTIX(R) oral tablets, 2014a).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of varenicline in humans.
    3.21.4) ANIMAL STUDIES
    A) HIBERNOMA
    1) In male Sprague-Dawley rats (n=65 per sex per dose group) administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years, incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC) (Prod Info CHANTIX(R) oral tablets, 2011).
    B) LACK OF EFFECT
    1) In studies of carcinogenicity in CD-1 mice, no evidence of carcinogenic effects was observed in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on AUC). In a study on Sprague-Dawley rats administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years, no evidence of carcinogenicity was observed in females (Prod Info CHANTIX(R) oral tablets, 2011).

Genotoxicity

    A) Varenicline did not induce genetic damage, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes (Prod Info CHANTIX(R) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) US FDA Category C. Adequate and well-controlled studies with varenicline in pregnant women are lacking. Until further data are available, varenicline should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) Adequate and well-controlled studies with varenicline in pregnant women are lacking. Until further data are available, varenicline should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus (Prod Info CHANTIX(TM) oral tablets, 2006).
    B) PREGNANCY CATEGORY
    1) US FDA Category C (Prod Info CHANTIX(TM) oral tablets, 2006)
    C) ANIMAL STUDIES
    1) As the succinate salt, varenicline did not display teratogenicity in rats and rabbits at oral doses up to 15 to 30 mg/kg/day, respectively (36 and 50 times the maximum recommended human daily dose (MRHDD) based on AUC with 1 mg twice-daily dosing, respectively). Although a reduction in fetal weight was observed at an oral dose of 30 mg/kg/day in pregnant rabbits, doses of 10 mg/kg/day (23-times the MRHDD) did not cause a similar effect. In pregnant rats, oral doses of varenicline succinate 15 mg/kg/day resulted in decreased fertility and increased auditory startle responses (Prod Info CHANTIX(TM) oral tablets, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ANIMAL STUDIES
    1) In animal studies varenicline was transferred to nursing pups, although it is unknown whether it is excreted into human milk. However, due to the potential for serious adverse reactions and until further data are available, a decision should be made whether to discontinue varenicline or to discontinue nursing, considering the importance of varenicline to the mother (Prod Info CHANTIX(TM) oral tablets, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, varenicline succinate doses of up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg twice daily) did not affect fertility in male or female Sprague-Dawley rats. However, fertility was decreased in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg twice daily) (Prod Info CHANTIX(TM) oral tablets, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea.
    B) Monitor neuro status as indicated.
    C) Monitor patients for psychiatric disturbances (eg, agitation, confusion) following exposure.

Methods

    A) GAS-CHROMATOGRAPHY/MASS SPECTROMETRY
    1) Postmortem toxicological analyses using gas-chromatography-mass spectrometry revealed a massive overdose in a 37-year-old man that had ingested an estimated 83 1-mg varenicline tablets. The following concentrations included: blood (vena subclavia resp, vena femoralis), urine (non-hydrolysed) and vitreous humor of 262, 257, 687 and 165 ng/mL, respectively. The blood concentration of more than 250 ng/mL was almost 10-fold higher than a previously reported concentration (ie, 28.3 ng/mL following a multiple-day high dose regimen of up to 3 mg daily). Other findings were positive for ethanol (1.57 g/L (blood) and 2.79 g/L (urine) and caffeine (Stove et al, 2013).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with a minor unintentional exposure (1.5 mg or less) who are asymptomatic or have mild symptoms (eg, gastrointestinal) can likely be managed at home (Kreshak et al, 2009).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison control center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Mild to moderately symptomatic patients should be sent to a health care facility for evaluation and treatment as necessary. Neuropsychiatric events (eg, agitation, confusion) have been observed in some patients (adults and children) following inadvertent exposure to varenicline (Kreshak et al, 2009).

Monitoring

    A) Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea.
    B) Monitor neuro status as indicated.
    C) Monitor patients for psychiatric disturbances (eg, agitation, confusion) following exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Severe toxicity is not expected. Vomiting is likely to occur shortly after exposure. Prehospital decontamination should be avoided if vomiting is present.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastrointestinal decontamination is not routinely required.
    2) Vomiting is likely to occur shortly after exposure (Rollema et al, 2009; Stove et al, 2013). Activated charcoal should be considered after extremely large ingestions or if more toxic coingestants are involved and the airway is protected.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea. Monitor neuro status as indicated. Monitor patients for psychiatric disturbances (eg, agitation, confusion) following exposure.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. If significant agitation occurs, large doses of benzodiazepines may be required. Seizure activity has developed infrequently with therapeutic use. Initially, treat with benzodiazepines (eg, diazepam, lorazepam). If seizures persist or recur, consider phenobarbital or propofol.
    B) MONITORING OF PATIENT
    1) Monitor patients for psychiatric disturbances following exposure. Neuropsychiatric events (eg, agitation, confusion) have been observed in some patients (adults and children) following inadvertent exposure to varenicline (Kreshak et al, 2009).
    2) Monitor neuro status as indicated.
    3) Monitor fluid and electrolytes in patients with prolonged vomiting and/or diarrhea.
    C) SEIZURE
    1) Seizures have been reported infrequently during clinical trials and postmarketing experience. In some patients, there was no prior history of seizure disorder (Prod Info CHANTIX(R) oral tablets, 2014a).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Although there is no experience with dialysis following overdose, dialysis was found to be effective in removing varenicline in patients with end-stage renal disease who were receiving 0.5 mg daily (Prod Info CHANTIX(R) oral tablets, 2014a).

Abstracts

Case Reports

    A) PEDIATRIC
    1) A 16-year-old girl ingested 15 mg varenicline and developed tachycardia (heart rate 129 beats/min), mild hypertension (135/90 mm Hg) and one episode of vomiting; pulse and blood pressure were normal 4 hours later (Hedlund et al, 2009).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Transient tachycardia and vomiting, and mild hypertension developed in an adolescent who ingested 15 mg. Another teenager ingested 10 mg and developed agitation, vomiting, tachycardia and tachypnea; symptoms resolved completely with supportive care. Varenicline was associated with the death of a 37-year-old man following an estimated ingestion of 83 mg.
    B) THERAPEUTIC DOSE: ADULT: The maximum total daily therapeutic dose is 2 mg. In clinical trials, a daily dose of 3 mg twice daily produced minimal increases in the incidence of common side effects. PEDIATRIC: The safety and efficacy of varenicline have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial Dose: 0.5 mg orally once daily for days 1 through 3, then 0.5 mg twice daily for days 4 through 7. For the duration of treatment, 1 mg twice daily for 12 weeks (Prod Info CHANTIX(R) oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) Safety and effectiveness in pediatric or adolescent patients have not been established (Prod Info CHANTIX(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) CASE REPORT: A 37-year-old man, with a history of alcohol abuse, was found unclothed along the side of a road after an argument with his family. He died sometime during the previous night. The ambient temperature was 7 degrees C when the body was found. Six empty blisters (14 tablets) and a single tablet of varenicline 1 mg were found in his car suggesting an ingestion of up to 83 tablets. Toxicological analyses were positive for ethanol (1.57 g/L (blood) and 2.79 g/L (urine)), caffeine and varenicline only. Analysis revealed a varenicline blood concentration of more than 250 ng/mL (in a previous study a plasma concentration following a multiple-day high-dose regimen of up to 3 mg/day was 28.3 ng/mL). It was concluded that the overdose of varenicline was directly involved in this fatality; however, contributing factors included ethanol consumption and possibly fatal hypothermia (Stove et al, 2013).

Maximum Tolerated Exposure

    A) SUMMARY
    1) The maximum total daily therapeutic dose is 2 mg (Prod Info CHANTIX(R) oral tablets, 2014a). In clinical trials, a daily dose of 3 mg twice daily produced minimal increases in the incidence of common side effects (Jorenby et al, 2006; Gonzales et al, 2006).
    B) CASE REPORTS
    1) ADOLESCENT: A 16-year-old girl intentionally ingested 30 0.5 mg varenicline tablets and developed transient tachycardia (129 bpm) and mild hypertension (135/90 mmHg). She had one episode of spontaneous vomiting and received a single dose of activated charcoal and was discharged to home 4 hours later (Hedlund et al, 2009).
    2) CASE SERIES: In a two year, retrospective, descriptive study conducted by the California Poison Control System, mild gastrointestinal symptoms (i.e., nausea, abdominal pain, vomiting) were the most commonly reported adverse events following inadvertent exposure in pediatric patients and among adults with a minor exposure (an extra dose of varenicline). Neuropsychiatric events (e.g., agitation, confusion, ataxia) were also observed in a 2-year-old girl following 1 mg of varenicline and in a 30-year-old schizophrenic man after taking a therapeutic dose. Both recovered completely (Kreshak et al, 2009).
    a) A 16-year-old girl developed agitation, vomiting, tachycardia and tachypnea following the intentional ingestion of 10 mg varenicline. She was treated with activated charcoal and observed. Symptoms resolved without hospital admission (Kreshak et al, 2009).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Steady state plasma concentrations were reached within 4 days following multiple doses of oral varenicline (Prod Info CHANTIX(R) oral tablets, 2014a).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Studies have shown that varenicline binds with high affinity and selectivity at alpha-4-beta-2 neuronal nicotinic acetylcholine receptors. Its binding produces agonist activity at a sub-type of the nicotinic receptor, but at a significantly lower level than nicotine. Varenicline also prevents nicotine binding to alpha-4-beta-2 receptors, which prevents stimulation of the central nervous mesolimbic dopamine system (the mechanism responsible for the reinforcement and reward experience associated with smoking) (Prod Info CHANTIX(R) oral tablets, 2014a).
    B) Varenicline alleviates the symptoms of craving and withdrawal via its agonist activity while inhibiting the effects of repeated exposure via its antagonist activity (Potts & Garwood, 2007).

Toxicologic Mechanism

    A) PROTECTIVE EFFECT: It has been suggested that vomiting following a high dose of varenicline may be due to the activation of gastrointestinal 5-HT3 receptors. Varenicline is a 5-HT3A receptor agonist and it is thought that high gut concentrations would allow transient activation of local 5-HT3 receptors thus producing the rapid onset of vomiting following ingestion which could limit systemic exposure (Rollema et al, 2009).

Physicochemical

Physical Characteristics

    A) VARENICLINE TARTRATE - A white to off-white to slightly yellow powder, highly soluble in water (Prod Info CHANTIX(TM) oral tablets, 2006).

Molecular Weight

    A) 361.35 daltons (varenicline tartrate) (Prod Info CHANTIX(TM) oral tablets, 2006).

References

General Bibliography

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