Drug Safety-related Labeling Changes (SrLC)

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CHANTIX (NDA-021928)

(VARENICLINE TARTRATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/22/2019 (SUPPL-48)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

CHANTIX is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated.

Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose- proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight less than or equal to 55 kg compared to that noted in the adult population.

The efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, had a score of at least 4 on the Fagerstrom Test for Nicotine Dependence scale, and at least one previous failed quit attempt. Patients were stratified by age (12 to 16 years of age, n = 216 and 17 to 19 years of age, n = 96) and by body weight (?55 kg and >55 kg). Patients were randomized to one of two doses of varenicline, adjusted by weight to provide plasma levels in the efficacious range (based on adult studies) and placebo. Patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study. Results from this study showed that varenicline, at either dose studied, did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 to 19 years of age. The varenicline safety profile in this study was consistent with that observed in adult studies.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions are underlined)

 

………..

What is CHANTIX?

CHANTIX is a prescription medicine to help people stop smoking.

Quitting smoking can lower your chances of having lung disease, heart disease or getting certain types of cancer that are related to smoking.

CHANTIX has not been shown to be effective in children 16 years of age and under. CHANTIX should not be used in children 16 years of age and under.

It is not known if CHANTIX is safe and effective when used with other stop smoking medicines.

06/01/2018 (SUPPL-45)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke.  Smoking during pregnancy is associated …

Data

Human Data

A population-based observational cohort study using the national registers of Denmark and Sweden compared pregnancy and birth outcomes among women exposed to varenicline (N=335, includes 317 first trimester exposed) with women who smoked during pregnancy (N=78,412) and with non-smoking pregnant women (N=806,438). The prevalence of major malformations, the primary outcome, was similar in all groups, including between smoking and non-smoking groups. The prevalence of adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked, and differed somewhat between the three cohorts. The prevalences of the primary and secondary outcomes are shown in Table 6.

Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts

Please see label for complete information

The study limitations include the inability to capture malformations in pregnancies that do not result in a live birth, and possible misclassification of outcome and of exposure to varenicline or to smoking.

Other small epidemiological studies of pregnant women exposed to varenicline did not identify an association with major malformations, consistent with the Danish and Swedish observational cohort study. Methodological limitations of these studies include small samples and lack of adequate controls.

Overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy.

06/01/2018 (SUPPL-46)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Cardiovascular Events

Extensive revisions to this subsection; as below:

A comprehensive evaluation of cardiovascular (CV) risk with CHANTIX suggests that patients with underlying CV disease may be at increased risk; however, these concerns must be balanced with the health benefits of smoking cessation. CV risk has been assessed for CHANTIX in randomized controlled trials (RCT) and meta-analyses of RCTs. In a smoking cessation trial in patients with stable CV disease, CV events were infrequent overall; however, nonfatal myocardial infarction (MI) and nonfatal stroke occurred more frequently in patients treated with CHANTIX compared to placebo. All-cause and CV mortality was lower in patients treated with CHANTIX. This study was included in a meta-analysis of 15 CHANTIX efficacy trials in various clinical populations that showed an increased hazard ratio for Major Adverse Cardiovascular Events (MACE) of 1.95; however, the finding was not statistically significant (95% CI: 0.79, 4.82). In the large postmarketing neuropsychiatric safety outcome trial, an analysis of adjudicated MACE events was conducted for patients while in the trial and during a 28-week non-treatment extension period. Few MACE events occurred during the trial; therefore, the findings did not contribute substantively to the understanding of CV risk with CHANTIX. Instruct patients to notify their healthcare providers of new or worsening CV symptoms and to seek immediate medical attention if they experience signs and symptoms of MI or stroke.

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 3 is now labelled as Table 1

Additions and/or revisions underlined:

CHANTIX has also been studied in postmarketing trials including (1) … (7) a postmarketing neuropsychiatric safety outcome trial in patients without or with a history of psychiatric disorder, (8) a non-treatment extension of the postmarketing neuropsychiatric safety outcome trial that assessed CV safety, (9) a trial in patients who were not able …

Adverse events in the trial of patients with COPD (1), in the alternative quit date instruction trial (2), and in the gradual approach to quitting smoking trial (9) were similar to those observed in premarketing studies. In the re-treatment trial (3), the profile of common adverse events was similar …

In the trial of patients with stable cardiovascular disease (4), more types and a greater number of cardiovascular events were reported compared to premarketing studies, as shown in Table 1 and in Table 2 below.

Table 2: Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency greater than 1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease Please refer to label for complete information.

In the trial of patients with stable schizophrenia or schizoaffective disorder (5), 128 smokers on antipsychotic medication were randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up. The most common treatment emergent adverse events reported in this trial are shown in Table 3 below.

Table 3. Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia or Schizoaffective Disorder Please refer to label for complete information.

For the trial of patients with major depressive disorder (6), the most common treatment emergent adverse events reported are shown in Table 4 below. Additionally, in this trial, patients treated with varenicline were more likely than patients treated with placebo to report one of events related to hostility and aggression (3% vs. 1%).

Table 4. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder Please refer to label for complete information.

In the trial of patients without or with a history of psychiatric disorder (7), the most common adverse events in subjects treated with varenicline were similar to those observed in premarketing studies. Most common treatment-emergent adverse events reported in this trial are shown in Table 5 below.

Table 5. Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History of Psychiatric Disorder Please refer to label for complete information.

In the non-treatment extension of the postmarketing neuropsychiatric safety outcomes trial that assessed CV safety (8), the most common adverse events in subjects treated with varenicline and occurring up to 30 days after last dose of treatment were similar to those observed in premarketing studies.

12/16/2016 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Neuropsychiatric Adverse Events including Suicidality

(additions underlined)

Serious neuropsychiatric adverse events have been reported in patients being treated with CHANTIX. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking CHANTIX who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses.Some adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, 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. The healthcare provider should evaluate the severity of the symptoms and the extent to which the patient is benefiting from treatment, and consider options including dose reduction, continued treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported. . However, the symptoms persisted  in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The  neuropsychiatric safety of CHANTIX was evaluated in a randomized, double-blind, active and placebo-controlled  study that included patients without a history of psychiatric disorder (non-psychiatric cohort, N=3912) and patients with a history of psychiatric disorder (psychiatric cohort, N=4003). In the non-psychiatric cohort, CHANTIX was not associated with increased incidence of clinically significant neuropsychiatric adverse events in a composite endpoint comprising anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability. In the psychiatric cohort, there were more events reported in each treatment group compared to the non-psychiatric cohort, and the incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo: Risk Differences (RDs) (95%CI) vs. placebo were 2.7% (-0.05, 5.4) for CHANTIX, 2.2% (-0.5, 4.9) for bupropion, and 0.4% (-2.2, 3.0) for transdermal nicotine. In the non-psychiatric cohort, neuropsychiatric adverse events of a serious nature were reported in 0.1% of CHANTIX-treated patients and 0.4% of placebo-treated patients. In the psychiatric cohort, neuropsychiatric events of a serious nature were reported in 0.6% of CHANTIX-treated patients, with 0.5% involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring psychiatric hospitalization.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

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, (6) a trial conducted in patients with major depressive disorder, (7) a postmarketing neuropsychiatric safety outcome trial in patients without or with a history of psychiatric disorder, and (8) a trial in patients who were not able or willing to quit abruptly and who were instructed to quit gradually (“gradual approach to quitting smoking trial”).

…In the trial of patients without or with a history of psychiatric disorder, the most common adverse events in subjects treated with varenicline were similar to those observed in premarketing studies. Adverse events reported in greater than or equal to10% of subjects treated with varenicline in the entire study population were nausea (25% vs. 7% on placebo) and headache (12% vs. 10% on placebo). Additionally, the following psychiatric adverse events were reported in ? 2% of patients in either treatment group (varenicline vs. placebo) by cohort. For the non-psychiatric cohort, these adverse events were abnormal dreams (8% vs. 4%), agitation (3% vs. 3%), anxiety (5% vs. 6%), depressed mood (3% vs. 3%), insomnia (10% vs. 7%), irritability (3% vs. 4%), sleep disorder (3% vs. 2%). For the psychiatric cohort, these adverse events were abnormal dreams (12% vs. 5%), agitation (5% vs. 4%), anxiety (8% vs. 6%), depressed mood (5% vs. 5%), depression (5% vs. 5%), insomnia (9% vs. 7%), irritability (5% vs. 7%), nervousness (2% vs. 3%), sleep disorder (3% vs. 2%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 Patient Counceling Information

(additions underlined)

Neuropsychiatric  Adverse Events

 

Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking CHANTIX. Instruct patients to discontinue CHANTIX and contact a healthcare professional if they experience such symptoms.

Medication Guide

(additions underlined)

 

What is the most important information I should know about CHANTIX?

Some people have had serious side effects while taking CHANTIX to help them quit smoking, including: New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depressed mood, or suicidal thoughts or actions. Some people had these symptoms when they began taking CHANTIX, and others developed them after several weeks of treatment, or after stopping CHANTIX. These symptoms happened more often in people who had a history of mental health problems before taking CHANTIX, than in people without a history of mental health problems.

Stop taking CHANTIX and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms. Work with your healthcare provider to decide whether you should continue to take CHANTIX. In many people, these symptoms went away after stopping CHANTIX, but in some people symptoms continued after stopping CHANTIX. It is important for you to follow-up with your healthcare provider until your symptoms go away.

Before taking CHANTIX, tell your healthcare provider if you have ever had depression or other mental health problems. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without CHANTIX.

08/12/2016 (SUPPL-39)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - Modification to the approved risk evaluation and mitigation strategy (REMS) , comprising of revisions to the MG, to support the reduce-to-quit paradigm

There are 3 ways that you can use CHANTIX to help you quit smoking.

Addition of:

OR

If you are sure that you are not able or willing to quit smoking right away, start taking CHANTIX and reduce smoking during the first 12 weeks of treatment, as follows:

·       Weeks 1 through 4: Reduce your smoking to reach one-half of your starting daily number of cigarettes. Example: If you usually smoke 20 cigarettes each day, reduce your smoking to 10 cigarettes each day during weeks 1 through 4.

·       Weeks 5 through 8: Reduce your smoking to reach one-quarter of your starting daily number of cigarettes. Example: If you usually smoked 20 cigarettes each day, reduce your smoking to 5 cigarettes each day during weeks 5 through 8.

·       Weeks 9 through 12: Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day). Aim to quit by the end of the 12th week of treatment, or sooner if you feel ready. Continue to take CHANTIX for another 12 weeks, for a total of 24 weeks of treatment.

 

 

 

08/12/2016 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

Somnambulism (addition)

·       Cases of somnambulism have been reported in patients taking CHANTIX. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue CHANTIX and notify their healthcare provider if they experience somnambulism.

6 Adverse Reactions

Addition of:

·       Somnambulism

Postmarketing Experience (addition of the following)

·       There have been reports of hyperglycemia in patients following initiation of CHANTIX.

·       There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with CHANTIX.

8 Use in Specific Populations

Lactation (PLLR Conversion)

Risk Summary

·       There are no data on the presence of varenicline in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies varenicline was present in milk of lactating rats. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of CHANTIX to an infant during lactation; however the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CHANTIX and any potential adverse effects on the breastfed child from CHANTIX or from the underlying maternal condition.

Clinical Considerations

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

Data

·       In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate through gestation and lactation Mean serum concentrations of varenicline in the nursing pups were 5-22% of maternal serum concentrations.

Pregnancy (PLLR Conversion)

Risk Summary

·       Available human data on the use of CHANTIX in pregnant women are not sufficient to inform a drug associated risk. Smoking during pregnancy is associated with maternal, fetal, and neonatal risks. In animal studies, varenicline did not result in major malformations but caused decreased fetal weights in rabbits when dosed during organogenesis at exposures equivalent to 50 times the exposure at the maximum recommended human dose (MRHD). Additionally, administration of varenicline to pregnant rats during organogenesis through lactation produced developmental toxicity in offspring at maternal exposures equivalent to 36 times human exposure at the MRHD.

·       The estimated background risk of oral clefts is increased by approximately 30% in infants of women who smoke during pregnancy, compared to pregnant women who do not smoke. The background risk of other major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

·       Smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. It is not known whether quitting smoking with CHANTIX during pregnancy reduces these risks.

Data

Animal Data

·       Pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. While no fetal structural abnormalities occurred in either species, maternal toxicity, characterized by reduced body weight gain, and reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD of 1 mg twice daily based on AUC). Fetal weight reduction did not occur in rabbits at exposures 23 times the human exposure at the MRHD based on AUC.

·       In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. Maternal toxicity, characterized by a decrease in body weight gain was observed at 15 mg/kg/day (36 times the human exposure at the MRHD based on AUC). However, decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day.

 

 

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG

What are the possible side effects of CHANTIX?

Serious side effects of CHANTIX may include:

Addition of:

·       Sleepwalking can happen with CHANTIX, and can sometimes lead to behavior that is harmful to you or other people, or to property. Stop taking CHANTIX and tell your doctor if you start sleepwalking.

PCI

Initiate Treatment and Continue to Attempt to Quit if Lapse

Addition of the following:

·       For patients who are sure that they are not able or willing to quit abruptly, a gradual approach to quitting smoking with CHANTIX may be considered. Patients should begin CHANTIX dosing and reduce smoking during the first 12 weeks of treatment, then quit by the end of that period and continue treatment for an additional 12 weeks for a total of 24 weeks.

Somnambulism

·       Patients should be instructed to discontinue CHANTIX and notify their healthcare providers if they experience somnambulism.

Pregnancy and Lactation

·       Advise breastfeeding women to monitor the infant for seizures and vomiting.