Varenicline Tartrate Tablets Instructions

Approval Date: 07/31/2008

Revision date: 09/18/2009; 12/21/2009; 07/18/2011; 09/27/2011.

June 07, 2012; October 30, 2012; February 21, 2013; June 14, 2013; January 06, 2014; June 20, 2014; November 21, 2014; November 24, 2014; 2015 January 20; November 07, 2016; December 20, 2016; February 24, 2017

Varenicline Tartrate Tablets Instructions

Please read the instructions carefully and use under the guidance of your physician.

[Drug Name].

Generic Name: Varenicline Tartrate Tablets
Trade Name: Champix
English Name: Varenicline Tartrate Tablets
Hanyu Pinyin: Jiushisuan Fanikelan Pian

[Ingredients

The main ingredient of this product is varenicline tartrate

Chemical name: 7,8,9,10-tetrahydro-6,10-methylene-6H-pyrazinamide [2,3-h][3]benzazepine-(2R,3R)-2,3-bis Hydroxybutanedioate (1:1)

Chemical structure formula.

Molecular formula: C₁₃H₁₃N₃-C₄H₆O₆

Molecular weight: 361.36

[Properties

This product is a white to off-white film-coated tablet (0.5mg size) or light blue film-coated tablet (1.0mg size), which appears white after removing the coating.

[Indications

This product is indicated for smoking cessation in adults.

[Specifications

0.5mg, 1.0mg

[Dosage].

Dosage

This product is for oral administration. First in 1-week dose increments as follows, after which the recommended dose is 1 mg twice daily.

Day 1 to 3:	0.5mg once daily (white tablets)
Day 4 to Day 7:	0.5mg twice daily (white tablets)
Day 8 ~ end of treatment:	1mg twice daily (light blue tablets)

Patients should set a quit date and start taking this product 1 to 2 weeks before this date.

Patients should take this product for 12 weeks of treatment.

For patients who have successfully quit after 12 weeks of treatment, consider renewing for an additional 12-week course at the same dose of 1 mg twice daily to maintain abstinence.

For patients who are unable or unwilling to quit abruptly, a gradual approach to smoking cessation should be considered. Patients should reduce smoking for the first 12 weeks of treatment and quit at the end of the treatment period. Patients should then continue to take this product for an additional 12 weeks to complete a total of 24 weeks of treatment (see [Clinical Trials]).

Patients who are very eager to quit and who have not successfully quit with prior treatment with this product, or who have relapsed after treatment, may benefit from trying again to quit with this product (see [Clinical Trials]).

For patients who cannot tolerate the adverse effects of this product, the dose may be temporarily or chronically reduced to 0.5 mg twice daily.

In smoking cessation treatment, the risk of relapse is elevated in the period immediately following the end of treatment. In patients with a high risk of relapse, medication tapering may be considered. Smoking cessation treatment is more likely to be successful in patients who have a desire to quit and who receive more advice and support.

Patients with renal impairment

Patients with mild (estimated creatinine clearance>50 ml/min and ≤80 ml/min) to moderate (estimated creatinine clearance ≥30 ml/min and ≤50 ml/min) renal impairment do not require dose adjustment.

Patients with moderate renal impairment and intolerable adverse effects may have their dose reduced to 1 mg once daily.

In patients with severe renal impairment (estimated creatinine clearance<30 ml/min), the recommended dose is 1 mg once daily. dosing should be started at 0.5 mg once daily and increased to 1 mg once daily after 3 days. clinical experience with this product in patients with end-stage renal disease is limited, and therefore it is not recommended in this population (see < strong>[Pharmacokinetics]).

Patients with hepatic impairment

Patients with hepatic impairment do not require dose adjustment (see [Pharmacokinetics]).

Elderly Patients

No dose adjustment is required in elderly patients (see [Pharmacokinetics]). Prescribers should consider the renal function status of elderly patients because they are more likely to have decreased renal function.

Patients with sleepwalking disorder

Patients should be instructed to discontinue this product and notify their physician if they develop sleepwalking (see [Precautions]).

Pediatric Patients

The safety and efficacy of this product in children or adolescents under 18 years of age have not been established. The currently available data can be found in [Pharmacokinetics]. This product is not recommended for use in this population.

How to take

This product should be swallowed whole with water and taken before or after meals.

[Adverse Reactions

Smoking cessation itself is associated with a variety of symptoms, whether or not you receive cessation treatment. For example, irritability, depression, insomnia, irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite, or weight gain have been reported in patients attempting to quit. The design of the clinical study and analysis of the results of this product did not distinguish between the adverse events that occurred and drug or nicotine withdrawal correlations.

Multiple clinical studies of this product have involved approximately 4,000 patients treated for up to 1 year (mean 84 days of dosing). Adverse reactions, if any, usually occurred in the first week of treatment and were mostly mild to moderate in severity. There was no difference in the incidence of adverse reactions by age, race, or sex.

After completing the initial dose escalation, patients took the recommended dose of 1 mg twice daily. the most frequently reported adverse event was nausea (28.6%). Most nausea occurred early in treatment, was mild to moderate in severity, and rarely led to treatment interruption.

The proportion of patients who discontinued treatment due to adverse events was 11.4% in the treatment arm and 9.7% in the placebo arm. Among these patients, the rates of treatment interruption for common adverse events in the treatment group were: nausea (2.7% versus 0.6% in the placebo group), headache (0.6% versus 1.0% in the placebo group), insomnia (1.3% versus 1.2% in the placebo group), and abnormal dreams (0.2% versus 0.2% in the placebo group).

Adverse Reaction Table

The adverse reactions listed in the table below that occurred more frequently in the treatment group than in the placebo group were ranked by system organ type and frequency: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000)). Adverse reactions that occurred with similar frequency are listed in order of increasing severity. All adverse drug reactions (ADRs) listed in the table below are based on the assessment of data from pre-marketing Phase 2-3 studies and updated based on pooled data from 18 placebo-controlled pre-marketing and post-marketing studies, which included approximately 5,000 patients treated with varenicline. Reported post-marketing adverse reactions are also included at frequencies unknown (not estimable from the available data). Within each frequency group, adverse reactions are listed in order of severity from highest to lowest.

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Common

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*Estimated frequency of occurrence based on post-marketing observational cohort study

System organ classification	Adverse Drug Reactions
< strong>Infection and Infestation
Very common	Nasopharyngitis
Common	Bronchitis, sinusitis
Rarely	Fungal infections, viral infections
Abnormalities of the blood and lymphatic system
Rare	Decreased platelet count
Metabolic and nutritional abnormalities
Weight gain, loss of appetite, increased appetite
Rare	Bothered by thirst
unknown	Diabetes, hyperglycemia
Psychiatric abnormalities
Very common	Abnormal dreams, insomnia
Rarely seen	Panic reaction, abnormal thinking, fidgeting, mood swings, depression, anxiety, hallucinations*, increased sexual desire, decreased sexual desire
Rare	Irritable, slow thinking
unknown	Suicide ideation, psychosis, aggression, abnormal behavior, sleepwalking disorder
Neurological abnormalities
Very common	Headaches
Common	Drowsiness, dizziness, taste disorders
Rarely seen	Seizures, tremors, lethargy, hyperalgesia
Rare	Cerebrovascular accidents, hypertonia, dysarthria, ataxia, hypoesthesia, circadian sleep rhythm disturbances
Eye abnormalities
Rarely seen	Conjunctivitis, eye pain
Rare	Dark spots, scleral decoloration, dilated pupils, photophobia, myopia, tearfulness
Ear and vagal abnormalities
Rarely seen	Tinnitus
Cardiac abnormalities
Rarely	Angina pectoris, tachycardia, palpitations, rapid heart rate
Rare	Atrial fibrillation, ECG ST-segment depression, ECG T-wave amplitude depression
unknown	myocardial infarction
Vascular abnormalities
rare	Increased blood pressure, hot flashes
Respiratory, thoracic and mediastinal abnormalities
Common	Hard to breathe, coughing
Rarely	Upper airway inflammation, airway congestion, vocal difficulties, allergic rhinitis, throat irritation, sinus congestion, upper airway cough syndrome, rhinorrhea
Sore throat, snoring
Gastrointestinal abnormalities
Very common	Nasty
Common	Gastroesophageal reflux disease, vomiting, constipation, diarrhea, bloating, abdominal pain, toothache, indigestion, flatulence, dry mouth
Rarely seen	Blood in stool, gastritis, change in bowel habits, belching, ulcerative stomatitis, gum pain
Rare	Vomiting blood, abnormal stools, and Thick and greasy tongue
Dermal and subcutaneous tissue abnormalities
Common	Rash, itching
Rarely	Redness, acne, hyperhidrosis, night sweats
unknown	Severe skin reactions include Stevens-Johnson syndrome, erythema multiforme, angioneurotic edema
Musculoskeletal and connective tissue abnormalities
Common	Joint pain, myalgia, back pain
Rarely	Muscle spasms, musculoskeletal pain in the chest
Rare	Joint stiffness, costochondritis
Kidney and urinary abnormalities<
Rarely seen	Frequent urination, nocturia
Rare	sugaruria, polyuria
Reproductive system and breast abnormalities
Rarely seen	Menstrual cramps
Rare	Vaginal discharge, sexual dysfunction
Systemic abnormalities and dosing site abnormalities
Common	chest pain, fatigue
< p>Rarely seen	Chest discomfort, flu-like illness, fever, malaise, discomfort
Rare	Cold sensation, cysts
< p>Check
Common	Abnormal liver function tests
Rarely seen	Abnormal semen analysis, elevated C-reactive protein, decreased blood calcium,

Postmarketing experience.

The following adverse events were reported during the post-marketing use of this product. Because these events were spontaneously reported by a population of uncertain size, it was not possible to estimate the incidence of the events or to establish a causal relationship with the drug.

In patients taking this product for smoking cessation, reported events included depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, and suicidal ideation, suicide attempts, and completed suicide (see [Precautions]). With or without pharmacotherapy for smoking cessation, patients may experience nicotine withdrawal symptoms and exacerbation of pre-existing psychiatric disorders. Not all patients understand whether they have a psychiatric disorder, and not all patients are no longer smoking.

Post-marketing reports of new onset or worsening of pre-existing epilepsy have been reported in patients taking this product for treatment (see [Precautions]).

Postmarketing reports of increased alcohol euphoria in patients while taking varenicline. Some patients reported neuropsychiatric symptoms, including abnormal behavior and sometimes aggressive behavior (see [Precautions]).

There are postmarketing reports of hypersensitivity reactions, including angioneurotic edema, in patients treated with varenicline (see [Precautions]).

There are postmarketing reports of rare but serious skin reactions in patients taking varenicline, including Stevens-Johnson syndrome and erythema multiforme (see [Precautions]).

There have been postmarketing reports of myocardial infarction (MI) and cerebrovascular accidents (CVA) including ischemic and hemorrhagic events in patients treated with varenicline. In the majority of such reported events, patients had prior cardiovascular system disease and/or other risk factors. Although smoking is a risk factor for myocardial infarction and cerebrovascular accident, varenicline cannot yet be excluded based on a temporal correlation between varenicline use and events (see [Cautions]).

There have been reports of hyperglycemia in patients taking varenicline.

Sleepwalking has been reported in patients treated with varenicline, leading in some cases to behaviors harmful to self, others, or property (see [precautions]).

[Contraindications

People with hypersensitivity to the active ingredient or any of the excipient ingredients of this product.

[Precautions

Warning

1. Neuropsychiatric symptoms and suicide

In post-marketing experience with this product, there have been reports of behavioral or thought changes, anxiety, psychosis, mood changes, aggressive behavior, depression, suicidal ideation and behavior, and suicide attempts.

A large randomized, double-blind, active and placebo-controlled study compared the risk of serious psychoneurological events with varenicline, bupropion, nicotine replacement therapy patch (NRT), or placebo for smoking cessation in patients with and without a history of psychiatric illness. The primary safety endpoint was a composite of psychoneurological adverse events reported in the postmarketing experience.

Compared with the primary composite endpoint in the placebo group, the use of varenicline in patients with and without a history of psychiatric illness did not increase the risk of serious psychoneurological adverse events (see [clinical trial]-for subjects with and without a Psychoneurological Safety Study in Subjects with and without a History of Psychiatric Disorders).

Depressed mood may be a nicotine withdrawal symptom. Depression, including rare suicidal ideation and suicide attempts.

Clinicians should be aware of the potential for severe psychoneurologic symptom emergencies in patients who are attempting to quit with or without treatment. If a patient develops severe psychoneurologic symptoms while on varenicline therapy, the patient should immediately discontinue varenicline and contact a health care provider for reassessment of therapy.

History of psychiatric illness

With or without medication, smoking cessation itself is associated with worsening of an underlying psychiatric illness, such as depression.

The varenicline smoking cessation study provided data related to patients with a history of mental illness (see [Clinical Trials]).

In smoking cessation clinical trials, patients with a history of psychiatric disorders reported a higher frequency of psychoneurological adverse events compared with patients without a history of psychiatric disorders, regardless of treatment (see [Clinical Trials]).

Patients with a history of psychiatric disorders should be given special attention and informed.

Analysis of clinical studies

A meta-analysis of 5 randomized, double-blind, placebo-controlled studies including 1907 patients (1130 in the varenicline group and 777 in the placebo group) assessed suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). The meta-analysis included one study of patients with a history of schizophrenia or schizoaffective disorder (N=127) and another study of patients with a history of depression (N=525). The results showed that the incidence of suicidal ideation and/or behavior was not increased in patients treated with varenicline compared with those treated with placebo, with a risk ratio (RR) of 0.79 (95% confidence interval [CI]: 0.46, 1.36), as shown in Table 1. Of the 55 patients who reported suicidal ideation or behavior, 48 (24 in the varenicline group and 24 in the placebo group) were from two trials that included patients with a history of schizophrenia, schizoaffective disorder, or depression. Fewer events were observed in the other three trials (4 in the varenicline group and 3 in the placebo group).

Table 1. Number and risk ratio of patients with suicidal ideation and/or behavior as assessed by the C-SSRS in a meta-analysis of 5 clinical studies comparing varenicline and placebo

	Vaniklang (N=1130)	Placebo (N=777)
Patients with suicidal ideation and/or behavior[n (%)]*	28 (2.5)	27 (3.5)
Exposure (patient years)	325	217
Risk ratio^# (RR; 95% CI)	0.79 (0.46, 1.36)
* In these events, one patient in each treatment group reported suicidal behavior ** Patients with an event within 30 days of treatment; % not weighted according to study # RR per 100 patient-years

A meta-analysis of 18 double-blind, randomized, placebo-controlled clinical studies (including the 5 studies that collected the C-SSRS described in Table 1) was conducted to assess the psychoneurological safety of varenicline. This pooled analysis included 8521 patients (5072 in the varenicline group and 3449 in the placebo group), some of whom had psychiatric disorders at baseline. The results showed that patients in the varenicline and placebo treatment groups had similar rates of total psychoneurological adverse events (excluding insomnia) with a risk ratio (RR) of 1.01 (95% CI: 0.891.15). Pooled data from these 18 trials showed that patients in the varenicline group had similar rates of all types of adverse psychiatric events to those in the placebo group. Table 2 describes the most frequently reported (≥1%) categories of adverse events related to psychiatric safety (excluding insomnia and sleep disturbances).

Table 2. Psychiatric Adverse Events Occurring in ≥1% of Patients in a Pooled Analysis of 18 Clinical Studies

	Vaniklang (N=5072)	Placebo (N=3449)
Anxiety disorders and symptoms	253 (5.0)	206 (6.0)
Depressive mood disorders and disturbances	179 (3.5)	108 (3.1)
Mood disorders and disorders NEC*	116 (2.3)	53 (1.5)
* NEC=Not Elsewhere Classified Count (percentage) equals number of patients reporting events

Observational studies

Four observational studies, each containing 10,000 to 30,000 varenicline users with adjusted analyses, compared the risk of serious neuropsychiatric symptoms (including hospitalization for neuropsychiatric disorders, fatal and nonfatal self-harm) between varenicline users and users prescribed NRT or bupropion. All studies were retrospective cohort studies that included patients with and without a history of psychiatric disorders. All studies used statistical methods to control for confounding factors (including preferential prescribing of varenicline to healthier patients), but residual confounding may still exist.

Two of the studies found no difference in the risk of hospitalization for neuropsychiatric disorders between varenicline users and nicotine patch users (hazard ratio [HR] 1.14; 95% confidence interval [CI]: 0.56-2.34 in the first study; hazard ratio 0.76 in the second study; 95% CI. 0.40-1.46). However, neither study validated the diagnostic codes used to determine outcomes based on medical records. The test efficacy required to detect differences between these two studies was insufficient. The third study reported no difference between varenicline users and bupropion users in the risk of psychiatric adverse events diagnosed during emergency department visits or hospitalizations (HR 0.85; 95% CI: 0.55-1.30). Bupropion was also associated with neuropsychiatric adverse events. A fourth study showed no evidence of a higher risk of fatal and nonfatal self-harm in patients using varenicline compared with those using NRT (HR 0.88; 95% CI: 0.521.49). Although detectable suicides that occurred during the three months after patients started any drug therapy were relatively rare (two cases in 31,260 varenicline users and six cases in 81,545 NRT users), the study also had serious limitations. Most importantly, these data were collected after reports of neuropsychiatric adverse events in varenicline users became known to the public. Varenicline users presented with fewer comorbid conditions that might put them at risk for neuropsychiatric adverse events, suggesting that patients with a history of neuropsychiatric disorders were prescribed NRT preferentially and healthier patients were prescribed varenicline preferentially.

The results examined in these studies did not include the full range of reported neuropsychiatric adverse events.

2 Epilepsy

Seizures have been reported in patients treated with varenicline in clinical studies and post-marketing experience. Some patients had no history of epilepsy, while others had a distant or well-controlled history of epilepsy. In most cases, seizures occurred within the first month of treatment. This potential risk should be weighed against the benefit before prescribing varenicline to patients with a history of epilepsy or other factors that may lower the seizure threshold. If seizures occur during treatment, patients are advised to discontinue varenicline and contact their healthcare provider immediately (see [Adverse Reactions]).

3 Interactions with Alcohol

Post-marketing reports of increased alcohol euphoria in patients while taking varenicline have been reported. A causal relationship between these events and the administration of varenicline has not been confirmed. Some cases described abnormal and sometimes aggressive behavior, and the events were often accompanied by memory loss. While taking varenicline, patients are advised to reduce alcohol consumption without knowing whether varenicline may have an effect on their alcohol tolerance (see [Adverse Reactions]).

4 Accidental injury

Post-marketing reports of traffic accidents, attempted traffic accidents, or other unintentional injuries have been reported in patients taking this product. In some cases patients have reported drowsiness, dizziness, loss of consciousness, or difficulty concentrating while driving or operating machinery, which can lead to injury or cause concern that an injury may result. Patients should be advised to exercise caution when driving, operating machinery, or other potentially hazardous activities without knowing how taking this product may affect them.

5. Cardiovascular Events

This product was studied in a placebo-controlled clinical study in patients with stable cardiovascular disease in approximately 350 patients per treatment group. All-cause and cardiovascular mortality was lower in the varenicline treatment group than in the placebo group in the study, but the incidence of certain nonfatal cardiovascular events was higher than in the placebo group (see [Clinical Trials]). The table below shows the incidence of fatal events and selective non-fatal serious cardiovascular events in the varenicline group that were higher than in the placebo group. These events were adjudicated by an independent blinded committee. The incidence of non-fatal serious cardiovascular events that occurred at similar rates in both groups or were more common in the placebo group are not included. In each row, patients with multiple identical cardiovascular events were recorded only 1 time. Some of the measures performed in patients requiring coronary revascularization were performed as part of non-fatal myocardial infarction and hospitalization for angina pectoris.

Table 3 Mortality and adjudicated nonfatal serious cardiovascular events in clinical studies of varenicline tartrate tablets versus placebo control in patients with stable coronary heart disease

tr>

Mortality and cardiovascular events	Vanikram group (N=353) n (%)	Placebo group (N=350) n (%)
*Mortality (52 weeks cardiovascular or all-cause))*
Cardiovascular death	1 (0.3)	2 (0.6)
2 (0.6)
All-cause mortality	2 (0.6)	5 (1.4)

*Non-fatal cardiovascular events (ratio Varenicline group > placebo group)*
< span style="text-decoration:underline">within 30 days of treatment
Non-fatal myocardial infarction	4 (1.1)	1 (0.3)
Non-fatal stroke	2 ( 0.6)	0 (0)
30 days to 52 weeks post-treatment
Non-fatal myocardial infarction	3 (0.8)	2 (0.6)
Requiring coronary artery reconstruction	7 (2.0)	2 (0.6)
Hospitalized for angina	6 (1.7)	6 (1.7)	4 (1.1)
Transient ischemic attack	1 (0.3)	0 (0)
Newly diagnosed peripheral vascular disease (PVD) or hospitalization for peripheral vascular disease	5 (1.4)	2 (0.6)

A systematic evaluation of the cardiovascular safety of varenicline tartrate was performed in a meta-analysis including 15 clinical trials with a treatment duration of ≥12 weeks and a total of 7002 patients (4190 in the varenicline group and 2812 in the placebo group). The above-mentioned clinical studies in patients with stable cardiovascular disease were included in the meta-analysis. All-cause death (6 [0.14%] in the varenicline group and 7 [0.25%] in the placebo group) and cardiovascular death (2 [0.05%] in the varenicline group and 2 [0.07%] in the placebo group) occurred at lower rates in the varenicline group than in the placebo group as a result of the meta-analysis.

The critical cardiovascular safety analysis included the occurrence and timing of the composite end point of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. These events included in the endpoints were adjudicated by an independent blinded committee. In general, MACE occurred less frequently in the clinical trials included in the meta-analysis, as shown in the table below. These events occurred primarily in patients with known cardiovascular disease.

Table 4 Number of MACE cases, risk ratios, and ratio differences in the meta-analysis of the 15 clinical studies that included varenicline compared with placebo

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	Vanikram group N=4190	Placebo group N=2812
Number of MACE cases, n (%)	13 (0.31%)	6 (0.21%)
Patients – Year of Exposure	1316	839
Risk Ratio (95% CI)
	1.95 (0.79, 4.82)
Ratio difference per 1,000 patient-years (95% CI)
	6.30 (-2.40, 15.10)

*Including MACE occurring after 30 days of treatment

This product has not been studied in patients with unstable cardiovascular disease or in patients who developed cardiovascular disease within 2 months prior to screening. Patients are advised to contact their healthcare provider if they develop new or worsening symptoms of cardiovascular disease. The benefit-risk ratio should be weighed when using this product in smokers with cardiovascular disease. Smoking is an independent and important risk factor for cardiovascular disease. This product has been shown to be effective in increasing the odds of quitting smoking for up to 1 year compared with placebo.

6. Sleepwalking disorder

Sleepwalking has been reported in patients using varenicline. Some cases have described harmful behavior toward self, others, or property. Patients should be advised to discontinue varenicline and notify their physician if they experience sleepwalking (see [Adverse Reactions]). .

General Precautions

1. Angioneurotic edema and hypersensitivity reactions

Postmarketing reports of hypersensitivity reactions, including angioneurotic edema, have been reported in patients treated with this product (see [Adverse Reactions]). Clinical signs include swelling of the face, mouth (tongue, lips, gums), extremities, and neck (pharynx and larynx). In addition, there have been rare reports of life-threatening angioneurotic edema requiring emergency medical management due to resulting respiratory dysfunction. Patients should be advised to discontinue the product and seek immediate medical attention in the event of these symptoms.

2. Severe skin reactions

There have been postmarketing reports of rare but serious skin reactions in patients taking this product, including Stevens-Johnson syndrome and erythema multiforme [see [Adverse Reactions]]. Because these skin reactions can be life-threatening, patients should be advised to stop taking the product and contact their healthcare provider as soon as they develop a rash with mucosal lesions or any other signs of hypersensitivity reactions.

3. Nausea

Nausea is the most common adverse reaction in the treatment of this product. Nausea is usually mild to moderate and transient, but for some patients, nausea can persist for several months. The incidence of nausea is related to the dose administered. Initial dose titration is beneficial in reducing the incidence of nausea. When the maximum recommended dose of 1 mg twice daily was given to patients after a gradual increase in dose, the incidence of nausea was 30%, compared to 10% in the placebo control group. The incidence of nausea was 16% in the placebo group and 11% in the placebo group when varenicline was given to patients at 0.5 mg twice daily after a gradual dose increase in the starting phase. In the 12-week study in which patients were given 1 mg of varenicline twice daily, approximately 3% of patients discontinued treatment due to nausea. Dose reduction is recommended if the patient cannot tolerate it.

4. Drug abuse and dependence

Less than 1 in 1000 patients reported euphoria in clinical studies of this product. Higher doses (>2 mg) of this product are more likely to cause gastrointestinal distress, such as nausea and vomiting. No evidence was found in clinical studies that increasing doses were required to maintain therapeutic efficacy, suggesting that this product is not tolerated. When abruptly discontinued, irritability and sleep disturbances occur in no more than 3% of patients. This suggests that in some patients, varenicline may produce mild somatic dependence, but is not associated with addiction.

In a laboratory study of human propensity to abuse, a single oral dose of 1 mg of varenicline did not produce a significant positive or negative subjective response in smokers. In nonsmokers, 1 mg varenicline produced some increase in positive subjective responses, but was accompanied by an increase in negative adverse effects, particularly nausea. A single oral dose of 3 mg varenicline produced an uncomfortable subjective response in both smokers and nonsmokers.

[For pregnant and lactating women].

Pregnant women

Risk Summary

There are insufficient available human data on the use of varenicline in pregnant women to provide information on the risks associated with the drug. Smoking during pregnancy poses risks to the mother, fetus, and newborn (see Clinical Considerations). In animal studies, varenicline did not cause severe malformations when administered during the organogenesis phase at exposures equivalent to 50 times the maximum recommended human dose (MRHD), but resulted in reduced fetal weight in rabbits. In addition, maternal exposure of varenicline administered to pregnant rats during organogenesis through lactation at a maternal exposure equivalent to 36 times the human exposure at MRHD produced developmental toxicity in the offspring (see data).

The predicted background risk of cleft lip and palate in infants born to pregnant women who smoked during gestation was increased by approximately 30% compared with nonsmoking pregnant women. For the referred population, the background risk for other major birth defects and miscarriages is unknown. In the general US population, the predicted background risks for clinically confirmed major birth defects and miscarriage in pregnancy are 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal and/or embryonic/fetal risks associated with disease

Smoking during pregnancy results in an increased risk of cleft lip and palate, premature rupture of membranes, placenta praevia, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and gestational shortening, neonatal death, sudden infant death syndrome, and infant pulmonary hypoplasia. It is not known whether smoking cessation with varenicline during pregnancy reduces these risks.

Data

Animal data

Pregnant rats and rabbits were given oral doses of varenicline succinate up to 15 and 30 mg/kg/day, respectively, during organogenesis. Although no fetal structural abnormalities were observed in either animal, maternal toxicity (as evidenced by reduced body weight gain) and fetal weight loss were seen in pregnant rabbits given high doses of varenicline (50 times the maximum recommended human dose of 1 mg twice daily exposure based on AUC); no fetal weight loss was seen in rabbits exposed at 23 times the maximum recommended human dose (based on AUC).

In a prenatal and postnatal developmental study, pregnant rats received 15 mg/kg/day of oral varenicline succinate from fetal organogenesis to lactation. Maternal toxicity (as evidenced by reduced body weight gain) was observed at a dose of 15 mg/kg/day (equivalent to 36 times the exposure at the maximum recommended human dose, based on AUC). However, at the highest maternal dose of 15 mg/kg/day, the offspring showed reduced fertility and increased auditory startle response.

Lactation

Risk summary

No information is available on the presence of varenicline in breast milk, its effect on breastfed infants, or its effect on lactation. In animal studies, varenicline was present in the milk of lactating rats (see data). However, animal data cannot reliably predict drug levels in breast milk due to differences in lactation physiology between species. The lack of clinical data during lactation makes it impossible to definitively determine the risk of varenicline to the nursing infant; however, the developmental and health benefits of breastfeeding, the maternal clinical need for varenicline, and any potential adverse effects of varenicline or the underlying maternal condition on the breastfed infant should be considered together.

Clinical Considerations

Because there are no data on the presence of varenicline in breast milk and the effects on breastfed infants, breastfeeding women should monitor their infants for seizures and excessive vomiting, which are adverse reactions that have been seen in adults and may be clinically relevant in breastfed infants.

Data

In a prenatal and postnatal developmental study, pregnant rats were given up to 15 mg/kg/day of oral varenicline succinate from gestation to lactation, and the mean serum concentration of varenicline in the lactated pups was 5-22% of the maternal serum concentration.

Fertility

There are no clinical data on the effect of this product on fertility.

Results from male and female fertility studies in rats suggest that this product may not be harmful to human fertility (see [Pharmacology and Toxicology]).

[Pediatric use

See [Dosage].

[Geriatric Use

See [Dosage].

[Drug Interactions].

Based on the properties of varenicline and current clinical experience, no clinically meaningful interactions have been identified between this product and other drugs. No dose adjustment of this product and the following combination drugs is required.

In vitro studies have shown that varenicline is unlikely to alter pharmacokinetic parameters for compounds metabolized primarily by cytochrome P450; since less than 10% of varenicline is cleared by metabolism, the active substances known to affect the cytochrome P450 system are unlikely to affect the pharmacokinetic parameters of varenicline (see [Pharmacokinetics]) and therefore no dose adjustment of this product is required.

	Study 1 (n=1022)		Study 2 (n=1023)
	4W CQR	CA Wk 9 to 52	4W CQR	CA Wk 9 to 52
Varenicline Tartrate Tablets	44.4%	22.1%	44.0%	23.0%
Bupropion	29.5%	16.4%	30.0%	15.0%
Placebo	< p style="text-align: center">17.7%	8.4%	17.7%	10.3%
Ratio Varenicline tartrate tablets vs. placebo	3.91 p<0.0001	3.13 p<0.0001	3.85 p<0.0001	2.66 p<0.0001
Ratio Varenicline tartrate tablets vs. bupropion	1.96 p<0.0001	1.45 p=0.0640	1.89 p<0.0001	1.72 p=0.0062

	4W CQR	CA (Weeks 9-52)
Varenicline tartrate, (n = 248)	42.3%	18.5%
Placebo, (n = 251)	8.8%	5.6%
Ratio (varenicline tartrate and placebo)	8.40 p<0.0001	4.04 p<0.0001

	Non-psychiatric group N=3984
	Vaniklang	Bupropion	NRT	Placebo
Number of patients treated	990	989	1006
Composite NPS AE primary endpoints. n (%)	13 (1.3)	22 (2.2)	25 (2.5)	24 (2.4)
RD compared to placebo group (95% CI)	-1.28 (-2.40, -0.15)	-0.08 (-1.37, 1.21)	-0.21 (-1.54,1.12)
Severe Composite NPS AE n (%)	1 (0.1)	4 (0.4)	3 (0.3)	5 ( 0.5)