Varenicline (Page 3 of 12)

6.2 Postmarketing Experience

The following adverse events have been reported during post-approval use of varenicline. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide in patients attempting to quit smoking while taking varenicline [see Warnings and Precautions (5.1)].

There have been postmarketing reports of new or worsening seizures in patients treated with varenicline [see Warnings and Precautions (5.2)].

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior [see Warnings and Precautions (5.1) and (5.3)].

There have been reports of hypersensitivity reactions, including angioedema [see Warnings and Precautions (5.7)].

There have also been reports of serious skin reactions, including Stevens-Johnson syndrome and erythema multiforme, in patients taking varenicline [see Warnings and Precautions (5.8)].

There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking varenicline. In the majority of the reported cases, patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, based on temporal relationship between medication use and events, a contributory role of varenicline cannot be ruled out [see Warnings and Precautions (5.5)].

There have been reports of hyperglycemia in patients following initiation of varenicline.

There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with varenicline [see Warnings and Precautions (5.6)].

7 DRUG INTERACTIONS

Based on varenicline characteristics and clinical experience to date, varenicline has no clinically meaningful pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

7.1 Use with Other Drugs for Smoking Cessation

Safety and efficacy of varenicline in combination with other smoking cessation therapies have not been studied.

Bupropion
Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established.

Nicotine replacement therapy (NRT)
Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.

7.2 Effect of Smoking Cessation on Other Drugs

Physiological changes resulting from smoking cessation, with or without treatment with varenicline, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 [see Data]. Smoking during pregnancy is associated with maternal, fetal, and neonatal risks (see Clinical Considerations). 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 [see Data].

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 varenicline during pregnancy reduces these risks.

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

* Included only live births in the cohorts. Prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]). † There was a lag in death data in Denmark, so the cohorts were smaller.
Outcome	Varenicline Cohort (n=335)	Smoking Cohort (n=78,412)	Non-Smoking Cohort (n=806,438)
Major congenital malformation *	12 / 334 (3.6%)	3,382 / 78,028 (4.3%)	33,950 /804,020 (4.2%)
Stillbirth	1 (0.3%)	384 (0.5%)	2,418 (0.3%)
Small for gestational age	42 (12.5%)	13,433 (17.1%)	73,135 (9.1%)
Preterm birth	25 (7.5%)	6,173 (7.9%)	46,732 (5.8%)
Premature rupture of membranes	12 (3.6%)	4,246 (5.4%)	30,641 (3.8%)
Sudden infant death syndrome †	0/307 (0.0%)	51/71,720 (0.1%)	58/755,939 (<0.1%)

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.

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.