General

Nausea was the most common adverse event associated with SmokeLESS treatment. Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent over several months.
The incidence of nausea was dose-dependent.
Initial dose-titration was beneficial in reducing the occurrence of nausea.
Nausea was reported by approximately 30% of patients treated with SmokeLESS 1 mg BID after an initial week of dose titration.
In patients taking SmokeLESS 0.5 mg BID, the incidence of nausea was 16% following initial titration.
Approximately 3% of subjects treated with SmokeLESS 1 mg BID in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea.
For patients with intolerable nausea, dose reduction should be considered.

Effect of smoking cessation: Physiological changes resulting from smoking cessation, with or without treatment with SmokeLESS, may alter the pharmacokinetics or pharmacodynamics of some drugs, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin).

Drug Interactions
Based on varenicline characteristics and clinical experience to date, SmokeLESS has no clinically meaningful pharmacokinetic drug interactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats.
There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on AUC).
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). The clinical relevance of this finding to humans has not been established.
There was no evidence of carcinogenicity in female rats.

Mutagenesis: 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 and in vitro in human lymphocytes.

Impairment of fertility: There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg BID).
However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg BID).
This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1 mg BID).

Pregnancy
Pregnancy Category C.
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 at 1 mg BID, respectively).

Nonteratogenic effects
* 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 at 1 mg BID); 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 at 1 mg BID).

* There are no adequate and well-controlled studies in pregnant women.
SmokeLESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers
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 SmokeLESS, 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.

Labor and delivery The potential effects of SmokeLESS on labor and delivery are not known.

Pediatric Use
Safety and effectiveness of SmokeLESS in pediatric patients have not been established; therefore, SmokeLESS is not recommended for use in patients under 18 years of age.

Geriatric Use
* A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given QD or BID to 16 healthy elderly male and female smokers (aged 65-75 yrs) for 7 consecutive days was similar to that of younger subjects.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

* Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

* No dosage adjustment is recommended for elderly patients.

Information for Patients:
* Patients should be instructed to set a date to quit smoking and to initiate SmokeLESS treatment one week before the quit date.
* Patients should be advised that SmokeLESS should be taken after eating, and with a full glass of water.
* Patients should be instructed how to titrate SmokeLESS, beginning at a dose of 0.5 mg/day.
Prescribers should explain that one 0.5 mg tablet should be taken daily for the first three days, and that for the next four days, one 0.5 mg tablet should be taken in the morning and one 0.5 mg tablet should be taken in the evening.
* Patients should be advised that, after the first seven days, the dose should be increased to one 1 mg tablet in the morning and one 1 mg tablet in the evening.
* Patients should be encouraged to continue to attempt to quit if they have early lapses after quit day.
* Patients should be informed that nausea and insomnia are side effects of SmokeLESS and are usually transient; however, patients should be advised that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered.
* Patients should also be provided with educational materials and necessary counseling to support an attempt at quitting smoking.
* Patients should be informed that some medications may require dose adjustment after quitting smoking.
* Patients intending to become pregnant or planning to breast-feed an infant should be advised of the risks of smoking and risks and benefits of smoking cessation with SmokeLESS.
* Patients should be advised to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them.