Varenicline

211.26

211.26

N07BA03|N - Nervous system

152.87000

0.01010

1.247g/cm3

138.5 °C

400.6ºC at 760mmHg

196.1ºC

1.667

In water, 5.15X10+4 mg/L at 25 °C (est)

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place.|Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).

4.65X10-6 mm Hg at 25 °C (est)

Henry's Law constant = 2.68X10-11 atm-cu m/mol at 25 °C (est)

pKa1 = 1.82 (amine); pKa2 = 9.73 (secondary amine) (est)

White to off-white to slightly yellow solid; highly soluble in water /Verencline tartrate/|Hydroxyl radical reaction rate constant = 3.77X10-11 cu cm/molec-sec at 25 °C (est)

Stable under recommended storage conditions.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including varenicline tartrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Varenicline tartrate/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P273, P301+P312, P330, P391, and P501|Aggregated GHS information provided by 18 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302: Harmful if swallowed [Warning Acute toxicity, oral]

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: impervious clothing, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Skin protection: Handle with gloves.|Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection.

IDENTIFICATION AND USE: Varenicline is used as an adjunct in the cessation of cigarette smoking. HUMAN EXPOSURE AND TOXICITY: Safety and efficacy of varenicline as an adjunct for smoking cessation have been established in 6 placebo-controlled or active-comparator studies in 3659 patients (mean age: 43 years; 79-96% white; mean smoking history: about 25 years) who smoked at least 10 cigarettes daily (mean: about 21 cigarettes daily). Safety and efficacy of varenicline also have been evaluated in a randomized, double-blind, placebo-controlled study in 703 patients with stable, documented cardiovascular disease (other than hypertension) who smoked at least 10 cigarettes daily; patients receiving varenicline and placebo were comparable in baseline characteristics, including age (mean age 57 and 55.9 years, respectively), race (80.3 and 80.8% white, respectively), gender (75.2 and 82.2% male, respectively), and mean smoking history (40 and 39 years, and 22.1 and 22.9 cigarettes daily, respectively). Safety and efficacy of varenicline also have been evaluated in a randomized, double-blind, placebo-controlled study in 460 patients (mean age 57 years, 82-84% white, approximately 62% male, mean smoking history of approximately 40 years) with mild to moderate chronic obstructive pulmonary disease (postbronchodilator FEV1/FVC below 70% and FEV1 at least 50% of predicted normal value) who smoked at least 10 cigarettes daily. 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), have been reported during postmarketing experience in patients receiving varenicline. Hypersensitivity reactions, including angioedema, have been reported during postmarketing experience in patients receiving varenicline. Safety and efficacy of varenicline have not been established in patients younger than 18 years of age and use of the drug in this age group is not recommended. Varenicline was not genotoxic, with or without metabolic activation in vitro in human lymphocytes. ANIMAL STUDIES: Varenicline is distributed into milk in animals. Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), 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). There was no evidence of carcinogenicity in female rats. Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC). Varenicline succinate was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36 and 50 times the maximum recommended human daily exposure based on AUC, respectively). Varenicline was not genotoxic, 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.

Varenicline has not been associated with rates of serum enzyme elevations during therapy greater than occurs with placebo therapy, but information on these abnormalities is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation have been reported. In prelicensure pivotal registration trials in several thousand patients, varenicline was not associated with cases of jaundice or hepatitis. Since licensure, rare case reports of serum enzyme elevations without jaundice arising within 4 weeks of starting varenicline have been published, but largely in patients with other causes of liver injury (alcoholic liver disease, hepatitis C). The injury was self-limited in course and not associated with immunoallergic or autoimmune features. In Iceland, a single case of varenicline hepatotoxicity has been reported (Case 1), there having been an estimated 20,000 persons treated with the drug in the country since its introduction.

Pharmacokinetic interactions unlikely with drugs metabolized by or affecting cytochrome P-450 (CYP) isoenzymes. In vitro studies indicate that varenicline does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 in vitro. The drug also does not induce CYP isoenzymes 1A2 or 3A4.|Physiologic changes resulting from smoking cessation (with or without varenicline) may alter the pharmacokinetics or pharmacodynamics of some drugs (e.g., theophylline, warfarin, insulin); dosage adjustment may be required. The manufacturer states that clinical experience in patients receiving varenicline with other drugs has not revealed evidence of clinically important interactions.|Pharmacokinetic interaction unlikely. 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 placebo. Safety and efficacy of varenicline in combination with other smoking cessation therapies have not been studied.|Pharmacokinetic interaction unlikely. Warfarin pharmacokinetics may be affected by smoking cessation.|For more Interactions (Complete) data for VARENICLINE (7 total), please visit the HSDB record page.

Varenicline should be used with caution in patients with moderate to severe renal impairment and in patients with end-stage renal disease undergoing hemodialysis. Exposure to the drug was increased in patients with such impairment. Dosage adjustment is recommended for patients with creatinine clearance less than 30 mL/minute.|Varenicline has not been studied in patients with unstable cardiovascular disease or in patients who experienced a cardiovascular event during the 2 months prior to screening. Because smoking is an independent and major risk factor for cardiovascular disease, smoking cessation is of particular importance in this patient population. The risks of varenicline should be weighed against the benefits of its use in smokers with cardiovascular disease.

Less than 20%.

Varenicline's production and administration as an aid in smoking cessation(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5100(SRC), determined from a structure estimation method(2), indicates that varenicline is expected to be immobile in soil(SRC). The estimated pKa of varenicline is 9.73(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Varenicline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5100(SRC), determined from a structure estimation method(2), indicates that varenicline is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.73(3) indicates varenicline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 2(SRC), from an estimated log Kow of 1.03(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), varenicline, which has an estimated vapor pressure of 4.7X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase varenicline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3.4 hrs(SRC), calculated from its rate constant of 3.8X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase varenicline may be removed from the air by wet and dry deposition(SRC). Varenicline contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of varenicline with photochemically-produced hydroxyl radicals has been estimated as 3.8X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Varenicline is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Varenicline contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 2 was calculated in fish for varenicline(SRC), using an estimated log Kow of 1.03(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of varenicline can be estimated to be 5100(SRC). According to a classification scheme(2), this estimated Koc value suggests that varenicline is expected to be immobile in soil. The estimated pKa of varenicline is 9.73(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

An estimated pKa of 9.73(1) indicates varenicline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. Varenicline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-6 mm Hg(SRC), determined from a fragment constant method(2).

While data specific to varenicline were not located(SRC, 2015), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

EXPERIMENTAL: Although it is not known whether this drug is excreted in human milk, animal studies have demonstrated that varenicline can be transferred to nursing pups. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Chantix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Occupational exposure to varenicline may occur through inhalation and dermal contact with this compound at workplaces where varenicline is produced or used. Exposure to varenicline among the general population may be limited to those administered the drug, an aid to quitting smoking. (SRC)

For use as an aid in smoking cessation.|FDA Label|Champix is indicated for smoking cessation in adults.

Varenicline is a partial agonist of the nicotinic acetylcholine receptor and is used to help in smoking cessation. Varenicline has been associated with a low rate of serum enzyme elevations during therapy and, since approval and its widescale use, with rare instances of clinically apparent mild liver injury.

Substance Abuse Treatment Agents

Nicotinic Agonists|Varenicline is used as an adjunct in the cessation of cigarette smoking.|In this randomized, double-blind, multicenter trial, eligible adult smokers (18-75 years) who smoked an average of > or =10 cigarettes/day were randomized to either varenicline 1 mg twice daily (BID) or placebo for 52 weeks. Subjects made weekly clinic visits until week 8, and then every 4 weeks until week 52, with a follow-up visit at week 53. The target quit date was the morning of the week 1 clinic visit. Brief counseling was provided at each visit, and vital signs, adverse events, and smoking status were documented. Other laboratory measures were collected at specified visits. A total of 251 subjects were randomized to varenicline and 126 to placebo. Approximately half of the subjects in each arm completed the study (53.8% varenicline; 46.8% placebo). Treatment-emergent adverse events were observed in 96.4% of varenicline- and 82.5% of placebo-treated subjects during the study. Common varenicline-associated adverse events were nausea (40.2%), abnormal dreams (22.7%), and insomnia (19.1%). Most adverse events were considered mild or moderate in intensity. Adverse events leading to discontinuation of varenicline treatment included nausea (7.6%), insomnia (3.2%), and abnormal dreams (2.4%). A single varenicline-related serious AE, bilateral subcapsular cataracts, was observed. At week 52, 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo). Varenicline 1 mg BID can be safely administered for up to 1 year. Varenicline was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short- (12-week) and long-term (52-week) efficacy.

/BOXED WARNING/ WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS. Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking CHANTIX. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke. All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking CHANTIX in the postmarketing experience. When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy. These events have occurred in patients with and without pre-existing psychiatric disease. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX. Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.|The U.S. Food and Drug Administration (FDA) is warning that the prescription smoking cessation medicine Chantix (varenicline) can change the way people react to alcohol. In addition, rare accounts of seizures in patients treated with Chantix have been reported. We have approved changes to the Chantix label to warn about these risks. Until patients know how Chantix affects their ability to tolerate alcohol, they should decrease the amount of alcohol they drink. Patients who have a seizure while taking Chantix should stop the medicine and seek medical attention immediately. Millions of Americans have serious health problems caused by smoking, which can be reduced by quitting. Chantix is a prescription medicine that is FDA-approved to help adults quit smoking. In clinical trials, Chantix increased the likelihood of quitting smoking and "staying quit" for as long as 1 year compared to treatment with a placebo, an inactive treatment. We reviewed the case series submitted by Pfizer, the manufacturer of Chantix, as well as the cases in the FDA Adverse Event Reporting System (FAERS) database describing patients who drank alcohol during treatment with Chantix and experienced adverse reactions. Some patients experienced decreased tolerance to alcohol, including increased drunkenness, unusual or aggressive behavior, or they had no memory of things that happened (see Data Summary). We also reviewed FAERS and the medical literature1 for cases of seizures with Chantix and identified cases in which the patients who had seizures while taking Chantix either had no history of seizures or had a seizure disorder that had been well-controlled. In most of these cases, the seizures occurred within the first month of starting Chantix. Information about these risks has been added to the Warnings and Precautions section of the drug label and to the patient Medication Guide. We also updated the Warnings and Precautions section of the label to include information about several studies that investigated the risk of neuropsychiatric side effects on mood, behavior, or thinking occurring with Chantix. These included observational studies,2-5 as well as analyses that Pfizer conducted of randomized controlled clinical trial data.6 These studies did not show an increased risk of neuropsychiatric side effects with Chantix; however, they did not examine all types of neuropsychiatric side effects, and they had limitations that prevented us from drawing reliable conclusions. We previously communicated about possible serious neuropsychiatric side effects with Chantix in 2009 and 2011, and these recent studies were discussed at an FDA Advisory Committee meeting in October 2014. Pfizer is conducting a large clinical safety trial of Chantix to investigate this risk and results from this study are expected in late 2015. We will update the public as appropriate when this new information becomes available.|Varenicline is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to the drug.|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), have been reported during postmarketing experience in patients receiving varenicline. In most cases, symptoms developed during varenicline therapy but, in others, symptoms developed after discontinuance of the drug. Some of these reported cases may have been complicated by nicotine withdrawal symptoms in patients who had stopped smoking; depressed mood also may be a symptom of nicotine withdrawal, and depression, which rarely has included suicidal ideation, has been reported in patients undergoing a smoking cessation attempt without medication. However, some of these symptoms occurred in patients receiving varenicline who continued to smoke. Such effects have occurred in patients with or without psychiatric illnesses; worsening of preexisting psychiatric illness also has been reported. Nicotine withdrawal also has been associated with exacerbation of an underlying psychiatric illness.|For more Drug Warnings (Complete) data for VARENICLINE (19 total), please visit the HSDB record page.

Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.

Drugs that bind to and activate nicotinic cholinergic receptors (RECEPTORS, NICOTINIC). Nicotinic agonists act at postganglionic nicotinic receptors, at neuroeffector junctions in the peripheral nervous system, and at nicotinic receptors in the central nervous system. Agents that function as neuromuscular depolarizing blocking agents are included here because they activate nicotinic receptors, although they are used clinically to block nicotinic transmission. (See all compounds classified as Nicotinic Agonists.)|Substances that facilitate the cessation of tobacco smoking. (See all compounds classified as Smoking Cessation Agents.)

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.|Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (

Metabolism is limited (<10%). Most of the active compound is excreted by the kidneys (81%). A minor amount of varenicline is glucuronidated, oxidated, N-formylated, as well as conjugated to form a hexose.|Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.|Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

The elimination half-life of varenicline is approximately 24 hours|The elimination half-life of varenicline is approximately 24 hours.

Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectivity for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms.|Varenicline is a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist. The drug binds with high affinity and selectivity to alpha4beta2 nicotinic acetylcholine receptors located in the brain and stimulates receptor-mediated activity, but at a substantially lower level than nicotine;1 6 this low-level receptor stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation. Varenicline also blocks the ability of nicotine to activate alpha4beta2 receptors, preventing nicotine-induced stimulation of the mesolimbic dopaminergic system and thereby reducing the reinforcement and reward effects of cigarette smoking.|... The rationale for and the design of alpha(4)beta(2) neuronal nicotinic acetylcholine receptor (nAChR) partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating alpha(4)beta(2)-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective alpha(4)beta(2) nAChR partial agonists that exhibit dual agonist and antagonist activity in preclinical models can be identified. The validity of this approach is demonstrated by the clinical efficacy of the alpha(4)beta(2) nAChR partial agonist varenicline, which has significantly better quit rates than do other treatments and offers a new option for smoking cessation pharmacotherapy.|... Varenicline has been shown to be a partial agonist of alpha4beta2 receptors, and in equilibrium binding assays, it is highly selective for the alpha4beta2 receptor. ... The functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp /was examined/ . Varenicline is a potent, partial agonist at alpha4beta2 receptors, with an EC50 of 2.3 +/- 0.3 microM and an efficacy (relative to acetylcholine) of 13.4 +/- 0.4%. Varenicline has lower potency and higher efficacy at alpha3beta4 receptors, with an EC50 of 55 +/- 8 microM and an efficacy of 75 +/- 6%. Varenicline also seems to be a weak partial agonist at alpha3beta2 and alpha6-containing receptors, with an efficacy <10%. It is remarkable that varenicline is a potent, full agonist at alpha7 receptors with an EC50 of 18 +/- 6 microM and an efficacy of 93 +/- 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric alpha7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

In case of overdose, standard supportive measures should be instituted as required. Varenicline has been shown to be dialyzed in patients with end stage renal disease, however, there is no experience in dialysis following overdose.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ CHANTIX has also been studied in postmarketing trials including (1) a trial conducted in patients with chronic obstructive pulmonary disease (COPD), (2) a trial conducted in generally healthy patients (similar to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and 35 of treatment ("alternative quit date instruction trial"), (3) a trial conducted in patients who did not succeed in stopping smoking during prior CHANTIX therapy, or who relapsed after treatment ("re-treatment trial"), (4) a trial conducted in patients with stable cardiovascular disease, (5) a trial conducted in patients with stable schizophrenia or schizoaffective disorder and (6) a trial conducted in patients with major depressive disorder. Adverse events in the trial of patients with COPD, in the alternative quit date instruction trial, were quantitatively and qualitatively similar to those observed in premarketing studies. In the re-treatment trial, the profile of common adverse events was similar to that previously reported, but, in addition, varenicline-treated patients also commonly reported diarrhea (6% vs 4% in placebo-treated patients), depressed mood disorders and disturbances (6% vs 1%), and other mood disorders and disturbances (5% vs 2%).|/HUMAN EXPOSURE STUDIES/ In the trial of patients with stable cardiovascular disease, more types and a greater number of cardiovascular events were reported compared to premarketing studies. Treatment-emergent (on-treatment or 30 days after treatment) cardiovascular events reported with a frequency = 1% in either treatment group in this study were angina pectoris (3.7% and 2.0% for varenicline and placebo, respectively), chest pain (2.5% vs. 2.3%), peripheral edema (2.0% vs. 1.1%), hypertension (1.4% vs. 2.6%), and palpitations (0.6 % vs. 1.1%). Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by a blinded, independent committee. The following treatment-emergent adjudicated events occurred with a frequency =1% in either treatment group: nonfatal MI (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalization for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, the adjudicated events included need for coronary revascularization (2.0% vs. 0.6%), hospitalization for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study.|/HUMAN EXPOSURE STUDIES/ During a controlled clinical trial of varenicline in patients with stable cardiovascular disease who smoked, certain cardiovascular events were reported more frequently in patients receiving varenicline than in patients receiving placebo. All-cause and cardiovascular mortality at 52 weeks of nontreatment follow-up were lower in patients receiving varenicline than in patients receiving placebo.1 Serious, nonfatal treatment-emergent events (events that occurred during treatment or within 30 days of completion) included nonfatal myocardial infarction (MI) and nonfatal stroke. Events occurring during 30 or more days after completing treatment (up to 52 weeks) included nonfatal MI, need for coronary revascularization, hospitalization for angina pectoris, transient ischemic attack, new diagnosis of peripheral vascular disease, or hospital admission for a peripheral vascular disease procedure. The US Food and Drug Administration (FDA) analysis of this trial revealed a possible increased risk of these adverse cardiovascular events in patients with cardiovascular disease who received varenicline.|/SIGNS AND SYMPTOMS/ Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking CHANTIX. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke. All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking CHANTIX in the postmarketing experience. When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy. These events have occurred in patients with and without pre-existing psychiatric disease. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX. Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.|For more Human Toxicity Excerpts (Complete) data for VARENICLINE (13 total), please visit the HSDB record page.

6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino(2,3-h)benzazepine

CHANTIX is supplied for oral administration in two strengths: a 0.5 mg varenicline tartrate (UNII: 82269ASB48) (varenicline - UNII:W6HS99O8ZO) capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg varenicline tartrate capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. Both tablets are comprised of the following inactive ingredients:cellulose, microcrystalline (UNII: OP1R32D61U) calcium phosphate, dibasic, anhydrous (UNII: L11K75P92J) croscarmellose sodium (UNII: M28OL1HH48) silicon dioxide (UNII: ETJ7Z6XBU4) magnesium stearate (UNII: 70097M6I30) hypromelloses (UNII: 3NXW29V3WO) titanium dioxide (UNII: 15FIX9V2JP) polyethylene glycols (UNII: 3WJQ0SDW1A) triacetin (UNII: XHX3C3X673) FD&C Blue NO. 2 (UNII: L06K8R7DQK).

Chantix tablets contain the active ingredient varenicline (as the tartrate salt)

Human drugs -> Champix -> EMA Drug Category|Other nervous system drugs -> Human pharmacotherapeutic group