TYRVAYA (varenicline solution) nasal spray is indicated for the treatment of the signs and symptoms of dry eye disease.

{ "type": "p", "children": [], "text": "TYRVAYA (varenicline solution) nasal spray is indicated for the treatment of the signs and symptoms of dry eye disease." }

Spray TYRVAYA once in each nostril twice daily (approximately 12 hours apart). If a dose is missed, resume regular dosing at the next scheduled dose time.

Priming: Prime TYRVAYA before initial use by pumping seven (7) actuations into the air away from the face. When TYRVAYA has not been used for more than 5 days, re-prime with 1 spray into the air. Do not shake.

Nasal spray delivering 0.03 mg of varenicline in each spray (0.05 mL).

{ "type": "p", "children": [], "text": "Nasal spray delivering 0.03 mg of varenicline in each spray (0.05 mL)." }

None

{ "type": "p", "children": [], "text": "None" }

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In three clinical studies of dry eye disease conducted with varenicline solution nasal spray, 349 patients received at least 1 dose of TYRVAYA. The majority of patients had 31 days of treatment exposure, with a maximum exposure of 105 days.

The most common adverse reactions reported in 82% of TYRVAYA treated patients was sneezing. Other common adverse reactions that were reported in >5% of patients include cough (16%), throat irritation (13%), and instillation-site (nose) irritation (8%).

Risk Summary

There are no available data on TYRVAYA use in pregnant women to inform any drug associated risks. In animal reproduction studies, varenicline did not produce malformations at clinically relevant doses.

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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 (4864 times the MRHD on a mg/m2 basis).

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 (1216 times the MRHD on a mg/m2 basis). Decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day.

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 TYRVAYA to an infant during lactation; however, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TYRVAYA and any potential adverse effects on the breastfed child from TYRVAYA.

Safety and efficacy of TYRVAYA in pediatric patients have not been established. 

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

TYRVAYA nasal spray contains varenicline which is a partial nicotinic acetylcholine receptor agonist of α4β2, α4α6β2, α3β4, and α3α5β4 receptors and a full α7 receptor agonist.

{ "type": "p", "children": [], "text": "TYRVAYA nasal spray contains varenicline which is a partial nicotinic acetylcholine receptor agonist of α4β2, α4α6β2, α3β4, and α3α5β4 receptors and a full α7 receptor agonist." }

Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid whose chemical name is 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons and a molecular formula of C13H13N3 ⋅ C4H6O6. The chemical structure is:

{ "type": "p", "children": [], "text": "Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid whose chemical name is 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons and a molecular formula of C13H13N3 ⋅ C4H6O6. The chemical structure is:" }

TYRVAYA (varenicline solution) nasal spray is formulated for intranasal use as a clear 0.6 mg/mL strength solution, at pH 6.4. After priming [see Dosage and Administration (2.2)], each actuation delivers a 0.05 mL spray containing 0.03 mg varenicline free base, equivalent to 0.05 mg of varenicline tartrate. The formulation also contains the following inactive ingredients: sodium phosphate dibasic heptahydrate, monobasic sodium phosphate anhydrous, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection.

{ "type": "p", "children": [], "text": "TYRVAYA (varenicline solution) nasal spray is formulated for intranasal use as a clear 0.6 mg/mL strength solution, at pH 6.4. After priming [see Dosage and Administration (2.2)], each actuation delivers a 0.05 mL spray containing 0.03 mg varenicline free base, equivalent to 0.05 mg of varenicline tartrate. The formulation also contains the following inactive ingredients: sodium phosphate dibasic heptahydrate, monobasic sodium phosphate anhydrous, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection." }

The efficacy of TYRVAYA in dry eye disease is believed to be the result of varenicline's activity at heteromeric sub-type(s) of the nicotinic acetylcholine (nACh) receptor where its binding produces agonist activity and activates the trigeminal parasympathetic pathway resulting in increased production of basal tear film as a treatment for dry eye disease. Varenicline binds with high affinity and selectivity at human α4β2, α4α6β2, α3β4, α3α5β4 and α7 neuronal nicotinic acetylcholine receptors. The exact mechanism of action is unknown at this time.

Absorption/Distribution 

Following administration of 0.12 mg (0.06 mg per 50-µL spray in each nostril), a strength of varenicline that is higher than the labeled concentration, varenicline can be detected in plasma by 5 minutes, generally achieves peak concentration within 2 hours, with a mean Cmax of 0.34 ng/mL, and has an AUC0-inf of 7.46 h*ng/mL. The systemic exposure (AUC0-inf) following this intranasal dose was approximately 7.5% of the exposure observed following a 1 mg oral dose of varenicline.  

Metabolism/Elimination

The mean ± SD elimination half-life of varenicline after intranasal administration is approximately 19 ± 10 hours. Varenicline undergoes minimal metabolism with 92% excreted as unchanged drug in the urine.

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 (810 times the maximum recommended human dose [MRHD], on a mg/m2 basis). 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, 405 times the MRHD on a mg/m2 basis) and maximum dose (2 tumors, 15 mg/kg/day, 1216 times the MRHD on a mg/m2 basis). 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 (1216 times the MRHD on a mg/m2 basis). Maternal toxicity, characterized by a decrease in body weight gain, was observed at 15 mg/kg/day. A decrease in fertility was noted in the offspring of pregnant rats administered varenicline succinate at an oral dose of 15 mg/kg/day. The decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (243 times the MRHD, on a mg/m2 basis).

The efficacy of TYRVAYA for the treatment of dry eye disease was supported by two randomized, multi-center, double-masked, vehicle-controlled studies (ONSET-1 and ONSET-2).  In the ONSET-1 study, 182 patients were randomized in a 1:1:1:1 ratio to receive one spray in each nostril twice daily of varenicline solution 0.006 mg (N=47), TYRVAYA 0.03 mg (N=48), varenicline solution 0.06 mg (N=44), or vehicle (N=43). In the ONSET-2 study, 758 patients were randomized in a 1:1:1 ratio to receive one spray in each nostril twice daily of TYRVAYA 0.03 mg (N=260), varenicline solution 0.06 mg (N=246), or vehicle (N=252).

{ "type": "p", "children": [], "text": "The efficacy of TYRVAYA for the treatment of dry eye disease was supported by two randomized, multi-center, double-masked, vehicle-controlled studies (ONSET-1 and ONSET-2).  In the ONSET-1 study, 182 patients were randomized in a 1:1:1:1 ratio to receive one spray in each nostril twice daily of varenicline solution 0.006 mg (N=47), TYRVAYA 0.03 mg (N=48), varenicline solution 0.06 mg (N=44), or vehicle (N=43). In the ONSET-2 study, 758 patients were randomized in a 1:1:1 ratio to receive one spray in each nostril twice daily of TYRVAYA 0.03 mg (N=260), varenicline solution 0.06 mg (N=246), or vehicle (N=252)." }

The majority of patients were female (74%), the mean (standard deviation [SD]) age was 61 (12.5) years, the mean (SD) baseline anesthetized Schirmer’s score was 5.1 mm (2.9), and the mean (SD) baseline eye dryness score (EDS) was 59.3 (21.6). Use of artificial tears was allowed during the studies. Enrollment criteria included minimal signs [i.e., anesthetized Schirmer's test score (range, 0-10 mm) and corneal fluorescein staining (range, 2-14)] and was not limited by baseline EDS (range, 2-100). 

{ "type": "p", "children": [], "text": "The majority of patients were female (74%), the mean (standard deviation [SD]) age was 61 (12.5) years, the mean (SD) baseline anesthetized Schirmer’s score was 5.1 mm (2.9), and the mean (SD) baseline eye dryness score (EDS) was 59.3 (21.6). Use of artificial tears was allowed during the studies. Enrollment criteria included minimal signs [i.e., anesthetized Schirmer's test score (range, 0-10 mm) and corneal fluorescein staining (range, 2-14)] and was not limited by baseline EDS (range, 2-100). " }

Efficacy

{ "type": "p", "children": [], "text": "\nEfficacy\n" }

Tear film production was measured by anesthetized Schirmer’s score assessed using a Schirmer’s strip (0-35 mm). The average baseline Schirmer’s score was 5.0 mm in the ONSET-1 study and 5.1 mm in the ONSET-2 study. Of the patients treated with TYRVAYA, 52% achieved ≥10 mm increase in Schirmer’s score from baseline in the ONSET-1 study and 47% achieved ≥10 mm increase in Schirmer’s score from baseline in the ONSET-2 study, compared to 14% and 28% of vehicle-treated patients in the ONSET-1 study and the ONSET-2 study, respectively at Day 28 (see Table 1).   Of the patients treated with TYRVAYA, the mean change in Schirmer’s score was 11.7 mm and 11.3 mm as compared to 3.2 mm and 6.3 mm in the vehicle treated patients in the ONSET-1 study and ONSET-2 study, respectively at Day 28. 

{ "type": "p", "children": [], "text": "Tear film production was measured by anesthetized Schirmer’s score assessed using a Schirmer’s strip (0-35 mm). The average baseline Schirmer’s score was 5.0 mm in the ONSET-1 study and 5.1 mm in the ONSET-2 study. Of the patients treated with TYRVAYA, 52% achieved ≥10 mm increase in Schirmer’s score from baseline in the ONSET-1 study and 47% achieved ≥10 mm increase in Schirmer’s score from baseline in the ONSET-2 study, compared to 14% and 28% of vehicle-treated patients in the ONSET-1 study and the ONSET-2 study, respectively at Day 28 (see Table 1).   Of the patients treated with TYRVAYA, the mean change in Schirmer’s score was 11.7 mm and 11.3 mm as compared to 3.2 mm and 6.3 mm in the vehicle treated patients in the ONSET-1 study and ONSET-2 study, respectively at Day 28. " }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Percent of Patients Achieving ≥10 mm Improvement from Baseline in Schirmer’s Score in 28-day Studies in Patients with Dry Eye Disease</span> </caption> <col width="35%"/> <col width="19%"/> <col width="13%"/> <col width="20%"/> <col width="13%"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">ONSET-1</span> </p> </td><td align="center" class="Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">ONSET-2</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">TYRVAYA</span> <br/> <span class="Bold">N=48</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Vehicle</span> <br/> <span class="Bold">N=43</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">TYRVAYA</span> <br/> <span class="Bold">N=260</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Vehicle</span> <br/> <span class="Bold">N=252</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First">≥ 10-mm increase in tear production (% of eyes) at Day 28</p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First">52%</p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First">14%</p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First">47%</p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First">28%</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First">Proportion Difference (95% CI)</p> </td><td align="center" class="Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">38% (21%, 56%)</p> </td><td align="center" class="Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">20% (11%, 28%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">p-value versus control</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">&lt;0.01</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">&lt;0.01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 1: Percent of Patients Achieving ≥10 mm Improvement from Baseline in Schirmer’s Score in 28-day Studies in Patients with Dry Eye Disease</span>\n</caption>\n<col width=\"35%\"/>\n<col width=\"19%\"/>\n<col width=\"13%\"/>\n<col width=\"20%\"/>\n<col width=\"13%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Lrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ONSET-1</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ONSET-2</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">TYRVAYA</span>\n<br/>\n<span class=\"Bold\">N=48</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"bottom\">\n<p class=\"First\">\n<span class=\"Bold\">Vehicle</span>\n<br/>\n<span class=\"Bold\">N=43</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"bottom\">\n<p class=\"First\">\n<span class=\"Bold\">TYRVAYA</span>\n<br/>\n<span class=\"Bold\">N=260</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"bottom\">\n<p class=\"First\">\n<span class=\"Bold\">Vehicle</span>\n<br/>\n<span class=\"Bold\">N=252</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">≥ 10-mm increase in tear production (% of eyes) at Day 28</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">52%</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">14%</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">47%</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">28%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Proportion Difference (95% CI)</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">38% (21%, 56%)</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">20% (11%, 28%)</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">p-value versus control</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">&lt;0.01</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">&lt;0.01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Cochran-Mantel-Haenszel (CMH) test controlling for study site, baseline Schirmer’s test score (STS), and baseline EDS.All randomized and treated patients were included in the analysis and missing data were imputed using last-available data.

{ "type": "p", "children": [], "text": "Cochran-Mantel-Haenszel (CMH) test controlling for study site, baseline Schirmer’s test score (STS), and baseline EDS.All randomized and treated patients were included in the analysis and missing data were imputed using last-available data.\n" }

TYRVAYA (varenicline solution) nasal spray is available in a carton containing two (2) nasal spray amber glass Type I bottles. Each bottle consists of a white nasal pump and blue dust cover, delivering 0.03 mg varenicline per spray (0.05 mL). Each bottle delivers one spray in each nostril twice daily for 15 days.  

Two nasal spray bottles in each carton, containing 60 sprays per bottle, equivalent to 30-days’ supply with one spray in each nostril twice daily (NDC 73521-030-02).

{ "type": "", "children": [], "text": "" }

Manufactured for: Oyster Point Pharma, Inc., a Viatris company, 202 Carnegie Center, Suite 106, Princeton, NJ 08540

{ "type": "p", "children": [], "text": "Manufactured for: Oyster Point Pharma, Inc., a Viatris company, 202 Carnegie Center, Suite 106, Princeton, NJ 08540" }

Copyrights and Trademarks are property of their respective owners.

{ "type": "p", "children": [], "text": "Copyrights and Trademarks are property of their respective owners." }

TYRVAYA® is a registered trademark of Oyster Point Pharma, Inc., a Viatris company.

{ "type": "p", "children": [], "text": "TYRVAYA® is a registered trademark of Oyster Point Pharma, Inc., a Viatris company." }

TYRVAYA® and/or the use of TYRVAYA® in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices.

{ "type": "p", "children": [], "text": "TYRVAYA® and/or the use of TYRVAYA® in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices." }

©2023 Oyster Point Pharma, Inc., a Viatris Company. All Rights Reserved.

{ "type": "p", "children": [], "text": "©2023 Oyster Point Pharma, Inc., a Viatris Company. All Rights Reserved." }

OYP:TYRVA:R1

{ "type": "p", "children": [], "text": "OYP:TYRVA:R1" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="100%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">TYRVAYA<span class="Sup">®</span></span> (Teer-vye-ah)</p> <p>(varenicline solution)</p> <p>nasal spray, for intranasal use</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is TYRVAYA?</span> </p> <p>TYRVAYA is a prescription nasal spray used to treat the signs and symptoms of dry eye disease.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before you use TYRVAYA, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>are pregnant or plan to become pregnant. It is not known if TYRVAYA will harm your unborn baby.</dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. It is not known if TYRVAYA passes into your breast milk. You and your healthcare provider should decide if you will use TYRVAYA if you plan to breastfeed.</dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p> </p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I use TYRVAYA?</span> </p> <dl> <dt>•</dt> <dd>See the Instructions for Use at the end of this Patient Information leaflet for information about the right way to use TYRVAYA.</dd> <dt>•</dt> <dd>TYRVAYA increases tear production in the eye after being sprayed in the nose.</dd> <dt>•</dt> <dd>Use TYRVAYA exactly as your healthcare provider tells you to use it.</dd> <dt>•</dt> <dd>Do not shake the bottles.</dd> <dt>•</dt> <dd>Spray TYRVAYA 1 time in each nostril, 2 times daily (about 12 hours apart).</dd> <dt>•</dt> <dd>A 1-month supply of TYRVAYA consists of 2 nasal spray bottles. Finish 1 bottle before opening the second. TYRVAYA comes in glass bottles with a white nasal pump and blue dust cover.</dd> <dt>•</dt> <dd>If you miss a dose of TYRVAYA, skip that dose and take your next dose at your regular scheduled time. Do not take an extra dose to make up for a missed dose.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of TYRVAYA?</span> </p> <p>The most common side effects of TYRVAYA include sneezing, cough, and throat and nose irritation.</p> <p>These are not the only possible side effects of TYRVAYA. Call your doctor for medical advice about side effects.</p> <p>You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store TYRVAYA?</span> </p> <dl> <dt>•</dt> <dd>Store TYRVAYA at room temperature between 68°F to 77°F (20°C to 25°C).</dd> <dt>•</dt> <dd>Do not freeze.</dd> <dt>•</dt> <dd>Throw away (discard) TYRVAYA nasal spray bottle 30 days after first use.</dd> </dl> <p> <span class="Bold">Keep TYRVAYA and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of TYRVAYA.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TYRVAYA for a condition for which it was not prescribed. Do not give TYRVAYA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TYRVAYA that is written for health professionals.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in TYRVAYA?</span> </p> <p> <span class="Bold">Active ingredient:</span> varenicline tartrate</p> <p> <span class="Bold">Inactive ingredients:</span> sodium phosphate dibasic heptahydrate, monobasic sodium phosphate anhydrous, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection. </p> <p> </p> <p>TYRVAYA<span class="Sup">®</span> is a registered trademark of Oyster Point Pharma, Inc., a Viatris Company.</p> <p>TYRVAYA<span class="Sup">®</span> and/or the use of TYRVAYA<span class="Sup">®</span> in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices.</p> <p>Manufactured for: Oyster Point Pharma, Inc., 202 Carnegie Center, Suite 106, Princeton, NJ 08540</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">TYRVAYA<span class=\"Sup\">®</span></span> (Teer-vye-ah)</p>\n<p>(varenicline solution)</p>\n<p>nasal spray, for intranasal use</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is TYRVAYA?</span>\n</p>\n<p>TYRVAYA is a prescription nasal spray used to treat the signs and symptoms of dry eye disease.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before you use TYRVAYA, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. It is not known if TYRVAYA will harm your unborn baby.</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. It is not known if TYRVAYA passes into your breast milk. You and your healthcare provider should decide if you will use TYRVAYA if you plan to breastfeed.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n<p> </p>\n<p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use TYRVAYA?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See the Instructions for Use at the end of this Patient Information leaflet for information about the right way to use TYRVAYA.</dd>\n<dt>•</dt>\n<dd>TYRVAYA increases tear production in the eye after being sprayed in the nose.</dd>\n<dt>•</dt>\n<dd>Use TYRVAYA exactly as your healthcare provider tells you to use it.</dd>\n<dt>•</dt>\n<dd>Do not shake the bottles.</dd>\n<dt>•</dt>\n<dd>Spray TYRVAYA 1 time in each nostril, 2 times daily (about 12 hours apart).</dd>\n<dt>•</dt>\n<dd>A 1-month supply of TYRVAYA consists of 2 nasal spray bottles. Finish 1 bottle before opening the second. TYRVAYA comes in glass bottles with a white nasal pump and blue dust cover.</dd>\n<dt>•</dt>\n<dd>If you miss a dose of TYRVAYA, skip that dose and take your next dose at your regular scheduled time. Do not take an extra dose to make up for a missed dose.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of TYRVAYA?</span>\n</p>\n<p>The most common side effects of TYRVAYA include sneezing, cough, and throat and nose irritation.</p>\n<p>These are not the only possible side effects of TYRVAYA. Call your doctor for medical advice about side effects.</p>\n<p>You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store TYRVAYA?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store TYRVAYA at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n<dt>•</dt>\n<dd>Do not freeze.</dd>\n<dt>•</dt>\n<dd>Throw away (discard) TYRVAYA nasal spray bottle 30 days after first use.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep TYRVAYA and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of TYRVAYA.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TYRVAYA for a condition for which it was not prescribed. Do not give TYRVAYA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TYRVAYA that is written for health professionals.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in TYRVAYA?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> varenicline tartrate</p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> sodium phosphate dibasic heptahydrate, monobasic sodium phosphate anhydrous, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection. </p>\n<p> </p>\n<p>TYRVAYA<span class=\"Sup\">®</span> is a registered trademark of Oyster Point Pharma, Inc., a Viatris Company.</p>\n<p>TYRVAYA<span class=\"Sup\">®</span> and/or the use of TYRVAYA<span class=\"Sup\">®</span> in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices.</p>\n<p>Manufactured for: Oyster Point Pharma, Inc., 202 Carnegie Center, Suite 106, Princeton, NJ 08540</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration" }

Revised: 2/2024

{ "type": "p", "children": [], "text": "Revised: 2/2024" }

OYP:PL:TYRVA:R1

{ "type": "p", "children": [], "text": "OYP:PL:TYRVA:R1" }

TYRVAYA® (Teer-vye-ah) (varenicline solution)nasal spray, for intranasal use

{ "type": "p", "children": [], "text": "\nTYRVAYA® (Teer-vye-ah)\n(varenicline solution)nasal spray, for intranasal use\n" }

Read this Instructions for Use before you start using TYRVAYA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using TYRVAYA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment." }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Important information you need to know before using TYRVAYA:</span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Parts of your TYRVAYA nasal spray:</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold"> </span> <br/> </p> <dl> <dt>•</dt> <dd> <span class="Bold">TYRVAYA is for use in the nose.</span> <br/> </dd> <dt>•</dt> <dd> <span class="Bold">Do not shake the bottles.</span> <br/> </dd> <dt>•</dt> <dd>The TYRVAYA carton contains enough medicine for 30 days. <dl> <dt>o</dt> <dd>Each carton has 2 glass nasal spray bottles.<br/> </dd> <dt>o</dt> <dd>Each nasal spray bottle has enough medicine for 15 days of treatment.  <br/> </dd> <dt>o</dt> <dd> <span class="Bold">Do not </span>open the second nasal spray bottle until you have used the entire first bottle.<span class="Bold"> </span> </dd> </dl> </dd> </dl> </td><td valign="top"><a name="id-1190530298"></a><img alt="Tyrvaya Nasal Spray" src="/dailymed/image.cfm?name=image-01.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td align="center" colspan="2" valign="top"> <p class="First"> <span class="Bold">Steps for priming TYRVAYA before first Use</span> </p> </td> </tr> <tr> <td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 1.</span> Remove the cap and the clip. <br/> <br/> <span class="Bold">Do not</span> throw away the cap or the clip. The cap and the clip will be placed back on to the nasal applicator after each use.</p> </td><td valign="top"><a name="id2106912779"></a><img alt="Remove clip/cap" src="/dailymed/image.cfm?name=image-02.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 2. </span> Hold the nasal spray bottle upright and away from your face. Place 1 finger on each side of the base of the nasal applicator and place your thumb underneath the bottle.<br/> </p> </td><td valign="top"><a name="id668984916"></a><img alt="Step 2. Hold the nasal spray upright and away from your face. Place one finger on each side of the base of the nasal applicator, and place your thumb underneath the bottle." src="/dailymed/image.cfm?name=image-03.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Step 3.</span>  Prime the nasal spray bottle by fully pressing and releasing the nasal applicator 7 times with your thumb and fingers. <span class="Bold">You may feel some resistance but be sure to press all the way down.</span> You may not see a spray released each time you press and release the nasal applicator. You should see a spray by the 7<span class="Sup">th</span> time you press and release. Spray away from yourself and others. <br/>TYRVAYA is now primed for use.</p> </td><td class="Botrule" valign="top"> <br/> <a name="id145642366"></a><img alt="Press 7 times/Fully Press" src="/dailymed/image.cfm?name=image-04.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Important information you need to know before using TYRVAYA:</span>\n</p>\n</td><td class=\"Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Parts of your TYRVAYA nasal spray:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"> </span>\n<br/>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">TYRVAYA is for use in the nose.</span>\n<br/>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not shake the bottles.</span>\n<br/>\n</dd>\n<dt>•</dt>\n<dd>The TYRVAYA carton contains enough medicine for 30 days. <dl>\n<dt>o</dt>\n<dd>Each carton has 2 glass nasal spray bottles.<br/>\n</dd>\n<dt>o</dt>\n<dd>Each nasal spray bottle has enough medicine for 15 days of treatment.  <br/>\n</dd>\n<dt>o</dt>\n<dd>\n<span class=\"Bold\">Do not </span>open the second nasal spray bottle until you have used the entire first bottle.<span class=\"Bold\"> </span>\n</dd>\n</dl>\n</dd>\n</dl>\n</td><td valign=\"top\"><a name=\"id-1190530298\"></a><img alt=\"Tyrvaya Nasal Spray\" src=\"/dailymed/image.cfm?name=image-01.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td align=\"center\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Steps for priming TYRVAYA before first Use</span>\n</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\"></td><td valign=\"top\"></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1.</span> Remove the cap and the clip. <br/>\n<br/>\n<span class=\"Bold\">Do not</span> throw away the cap or the clip. The cap and the clip will be placed back on to the nasal applicator after each use.</p>\n</td><td valign=\"top\"><a name=\"id2106912779\"></a><img alt=\"Remove clip/cap\" src=\"/dailymed/image.cfm?name=image-02.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2. </span> Hold the nasal spray bottle upright and away from your face. Place 1 finger on each side of the base of the nasal applicator and place your thumb underneath the bottle.<br/>\n</p>\n</td><td valign=\"top\"><a name=\"id668984916\"></a><img alt=\"Step 2. Hold the nasal spray upright and away from your face. Place one finger on each side of the base of the nasal applicator, and place your thumb underneath the bottle.\" src=\"/dailymed/image.cfm?name=image-03.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3.</span>  Prime the nasal spray bottle by fully pressing and releasing the nasal applicator 7 times with your thumb and fingers. <span class=\"Bold\">You may feel some resistance but be sure to press all the way down.</span> You may not see a spray released each time you press and release the nasal applicator. You should see a spray by the 7<span class=\"Sup\">th</span> time you press and release. Spray away from yourself and others. <br/>TYRVAYA is now primed for use.</p>\n</td><td class=\"Botrule\" valign=\"top\">\n<br/>\n<a name=\"id145642366\"></a><img alt=\"Press 7 times/Fully Press\" src=\"/dailymed/image.cfm?name=image-04.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "", "children": [], "text": "" }

<div class="scrollingtable"><table width="100%"> <col width="46%"/> <col width="54%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Steps for using TYRVAYA nasal spray after priming</span> </p> </td> </tr> <tr> <td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 1. </span>Blow your nose to clear your nostrils, if needed.<span class="Bold"> </span> <br/> </p> </td><td valign="top"><a name="id219419619"></a><img alt="Step 1. Blow nose to clear nostrils if needed. " src="/dailymed/image.cfm?name=image-05.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 2.</span> Remove the cap and clip.  <br/> <br/> <span class="Bold">Do not</span> throw away the cap or the clip. The cap and the clip will be placed back on to the nasal applicator after each use.<br/> </p> </td><td valign="top"><a name="id1483728496"></a><img alt="Remove cap/clip" src="/dailymed/image.cfm?name=image-06.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 3.</span> Hold the nasal spray bottle upright. Place 1 finger on each side of the base of the nasal applicator and your thumb underneath the bottle.</p> </td><td valign="top"><a name="id-1948615965"></a><img alt="Step 3. Hold the nasal spray upright. Place one finger on each side of the base of the nasal applicator and your thumb underneath the bottle." src="/dailymed/image.cfm?name=image-07.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 4. </span>Tilt your head back slightly without lying down.<br/> </p> </td><td valign="top"><a name="id598378747"></a><img alt="Step 4. Tilt your head back slightly." src="/dailymed/image.cfm?name=image-08.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 5.</span> Insert the nasal applicator into the left or right nostril. Tilt the nasal applicator and point the tip of the nasal applicator towards the top of the ear on the same side as your nostril.  <br/> <span class="Bold">Do not</span> press the tip of the nasal applicator against the wall of the inside of your nose. Leave a space between the tip of the nasal applicator and the wall of the inside of your nose.</p> </td><td valign="bottom"><a name="id1806438604"></a><img alt="Step 5. Insert the nasal applicator into the left or right nostril. Tilt the nasal applicator and aim the tip towards the top of the ear on the same side. DO NOT press the tip of nasal applicator against the wall of the inside of your nose. Allow for a space between the tip of nasal applicator and the wall of the inside of your nose for proper dose administration. " src="/dailymed/image.cfm?name=image-09.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 6. </span>Place your tongue to the roof of your mouth and breathe gently while <span class="Bold">fully</span> pressing and releasing the nasal applicator <span class="Bold">1-time</span> to release a spray into your nostril. <br/>Repeat Steps 5 and 6 to deliver a second spray in the other nostril. <br/> </p> </td><td valign="top"><a name="id1103683865"></a><img alt="Step 6. Place tongue to the roof of the mouth and breathe gently while spraying 1 (one) time. Repeat administration in the other nostril. Wait 2 (two) or 3 (three) minutes before blowing nose if needed. " src="/dailymed/image.cfm?name=image-10.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Step 7.</span> Wipe the nasal applicator with a clean tissue.<br/> </p> </td><td valign="top"><a name="id2063519008"></a><img alt="Step 7. Wipe the nasal applicator with a clean tissue." src="/dailymed/image.cfm?name=image-11.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Step 8.</span> Replace the clip and the cap.<br/> <br/> <br/> <br/> <span class="Bold">Repeat Steps 1 to 8 each time you use TYRVAYA.</span> </p> </td><td class="Botrule" valign="top"><a name="id1560897125"></a><img alt="Step 8. Replace clip and cap." src="/dailymed/image.cfm?name=image-12.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"46%\"/>\n<col width=\"54%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Steps for using TYRVAYA nasal spray after priming</span>\n</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\"></td><td valign=\"top\"></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1. </span>Blow your nose to clear your nostrils, if needed.<span class=\"Bold\"> </span>\n<br/>\n</p>\n</td><td valign=\"top\"><a name=\"id219419619\"></a><img alt=\"Step 1. Blow nose to clear nostrils if needed. \" src=\"/dailymed/image.cfm?name=image-05.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2.</span> Remove the cap and clip.  <br/>\n<br/>\n<span class=\"Bold\">Do not</span> throw away the cap or the clip. The cap and the clip will be placed back on to the nasal applicator after each use.<br/>\n</p>\n</td><td valign=\"top\"><a name=\"id1483728496\"></a><img alt=\"Remove cap/clip\" src=\"/dailymed/image.cfm?name=image-06.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3.</span> Hold the nasal spray bottle upright. Place 1 finger on each side of the base of the nasal applicator and your thumb underneath the bottle.</p>\n</td><td valign=\"top\"><a name=\"id-1948615965\"></a><img alt=\"Step 3. Hold the nasal spray upright. Place one finger on each side of the base of the nasal applicator and your thumb underneath the bottle.\" src=\"/dailymed/image.cfm?name=image-07.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 4. </span>Tilt your head back slightly without lying down.<br/>\n</p>\n</td><td valign=\"top\"><a name=\"id598378747\"></a><img alt=\"Step 4. Tilt your head back slightly.\" src=\"/dailymed/image.cfm?name=image-08.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 5.</span> Insert the nasal applicator into the left or right nostril. Tilt the nasal applicator and point the tip of the nasal applicator towards the top of the ear on the same side as your nostril.  <br/>\n<span class=\"Bold\">Do not</span> press the tip of the nasal applicator against the wall of the inside of your nose. Leave a space between the tip of the nasal applicator and the wall of the inside of your nose.</p>\n</td><td valign=\"bottom\"><a name=\"id1806438604\"></a><img alt=\"Step 5. Insert the nasal applicator into the left or right nostril. Tilt the nasal applicator and aim the tip towards the top of the ear on the same side. DO NOT press the tip of nasal applicator against the wall of the inside of your nose. Allow for a space between the tip of nasal applicator and the wall of the inside of your nose for proper dose administration. \" src=\"/dailymed/image.cfm?name=image-09.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 6. </span>Place your tongue to the roof of your mouth and breathe gently while <span class=\"Bold\">fully</span> pressing and releasing the nasal applicator <span class=\"Bold\">1-time</span> to release a spray into your nostril. <br/>Repeat Steps 5 and 6 to deliver a second spray in the other nostril. <br/>\n</p>\n</td><td valign=\"top\"><a name=\"id1103683865\"></a><img alt=\"Step 6. Place tongue to the roof of the mouth and breathe gently while spraying 1 (one) time. Repeat administration in the other nostril. Wait 2 (two) or 3 (three) minutes before blowing nose if needed. \" src=\"/dailymed/image.cfm?name=image-10.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 7.</span> Wipe the nasal applicator with a clean tissue.<br/>\n</p>\n</td><td valign=\"top\"><a name=\"id2063519008\"></a><img alt=\"Step 7. Wipe the nasal applicator with a clean tissue.\" src=\"/dailymed/image.cfm?name=image-11.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 8.</span> Replace the clip and the cap.<br/>\n<br/>\n<br/>\n<br/>\n<span class=\"Bold\">Repeat Steps 1 to 8 each time you use TYRVAYA.</span> </p>\n</td><td class=\"Botrule\" valign=\"top\"><a name=\"id1560897125\"></a><img alt=\"Step 8. Replace clip and cap.\" src=\"/dailymed/image.cfm?name=image-12.jpg&amp;setid=014c93dc-5737-479c-a9f0-aaadac1ac298\"/></td>\n</tr>\n</tbody>\n</table></div>" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

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TYRVAYA® is a registered trademark of Oyster Point Pharma, Inc., a Viatris company.

{ "type": "p", "children": [], "text": "TYRVAYA® is a registered trademark of Oyster Point Pharma, Inc., a Viatris company." }

TYRVAYA® and/or the use of TYRVAYA® in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices.

{ "type": "p", "children": [], "text": "TYRVAYA® and/or the use of TYRVAYA® in a method may be covered by one or more patents or patent applications, available at www.oysterpointrx.com/patent-notices." }

Manufactured for: Oyster Point Pharma, Inc., 202 Carnegie Center, Suite 106, Princeton, NJ 08540

{ "type": "p", "children": [], "text": "Manufactured for: Oyster Point Pharma, Inc., 202 Carnegie Center, Suite 106, Princeton, NJ 08540" }

©2023 Oyster Point Pharma, Inc.

{ "type": "p", "children": [], "text": "©2023 Oyster Point Pharma, Inc." }

Revised: 2/2024

{ "type": "p", "children": [], "text": "Revised: 2/2024" }

OYP:IFU:TYRVA:R1

{ "type": "p", "children": [], "text": "OYP:IFU:TYRVA:R1" }

NDC 73521-030-02

{ "type": "p", "children": [], "text": "\nNDC 73521-030-02\n" }

tyrvaya® (varenicline solution)nasal spray 0.03 mg

{ "type": "p", "children": [], "text": "\ntyrvaya®\n(varenicline solution)nasal spray 0.03 mg\n" }

2 nasal spray bottlesfor a 30-day supply

{ "type": "p", "children": [], "text": "\n2 nasal spray bottlesfor a 30-day supply\n" }

Each bottle contains 60 sprays(Net Content 4.2 mL per bottle)

{ "type": "p", "children": [], "text": "\nEach bottle contains 60 sprays(Net Content 4.2 mL per bottle)\n" }

FOR INTRANASAL USE

{ "type": "p", "children": [], "text": "\nFOR INTRANASAL USE\n" }

Rx only.

{ "type": "p", "children": [], "text": "\nRx only.\n" }

Each 50 μL spray contains: varenicline 0.03 mg(equivalent to 0.05 mgvarenicline tartrate)

{ "type": "p", "children": [], "text": "\nEach 50 μL spray contains:\nvarenicline 0.03 mg(equivalent to 0.05 mgvarenicline tartrate)" }

Inactive ingredients: sodium phosphate dibasicheptahydrate, monobasicsodium phosphateanhydrous, sodium chloride,sodium hydroxide and/orhydrochloric acid (to adjustpH) and water for injection.

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Manufactured for: Oyster Point Pharma, Inc.Princeton, NJ 08540

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1-877-EYE-0123

{ "type": "p", "children": [], "text": "1-877-EYE-0123" }

Store Tyrvaya between20°C to 25°C (68°F to 77°F).

{ "type": "p", "children": [], "text": "Store Tyrvaya between20°C to 25°C (68°F to 77°F)." }

Do not freeze.

{ "type": "p", "children": [], "text": "Do not freeze." }

Do not shake the bottles.

{ "type": "p", "children": [], "text": "Do not shake the bottles." }

Discard individual bottle ofTyrvaya 30 days after first use.

{ "type": "p", "children": [], "text": "Discard individual bottle ofTyrvaya 30 days after first use." }

Keep Tyrvaya and allmedicines out of the reachof children.

{ "type": "p", "children": [], "text": "Keep Tyrvaya and allmedicines out of the reachof children." }

02TRADCTN, Rev 2.0

{ "type": "p", "children": [], "text": "02TRADCTN, Rev 2.0" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="100%"/> <tbody class="Headless"> <tr> <td align="center" class="Lrule Toprule" valign="middle"> <p class="First"> <span class="Bold">IMPORTANT</span> </p> </td> </tr> <tr> <td align="center" class="Lrule" valign="middle"> <p class="First">Read enclosed <span class="Bold">Patient</span> </p> <p> <span class="Bold">Information</span> and <span class="Bold">Instructions</span> </p> <p> <span class="Bold">for Use</span> for priming, dosing,</p> <p>and re-priming information.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="middle"> <p class="First"> <span class="Bold">PRIME BEFORE FIRST USE.</span> </p> <p> <span class="Bold">FOR INTRANASAL USE.</span> </p> </td> </tr> </tbody> </table></div>

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Tyrvaya, Oyster Point, and the respective logosare registered trademarks of Oyster Point Pharma, Inc.

{ "type": "p", "children": [], "text": "Tyrvaya, Oyster Point, and the respective logosare registered trademarks of Oyster Point Pharma, Inc." }

CHANTIX is indicated for use as an aid to smoking cessation treatment.

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Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.

The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.

CHANTIX should be taken orally after eating and with a full glass of water.

The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:

<div class="scrollingtable"><table width="50%"> <col align="left" valign="middle" width="50%"/> <col align="left" valign="middle" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Days 1 – 3:</td><td align="left" class="Rrule">0.5 mg once daily</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Days 4 – 7:</td><td align="left" class="Rrule">0.5 mg twice daily</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Day 8 – end of treatment:</td><td align="left" class="Rrule">1 mg twice daily</td> </tr> </tbody> </table></div>

Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.

For patients who are sure that they are not able or willing to quit abruptly, consider a gradual approach to quitting smoking with CHANTIX. Patients should begin CHANTIX dosing and reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the goal of reaching complete abstinence by 12 weeks. Continue CHANTIX treatment for an additional 12 weeks, for a total of 24 weeks of treatment. Encourage patients to attempt quitting sooner if they feel ready [see Clinical Studies (14.5)].

Patients who are motivated to quit, and who did not succeed in stopping smoking during prior CHANTIX therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with CHANTIX once factors contributing to the failed attempt have been identified and addressed.

Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.

Patients with Impaired Renal Function

No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance less than 30 mL per min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Elderly and Patients with Impaired Hepatic Function

No dosage adjustment is necessary for patients with hepatic impairment. 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 [see Use in Specific Populations (8.5)].

Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side).

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CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.

{ "type": "p", "children": [], "text": "CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX." }

Serious neuropsychiatric adverse events have been reported in patients being treated with CHANTIX [see Adverse Reactions (6.2)]. 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 neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)]. 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 an 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 [see Clinical Studies (14.10)].

During clinical trials and the postmarketing experience, there have been reports of seizures in patients treated with CHANTIX. Some patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy. Weigh this potential risk against the potential benefits before prescribing CHANTIX in patients with a history of seizures or other factors that can lower the seizure threshold. Advise patients to discontinue CHANTIX and contact a healthcare provider immediately if they experience a seizure while on treatment [see Adverse Reactions (6.2)].

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHANTIX. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking CHANTIX until they know whether CHANTIX affects their tolerance for alcohol [see Adverse Reactions (6.2)].

There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how CHANTIX may affect them.

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 [see Clinical Studies (14.8)]. 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 [see Clinical Studies (14.10)].

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 [see Adverse Reactions (6.2)].

There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2), Patient Counseling Information (17)]. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.

There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX [see Adverse Reactions (6.2)]. As these skin reactions can be life-threatening, instruct patients to stop taking CHANTIX and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.

Nausea was the most common adverse reaction reported with CHANTIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking CHANTIX 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.

Because clinical trials are conducted under widely varying conditions, the adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the premarketing development of CHANTIX, over 4500 subjects were exposed to CHANTIX, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less.

The most common adverse event associated with CHANTIX treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen [see Warnings and Precautions (5.9)].

Table 1 shows the adverse events for CHANTIX and placebo in the 12- week fixed dose premarketing studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).

MedDRA High Level Group Terms (HLGT) reported in ≥5% of patients in the CHANTIX 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥1% of CHANTIX patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1. Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies (HLGTs ≥5% of Patients in the 1 mg BID CHANTIX Group and More Commonly than Placebo and PT ≥1% in the 1 mg BID CHANTIX Group, and 1 mg BID CHANTIX at Least 0.5% More than Placebo)</span> </caption> <col align="left" valign="top" width="31%"/> <col align="center" valign="top" width="23%"/> <col align="center" valign="top" width="23%"/> <col align="center" valign="top" width="23%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule">SYSTEM ORGAN CLASS<br/>High Level Group Term</th><th align="center" class="Rrule">CHANTIX<br/>0.5 mg BID</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">Preferred Term</th><th align="center" class="Rrule">N=129</th><th align="center" class="Rrule">N=821</th><th align="center" class="Rrule">N=805</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">GASTROINTESTINAL (GI)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  GI Signs and Symptoms</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nausea</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">10</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Abdominal Pain <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Flatulence</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Dyspepsia</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Vomiting</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  GI Motility/Defecation Conditions</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Constipation</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Gastroesophageal reflux disease</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Salivary Gland Conditions</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Dry mouth</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">PSYCHIATRIC DISORDERS</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sleep Disorder/Disturbances</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Insomnia <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">13</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Abnormal dreams</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Sleep disorder</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nightmare</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">NERVOUS SYSTEM</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headaches</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Headache</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">13</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Neurological Disorders NEC</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Dysgeusia</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Somnolence</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Lethargy</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">GENERAL DISORDERS</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  General Disorders NEC</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fatigue/Malaise/Asthenia</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">RESPIR/THORACIC/MEDIAST</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Respiratory Disorders NEC</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Rhinorrhea</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Dyspnea</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Upper Respiratory Tract Disorder</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">SKIN/SUBCUTANEOUS TISSUE</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Epidermal and Dermal Conditions</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Rash</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Pruritis</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">METABOLISM and NUTRITION</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Appetite/General Nutrition Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Increased appetite</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">    Decreased appetite/Anorexia</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td> </tr> </tbody> </table></div>

The overall pattern and frequency of adverse events during the longer-term premarketing trials was similar to those described in Table 1, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg twice daily in a one year study, compared to 8% of placebo-treated patients).

Following is a list of treatment-emergent adverse events reported by patients treated with CHANTIX during all premarketing clinical trials and updated based on pooled data from 18 placebo-controlled pre- and postmarketing studies, including approximately 5,000 patients treated with varenicline. Adverse events were categorized using MedDRA, Version 16.0. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.

Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.

Cardiac Disorders. Infrequent: angina pectoris, myocardial infarction, palpitations, tachycardia. Rare: acute coronary syndrome, arrhythmia, atrial fibrillation, bradycardia, cardiac flutter, cor pulmonale, coronary artery disease, ventricular extrasystoles.

Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.

Endocrine Disorders. Infrequent: thyroid gland disorders.

Eye Disorders. Infrequent: conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment. Rare: blindness transient, cataract subcapsular, dry eye, night blindness, ocular vascular disorder, photophobia, vitreous floaters.

Gastrointestinal Disorders. Frequent: diarrhea, toothache. Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute.

General Disorders and Administration Site Conditions. Frequent: chest pain. Infrequent: chest discomfort, chills, edema, influenza-like illness, pyrexia.

Hepatobiliary Disorders. Rare: gall bladder disorder.

Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal. Rare: muscle enzyme increased, urine analysis abnormal.

Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hypoglycemia. Rare: hyperlipidemia, hypokalemia.

Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, myalgia. Infrequent: arthritis, muscle cramp, musculoskeletal pain. Rare: myositis, osteoporosis.

Nervous System Disorders. Frequent: disturbance in attention, dizziness. Infrequent: amnesia, convulsion, migraine, parosmia, syncope, tremor. Rare: balance disorder, cerebrovascular accident, dysarthria, mental impairment, multiple sclerosis, VIIth nerve paralysis, nystagmus, psychomotor hyperactivity, psychomotor skills impaired, restless legs syndrome, sensory disturbance, transient ischemic attack, visual field defect.

Psychiatric Disorders. Infrequent: dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, disorientation, euphoric mood.

Renal and Urinary Disorders. Infrequent: nocturia, pollakiuria, urine abnormality. Rare: nephrolithiasis, polyuria, renal failure acute, urethral syndrome, urinary retention.

Reproductive System and Breast Disorders. Frequent: menstrual disorder. Infrequent: erectile dysfunction. Rare: sexual dysfunction.

Respiratory, Thoracic and Mediastinal Disorders. Frequent: respiratory disorders. Infrequent: asthma, epistaxis, rhinitis allergic, upper respiratory tract inflammation. Rare: pleurisy, pulmonary embolism.

Skin and Subcutaneous Tissue Disorders. Infrequent: acne, dry skin, eczema, erythema, hyperhidrosis, urticaria. Rare: photosensitivity reaction, psoriasis.

Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.

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, (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 or willing to quit abruptly and who were instructed to quit gradually ("gradual approach to quitting smoking trial").

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 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%).

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency &gt;1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease</span> </caption> <col align="left" valign="top" width="56%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">N=353</th><th align="center" class="Rrule">N=350</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>some procedures were part of management of nonfatal MI and hospitalization for angina</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Adverse Events ≥1% in either treatment group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Up to 30 days after treatment</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Angina pectoris</td><td align="center" class="Rrule">3.7</td><td align="center" class="Rrule">2.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Chest pain</td><td align="center" class="Rrule">2.5</td><td align="center" class="Rrule">2.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Peripheral edema</td><td align="center" class="Rrule">2.0</td><td align="center" class="Rrule">1.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Hypertension</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">2.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Palpitations</td><td align="center" class="Rrule">0.6</td><td align="center" class="Rrule">1.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Adjudicated Cardiovascular Mortality (up to 52 weeks)</span></td><td align="center" class="Rrule">0.3</td><td align="center" class="Rrule">0.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in either treatment group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Up to 30 days after treatment</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nonfatal MI</td><td align="center" class="Rrule">1.1</td><td align="center" class="Rrule">0.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Hospitalization for angina pectoris</td><td align="center" class="Rrule">0.6</td><td align="center" class="Rrule">1.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Beyond 30 days after treatment and up to 52 weeks</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Need for coronary revascularization<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="center" class="Rrule">2.0</td><td align="center" class="Rrule">0.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Hospitalization for angina pectoris</td><td align="center" class="Rrule">1.7</td><td align="center" class="Rrule">1.1</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">    New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">0.6</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3. Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia or Schizoaffective Disorder</span> </caption> <col align="left" valign="top" width="56%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">N=84</th><th align="center" class="Rrule">N=43</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Adverse Events ≥10% in the varenicline group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">14</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">19</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Psychiatric Adverse Events ≥5% and at a higher rate than in the placebo group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">5</td> </tr> </tbody> </table></div>

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%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder</span> </caption> <col align="left" valign="top" width="56%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">N=256</th><th align="center" class="Rrule">N=269</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Adverse Events ≥10% in either treatment group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">27</td><td align="center" class="Rrule">10</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">11</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abnormal dreams</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Irritability</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Psychiatric Adverse Events ≥2% in any treatment group and not included above</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Depressed mood disorders and disturbances</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anxiety</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Agitation</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tension</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hostility</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0.4</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Restlessness</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5. Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="56%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Adverse Events ≥10% in the varenicline group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Bold">Entire study population,</span> N</td><td align="center" class="Rrule">1982</td><td align="center" class="Rrule">1979</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nausea</td><td align="center" class="Rrule">25</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Headache</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">10</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Psychiatric Adverse Events ≥2% in any treatment group</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Bold">Non-psychiatric cohort, N</span></td><td align="center" class="Rrule">975</td><td align="center" class="Rrule">982</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Abnormal dreams</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Agitation</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Anxiety</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Depressed mood</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Insomnia</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Irritability</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Sleep disorder</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Bold">Psychiatric cohort, N</span></td><td align="center" class="Rrule">1007</td><td align="center" class="Rrule">997</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Abnormal dreams</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Agitation</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Anxiety</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Depressed mood</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Depression</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Insomnia</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Irritability</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nervousness</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">    Sleep disorder</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> </tbody> </table></div>

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.

The following adverse events have been reported during post-approval use of CHANTIX. 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 CHANTIX [see Warnings and Precautions (5.1)].

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

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking CHANTIX. 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 CHANTIX [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 CHANTIX. 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 CHANTIX.

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

Safety and efficacy of CHANTIX 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.

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

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 US 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

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts</span> </caption> <col align="left" valign="top" width="29%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="27%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Outcome</th><th align="center" class="Rrule">Varenicline Cohort<br/>(n=335)</th><th align="center" class="Rrule">Smoking Cohort<br/>(n=78,412)</th><th align="center" class="Rrule">Non-Smoking Cohort<br/>(n=806,438)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Included only live births in the cohorts. Prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]).</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>There was a lag in death data in Denmark, so the cohorts were smaller.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Major congenital malformation<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></td><td align="center" class="Rrule">12 / 334 (3.6%)</td><td align="center" class="Rrule">3,382 / 78,028 (4.3%)</td><td align="center" class="Rrule">33,950 /804,020 (4.2%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Stillbirth</td><td align="center" class="Rrule">1 (0.3%)</td><td align="center" class="Rrule">384 (0.5%)</td><td align="center" class="Rrule">2,418 (0.3%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Small for gestational age</td><td align="center" class="Rrule">42 (12.5%)</td><td align="center" class="Rrule">13,433 (17.1%)</td><td align="center" class="Rrule">73,135 (9.1%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Preterm birth</td><td align="center" class="Rrule">25 (7.5%)</td><td align="center" class="Rrule">6,173 (7.9%)</td><td align="center" class="Rrule">46,732 (5.8%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Premature rupture of membranes</td><td align="center" class="Rrule">12 (3.6%)</td><td align="center" class="Rrule">4,246 (5.4%)</td><td align="center" class="Rrule">30,641 (3.8%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Sudden infant death syndrome<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></td><td align="center" class="Rrule">0/307 (0.0%)</td><td align="center" class="Rrule">51/71,720 (0.1%)</td><td align="center" class="Rrule">58/755,939 (&lt;0.1%)</td> </tr> </tbody> </table></div>

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.

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 [see Data]. 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.

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 ≤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.

A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 years) 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 [see Dosage and Administration (2.2)].

No dosage adjustment is recommended for elderly patients.

Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Varenicline is not a controlled substance.

Humans

Fewer than 1 out of 1,000 patients reported euphoria in clinical trials with CHANTIX. At higher doses (greater than 2 mg), CHANTIX produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of CHANTIX was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction.

In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers.

Animals

Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self-administration.

In case of overdose, standard supportive measures should be instituted as required.

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Varenicline has been shown to be dialyzed in patients with end-stage renal disease [see Clinical Pharmacology (12.3)], however, there is no experience in dialysis following overdose.

{ "type": "p", "children": [], "text": "Varenicline has been shown to be dialyzed in patients with end-stage renal disease [see Clinical Pharmacology (12.3)], however, there is no experience in dialysis following overdose." }

CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.

{ "type": "p", "children": [], "text": "CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α4β2 nicotinic acetylcholine receptor subtypes." }

Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 ∙ C4H6O6. The chemical structure is:

{ "type": "p", "children": [], "text": "Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 ∙ C4H6O6. The chemical structure is:" }

CHANTIX is supplied for oral administration in two strengths: a 0.5 mg 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 capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1 mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.

{ "type": "p", "children": [], "text": "CHANTIX is supplied for oral administration in two strengths: a 0.5 mg 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 capsular biconvex, light blue film-coated tablet debossed with \"Pfizer\" on one side and \"CHX 1.0\" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1 mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear." }

Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3,500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

Absorption

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%.

Food Effect

Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

Distribution

Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.

Elimination

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

Metabolism

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.

Excretion

Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.

Specific Populations

There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Age: Geriatric Patients

A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 years) for 7 consecutive days was similar to that of younger subjects.

Age: Pediatric Patients

CHANTIX is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated [see Use in Specific Populations (8.4)].

Renal Impairment

Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily [see Dosage and Administration (2.2), Use in Specific Populations (8.6)]. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis [see Overdosage (10)].

Hepatic Impairment

Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.

Drug-Drug Interactions

In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.

In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin [see below]) are unlikely to be affected by varenicline.

In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may not necessitate a dose adjustment of CHANTIX as the increase in systemic exposure to CHANTIX is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHANTIX [see Clinical Pharmacology (12.3)]; therefore, a dose adjustment of CHANTIX would not be required.

Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions have been identified.

Metformin

When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.

Cimetidine

Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.

Digoxin

Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.

Warfarin

Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics [see Drug Interactions (7.2)].

Use with Other Drugs for Smoking Cessation

Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers [see Drug Interactions (7.1)].

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 adverse reactions was greater for the combination than for NRT alone [see Drug Interactions (7.1)].

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 (MRHD) 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 MRHD exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the MRHD 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 MRHD exposure based on AUC at 1 mg twice daily). Maternal toxicity, characterized by a decrease in body weight gain, was observed at 15 mg/kg/day. 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. 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 MRHD exposure based on AUC at 1 mg twice daily).

Study 1

This was a six-week dose-ranging study comparing CHANTIX to placebo. This study provided initial evidence that CHANTIX at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.

Study 2

This study of 627 patients compared CHANTIX 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one-week titration) and then were followed for 40 weeks post-treatment. CHANTIX was given in two divided doses daily. Each dose of CHANTIX was given in two different regimens, with and without initial dose-titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.

Forty-five percent of patients receiving CHANTIX 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.

Study 3

This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of CHANTIX or placebo. After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.

Of the patients treated with CHANTIX, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.

Study 4 and Study 5

These identical double-blind studies compared CHANTIX 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The CHANTIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.

In Study 4, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.

Similarly in Study 5, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 1: Continuous Abstinence, Weeks 9 through 12</span></td> </tr> <tr> <td align="center"><img alt="Figure 1" src="/dailymed/image.cfm?name=chantix-02.jpg&amp;setid=875351eb-1c25-44ad-9a37-799919216044"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 7. Continuous Abstinence, Weeks 9 through 12 (95% confidence interval)</span> </caption> <col align="left" valign="top" width="10%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>0.5 mg BID</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">CHANTIX<br/>Flexible</th><th align="center" class="Rrule">Bupropion SR</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Study 2</td><td align="center" class="Rrule">45%<br/>(39%, 51%)</td><td align="center" class="Rrule">51%<br/>(44%, 57%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">12%<br/>(6%, 18%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Study 3</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">40%<br/>(32%, 48%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">12%<br/>(7%, 17%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Study 4</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">44%<br/>(38%, 49%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">30%<br/>(25%, 35%)</td><td align="center" class="Rrule">17%<br/>(13%, 22%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Study 5</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">44%<br/>(38%, 49%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">30%<br/>(25%, 35%)</td><td align="center" class="Rrule">18%<br/>(14%, 22%)</td> </tr> </tbody> </table></div>

Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale "urge to smoke" item, CHANTIX reduced urge to smoke compared to placebo.

Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, CHANTIX-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo (Figure 2, Table 8).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 2: Continuous Abstinence, Weeks 9 through 52</span></td> </tr> <tr> <td align="center"><img alt="Figure 2" src="/dailymed/image.cfm?name=chantix-03.jpg&amp;setid=875351eb-1c25-44ad-9a37-799919216044"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 8. Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) Across Different Studies</span> </caption> <col align="left" valign="top" width="15%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>0.5 mg BID</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">CHANTIX<br/>Flexible</th><th align="center" class="Rrule">Bupropion SR</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Study 2</td><td align="center" class="Rrule">19%<br/>(14%, 24%)</td><td align="center" class="Rrule">23%<br/>(18%, 28%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">4%<br/>(1%, 8%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Study 3</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">22%<br/>(16%, 29%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">8%<br/>(3%, 12%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Study 4</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">21%<br/>(17%, 26%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">16%<br/>(12%, 20%)</td><td align="center" class="Rrule">8%<br/>(5%, 11%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Study 5</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">22%<br/>(17%, 26%)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">14%<br/>(11%, 18%)</td><td align="center" class="Rrule">10%<br/>(7%, 13%)</td> </tr> </tbody> </table></div>

Study 6

This study assessed the effect of an additional 12 weeks of CHANTIX therapy on the likelihood of long-term abstinence. Patients in this study (N=1927) were treated with open-label CHANTIX 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (N= 1210) were then randomized to double-blind treatment with CHANTIX (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.

The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with CHANTIX (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (CHANTIX 54% versus placebo 39%).

In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of CHANTIX; post-CHANTIX follow-up begins at Week 13 for the placebo group and Week 25 for the CHANTIX group. The y-axis represents the percentage of patients who had been abstinent for the last week of CHANTIX treatment and remained abstinent at the given timepoint.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 3: Continuous Abstinence Rate during Nontreatment Follow-Up</span></td> </tr> <tr> <td align="center"><img alt="Figure 3" src="/dailymed/image.cfm?name=chantix-04.jpg&amp;setid=875351eb-1c25-44ad-9a37-799919216044"/></td> </tr> </tbody> </table></div>

CHANTIX was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to CHANTIX 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment. Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).

CHANTIX was evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomized to either CHANTIX 1 mg twice daily (N=760) or placebo (N=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with CHANTIX had a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32% vs. 7%) and weeks 15 through 52 (24% vs. 6%).

CHANTIX was evaluated in a double-blind, placebo-controlled trial of patients who had made a previous attempt to quit smoking with CHANTIX, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to CHANTIX 1 mg twice daily (N=249) or placebo (N=245) for 12 weeks of treatment and followed for 40 weeks post-treatment. Patients included in this study had taken CHANTIX for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks.

Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (45%) compared to patients treated with placebo (12%) and from weeks 9 through 52 (20%) compared to subjects treated with placebo (3%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 9. Continuous Abstinence (95% confidence interval), Re-Treatment Study</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Weeks 9 through 12</th><th align="center" class="Rrule" colspan="2">Weeks 9 through 52</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">Retreatment Study</td><td align="center" class="Rrule">45%<br/>(39%, 51%)</td><td align="center" class="Rrule">12%<br/>(8%, 16%)</td><td align="center" class="Rrule">20%<br/>(15%, 25%)</td><td align="center" class="Rrule">3%<br/>(1%, 5%)</td> </tr> </tbody> </table></div>

CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 ≥ 50% of predicted normal value. Subjects were randomized to CHANTIX 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 10. Continuous Abstinence (95% confidence interval), Studies in Patients with Chronic Obstructive Pulmonary Disease (COPD)</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Weeks 9 through 12</th><th align="center" class="Rrule" colspan="2">Weeks 9 through 52</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">COPD Study</td><td align="center" class="Rrule">41%<br/>(34%, 47%)</td><td align="center" class="Rrule">9%<br/>(6%, 13%)</td><td align="center" class="Rrule">19%<br/>(14%, 24%)</td><td align="center" class="Rrule">6%<br/>(3%, 9%)</td> </tr> </tbody> </table></div>

CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to CHANTIX 1 mg twice daily (N=353) or placebo (N=350) for a treatment period of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 11. Continuous Abstinence (95% confidence interval), Studies in Patients with Cardiovascular Disease (CVD)</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Weeks 9 through 12</th><th align="center" class="Rrule" colspan="2">Weeks 9 through 52</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">CVD Study</td><td align="center" class="Rrule">47%<br/>(42%, 53%)</td><td align="center" class="Rrule">14%<br/>(11%, 18%)</td><td align="center" class="Rrule">20%<br/>(16%, 24%)</td><td align="center" class="Rrule">7%<br/>(5%, 10%)</td> </tr> </tbody> </table></div>

In this study, all-cause and CV mortality was lower in patients treated with CHANTIX, but certain nonfatal CV events occurred more frequently in patients treated with CHANTIX than in patients treated with placebo [see Warnings and Precautions (5.5), Adverse Reactions (6.1)]. Table 12 below shows mortality and the incidence of selected nonfatal serious CV events occurring more frequently in the CHANTIX arm compared to the placebo arm. These events were adjudicated by an independent blinded committee. Nonfatal serious CV events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one CV event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 12. Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-Controlled CHANTIX Trial in Patients with Stable Cardiovascular Disease</span> </caption> <col align="left" valign="top" width="46%"/> <col align="center" valign="middle" width="27%"/> <col align="center" valign="middle" width="27%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Mortality and Cardiovascular Events</th><th align="center" class="Rrule">CHANTIX<br/>(N=353)<br/>n (%)</th><th align="center" class="Rrule">Placebo<br/>(N=350)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold Italics">Mortality (Cardiovascular and All-cause up to 52 weeks)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Cardiovascular</td><td align="center" class="Rrule">1 (0.3)</td><td align="center" class="Rrule">2 (0.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  All-cause</td><td align="center" class="Rrule">2 (0.6)</td><td align="center" class="Rrule">5 (1.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold Italics">Nonfatal Cardiovascular Events (rate on CHANTIX &gt; Placebo)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Up to 30 days after treatment</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nonfatal myocardial infarction</td><td align="center" class="Rrule">4 (1.1)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nonfatal Stroke</td><td align="center" class="Rrule">2 (0.6)</td><td align="center" class="Rrule">0 (0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Beyond 30 days after treatment and up to 52 weeks</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Nonfatal myocardial infarction</td><td align="center" class="Rrule">3 (0.8)</td><td align="center" class="Rrule">2 (0.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Need for coronary revascularization</td><td align="center" class="Rrule">7 (2.0)</td><td align="center" class="Rrule">2 (0.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Hospitalization for angina pectoris</td><td align="center" class="Rrule">6 (1.7)</td><td align="center" class="Rrule">4 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Transient ischemia attack</td><td align="center" class="Rrule">1 (0.3)</td><td align="center" class="Rrule">0 (0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">    New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure</td><td align="center" class="Rrule">5 (1.4)</td><td align="center" class="Rrule">2 (0.6)</td> </tr> </tbody> </table></div>

Following the CVD study, a meta-analysis of 15 clinical trials of ≥12 weeks treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was conducted to systematically assess the CV safety of CHANTIX. The study in patients with stable CV disease described above was included in the meta-analysis. There were lower rates of all-cause mortality (CHANTIX 6 [0.14%]; placebo 7 [0.25%]) and CV mortality (CHANTIX 2 [0.05%]; placebo 2 [0.07%]) in the CHANTIX arms compared with the placebo arms in the meta-analysis.

The key CV safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as CV death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred in the trials included in the meta-analysis, as described in Table 13. These events occurred primarily in patients with known CV disease.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 13. Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15 Clinical Trials Comparing CHANTIX to Placebo<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></span> </caption> <col align="left" valign="top" width="28%"/> <col align="center" valign="top" width="34%"/> <col align="center" valign="top" width="38%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>N=4190</th><th align="center" class="Rrule">Placebo<br/>N=2812</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Includes MACE occurring up to 30 days post-treatment.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold Italics">MACE cases, n (%)</span></td><td align="center" class="Rrule">13 (0.31%)</td><td align="center" class="Rrule">6 (0.21%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Patient-years of exposure</td><td align="center" class="Rrule">1316</td><td align="center" class="Rrule">839</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold Italics">Hazard Ratio (95% CI)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule">1.95 (0.79, 4.82)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold Italics">Rate Difference per 1,000 patient-years (95% CI)</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule">6.30 (-2.40, 15.10)</td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

The meta-analysis showed that exposure to CHANTIX resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up to 30 days after treatment; this is equivalent to an estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV endpoints in patients on CHANTIX relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.

Additionally, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension, [see Warnings and Precautions (5.5), Adverse Reactions (6.1), Clinical Studies (14.10)].

CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 18 to 75 years with major depressive disorder without psychotic features (DSM-IV TR). If on medication, subjects were to be on a stable antidepressant regimen for at least two months. If not on medication, subjects were to have experienced a major depressive episode in the past 2 years, which was successfully treated. Subjects were randomized to CHANTIX 1 mg twice daily (N=256) or placebo (N=269) for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (36%) compared to subjects treated with placebo (16%) and from week 9 through 52 (20%) compared to subjects treated with placebo (10%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 14. Continuous Abstinence (95% confidence interval), Study in Patients with Major Depressive Disorder (MDD)</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Weeks 9 through 12</th><th align="center" class="Rrule" colspan="2">Weeks 9 through 52</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">MDD Study</td><td align="center" class="Rrule">36%<br/>(30%, 42%)</td><td align="center" class="Rrule">16%<br/>(11%, 20%)</td><td align="center" class="Rrule">20%<br/>(15%, 25%)</td><td align="center" class="Rrule">10%<br/>(7%, 14%)</td> </tr> </tbody> </table></div>

CHANTIX was evaluated in a randomized, double-blind, active and placebo-controlled trial that included subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3912) and with a history of psychiatric disorder (psychiatric cohort, N=4003). Subjects aged 18–75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to CHANTIX 1 mg BID, bupropion SR 150 mg BID, NRT patch 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. [See Warnings and Precautions (5.1)]

A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse events included the following NPS adverse events: anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, irritability, suicidal ideation, suicidal behavior or completed suicide.

As shown in Table 15, the use of CHANTIX, bupropion, and NRT in the non-psychiatric cohort was not associated with an increased risk of clinically significant NPS adverse events compared with placebo. Similarly, in the non-psychiatric cohort, the use of CHANTIX was not associated with an increased risk of clinically significant NPS adverse events in the composite safety endpoint compared with bupropion or NRT.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 15. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients without a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="24%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>(N=975)<br/>n (%)</th><th align="center" class="Rrule">Bupropion<br/>(N=968)<br/>n (%)</th><th align="center" class="Rrule">NRT<br/>(N=987)<br/>n (%)</th><th align="center" class="Rrule">Placebo<br/>(N=982)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Clinically Significant NPS</td><td align="center" class="Rrule">30 (3.1)</td><td align="center" class="Rrule">34 (3.5)</td><td align="center" class="Rrule">33 (3.3)</td><td align="center" class="Rrule">40 (4.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Serious NPS</td><td align="center" class="Rrule">1 (0.1)</td><td align="center" class="Rrule">5 (0.5)</td><td align="center" class="Rrule">1 (0.1)</td><td align="center" class="Rrule">4 (0.4)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Psychiatric Hospitalizations</td><td align="center" class="Rrule">1 (0.1)</td><td align="center" class="Rrule">2 (0.2)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">1 (0.1)</td> </tr> </tbody> </table></div>

As shown in Table 16, there were more clinically significant NPS adverse events reported in patients in the psychiatric cohort in each treatment group compared with the non-psychiatric cohort. 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 NRT transdermal nicotine.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 16. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients with a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="24%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>(N=1007)<br/>n (%)</th><th align="center" class="Rrule">Bupropion<br/>(N=1004)<br/>n (%)</th><th align="center" class="Rrule">NRT<br/>(N=995)<br/>n (%)</th><th align="center" class="Rrule">Placebo<br/>(N=997)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Clinically Significant NPS</td><td align="center" class="Rrule">123 (12.2)</td><td align="center" class="Rrule">118 (11.8)</td><td align="center" class="Rrule">98 (9.8)</td><td align="center" class="Rrule">95 (9.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Serious NPS</td><td align="center" class="Rrule">6 (0.6)</td><td align="center" class="Rrule">8 (0.8)</td><td align="center" class="Rrule">4 (0.4)</td><td align="center" class="Rrule">6 (0.6)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Psychiatric hospitalizations</td><td align="center" class="Rrule">5 (0.5)</td><td align="center" class="Rrule">8 (0.8)</td><td align="center" class="Rrule">4 (0.4)</td><td align="center" class="Rrule">2 (0.2)</td> </tr> </tbody> </table></div>

There was one completed suicide, which occurred during treatment in a patient treated with placebo in the non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort.

In both cohorts, subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, nicotine patch and placebo.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 17 Continuous Abstinence (95% confidence interval), Study in Patients with or without a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="21%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>1 mg BID</th><th align="center" class="Rrule">Bupropion SR<br/>150 mg BID</th><th align="center" class="Rrule">NRT<br/>21 mg/day with taper</th><th align="center" class="Rrule">Placebo</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">BID = twice daily</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Weeks 9 through 12</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Non-Psychiatric Cohort</td><td align="center" class="Rrule">38%<br/>(35%, 41%)</td><td align="center" class="Rrule">26%<br/>(23%, 29%)</td><td align="center" class="Rrule">26%<br/>(24%, 29%)</td><td align="center" class="Rrule">14%<br/>(12%, 16%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric Cohort</td><td align="center" class="Rrule">29%<br/>(26%, 32%)</td><td align="center" class="Rrule">19%<br/>(17%, 22%)</td><td align="center" class="Rrule">20%<br/>(18%, 23%)</td><td align="center" class="Rrule">11%<br/>(10%, 14%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Weeks 9 through 24</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Non-Psychiatric Cohort</td><td align="center" class="Rrule">25%<br/>(23%, 28%)</td><td align="center" class="Rrule">19%<br/>(16%, 21%)</td><td align="center" class="Rrule">18%<br/>(16%, 21%)</td><td align="center" class="Rrule">11%<br/>(9%, 13%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Psychiatric Cohort</td><td align="center" class="Rrule">18%<br/>(16%, 21%)</td><td align="center" class="Rrule">14%<br/>(12%, 16%)</td><td align="center" class="Rrule">13%<br/>(11%, 15%)</td><td align="center" class="Rrule">8%<br/>(7%, 10%)</td> </tr> </tbody> </table></div>

Cardiovascular Outcome Analysis

To obtain another source of data regarding the CV risk of CHANTIX, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension. In the parent study (N=8027), subjects aged 18–75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to CHANTIX 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy (NRT) patch 21 mg/day or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. The extension study enrolled 4590 (57.2%) of the 8027 subjects who were randomized and treated in the parent study and followed them for additional 28 weeks. Of all treated subjects, 1743 (21.7%) had a medium CV risk and 640 (8.0%) had a high CV risk, as defined by Framingham score. Note that one site from the parent study was excluded in the assessment of CV safety and two sites were excluded in the assessment of neuropsychiatric safety.

The primary CV endpoint was the time to major adverse CV event (MACE), defined as CV death, nonfatal myocardial infarction or nonfatal stroke during treatment. Deaths and CV events were adjudicated by a blinded, independent committee. Table 18 below shows the incidence of MACE and Hazard Ratios compared to placebo for all randomized subjects exposed to at least 1 partial dose of study treatment in the parent study.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 18. The Incidence of MACE and Hazard Ratios in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="24%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>N=2006</th><th align="center" class="Rrule">Bupropion<br/>N=1997</th><th align="center" class="Rrule">NRT<br/>N=2017</th><th align="center" class="Rrule">Placebo<br/>N=2007</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">[IR] indicates incidence rate per 1000 person-years</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>during treatment in the parent neuropsychiatric safety study</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>either the end of the extension study or the end of parent neuropsychiatric safety study for those subjects not enrolled into the extension study</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold Italics">During treatment<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">MACE, n [IR]</td><td align="center" class="Rrule">1 [2.4]</td><td align="center" class="Rrule">2 [4.9]</td><td align="center" class="Rrule">1 [2.4]</td><td align="center" class="Rrule">4 [9.8]</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  <span class="Italics">Hazard Ratio (95% CI) vs. placebo</span></td><td align="center" class="Rrule">0.24<br/>(0.03, 2.18)</td><td align="center" class="Rrule">0.49<br/>(0.09, 2.69)</td><td align="center" class="Rrule">0.24<br/>(0.03, 2.18)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold Italics">Through end of study<a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">MACE, n [IR]</td><td align="center" class="Rrule">3 [2.1]</td><td align="center" class="Rrule">9 [6.3]</td><td align="center" class="Rrule">6 [4.3]</td><td align="center" class="Rrule">8 [5.7]</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  <span class="Italics">Hazard Ratio (95% CI) vs. placebo</span></td><td align="center" class="Rrule">0.36<br/>(0.10, 1.36)</td><td align="center" class="Rrule">1.09<br/>(0.42, 2.83)</td><td align="center" class="Rrule">0.74<br/>(0.26, 2.13)</td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

For this study, MACE+ was defined as any MACE or a new onset or worsening peripheral vascular disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina. Incidence rates of MACE+ and all-cause mortality for all randomized subjects exposed to at least 1 partial dose of study treatment in the parent study are shown for all treatment groups during treatment, and through end of study in the Table 19 below.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 19. The Incidence of MACE+ and All-Cause Death in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder</span> </caption> <col align="left" valign="top" width="24%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">CHANTIX<br/>N=2006</th><th align="center" class="Rrule">Bupropion<br/>N=1997</th><th align="center" class="Rrule">NRT<br/>N=2017</th><th align="center" class="Rrule">Placebo<br/>N=2007</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">[IR] indicates incidence rate per 1000 person-years</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>during treatment in the parent neuropsychiatric safety study</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">†</a> </dt> <dd>either the end of the extension study or the end of the parent neuropsychiatric safety study for those subjects not enrolled into the extension study</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold Italics">During treatment<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">MACE+, n [IR]</td><td align="center" class="Rrule">5 [12.1]</td><td align="center" class="Rrule">4 [9.9]</td><td align="center" class="Rrule">2 [4.8]</td><td align="center" class="Rrule">5 [12.2]</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">All-cause deaths, n [IR]</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 [4.9]</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 [4.9]</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold Italics">Through end of study<a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">MACE+, n [IR]</td><td align="center" class="Rrule">10 [6.9]</td><td align="center" class="Rrule">15 [10.5]</td><td align="center" class="Rrule">10 [7.1]</td><td align="center" class="Rrule">12 [8.6]</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">All-cause deaths, n [IR]</td><td align="center" class="Rrule">2 [1.4]</td><td align="center" class="Rrule">4 [2.8]</td><td align="center" class="Rrule">3 [2.1]</td><td align="center" class="Rrule">4 [2.9]</td> </tr> </tbody> </table></div>

The number of subjects who experienced MACE, MACE+ and all-cause death was similar or lower among patients treated with CHANTIX than patients treated with placebo. The number of events observed overall was too low to distinguish meaningful differences between the treatment arms.

Store at 25ºC (77ºF); excursions permitted to 15–30ºC (59–86ºF) (see USP Controlled Room Temperature).

Initiate Treatment and Continue to Attempt to Quit if Lapse

Instruct patients to set a date to quit smoking and to initiate CHANTIX treatment one week before the quit date. Alternatively, the patient can begin CHANTIX dosing and then set a date to quit smoking between days 8 and 35 of treatment. Encourage patients to continue to attempt to quit if they have early lapses after quit day [see Dosage and Administration (2.1)].

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 [see Dosage and Administration (2.1)].

Encourage patients who are motivated to quit and who did not succeed in stopping smoking during prior CHANTIX therapy for reasons other than intolerability due to adverse events, or who relapsed after treatment to make another attempt with CHANTIX once factors contributing to the failed attempt have been identified and addressed [see Dosage and Administration (2.1), Clinical Studies (14.6)].

How to Take

Advise patients that CHANTIX should be taken orally after eating, and with a full glass of water [see Dosage and Administration (2.1)].

Starting Week Dosage

Instruct patients on how to titrate CHANTIX, beginning at a dose of 0.5 mg/day. 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 [see Dosage and Administration (2.1)].

Continuing Weeks Dosage

Advise patients 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 [see Dosage and Administration (2.1)].

Dosage Adjustment for CHANTIX or Other Drugs

Inform patients that nausea and insomnia are side effects of CHANTIX and are usually transient; however, advise patients that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered.

Inform patients that some drugs may require dose adjustment after quitting smoking [see Dosage and Administration (2.1)].

Counseling and Support

Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking [see Dosage and Administration (2.1)].

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 [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].

History of Psychiatric Illness

Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.

Nicotine Withdrawal

Inform patients that quitting smoking, with or without CHANTIX, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of pre-existing psychiatric illness.

Seizures

Encourage patients to report any history of seizures or other factors that can lower seizure threshold. Instruct patients to discontinue CHANTIX and contact a healthcare provider immediately if they experience a seizure while on treatment [see Warnings and Precautions (5.2)].

Interaction with Alcohol

Advise patients to reduce the amount of alcohol they consume while taking CHANTIX until they know whether CHANTIX affects their tolerance for alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].

Driving or Operating Machinery

Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them [see Warnings and Precautions (5.4)].

Cardiovascular Events

Patients should be instructed to notify their healthcare providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Somnambulism

Patients should be instructed to discontinue CHANTIX and notify their healthcare providers if they experience somnambulism [see Warnings and Precautions (5.6)].

Angioedema

Inform patients that there have been reports of angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].

Serious Skin Reactions

Inform patients that serious skin reactions, such as Stevens-Johnson Syndrome and erythema multiforme, were reported by some patients taking CHANTIX. Advise patients to stop taking CHANTIX at the first sign of rash with mucosal lesions or skin reaction and contact a healthcare provider immediately [see Warnings and Precautions (5.8), Adverse Reactions (6.2)].

Vivid, Unusual, or Strange Dreams

Inform patients that they may experience vivid, unusual or strange dreams during treatment with CHANTIX.

Pregnancy and Lactation

Patients who are pregnant or breastfeeding or planning to become pregnant should be advised of: the risks of smoking to a pregnant mother and her developing baby, the potential risks of CHANTIX use during pregnancy and breastfeeding, and the benefits of smoking cessation with and without CHANTIX. Advise breastfeeding women to monitor the infant for seizures and vomiting [see Use in Specific Populations (8.1 and 8.2)].

This product's label may have been updated. For full prescribing information, please visit www.pfizer.com.

{ "type": "p", "children": [], "text": "This product's label may have been updated. For full prescribing information, please visit www.pfizer.com." }

LAB- 0327-24.0

{ "type": "p", "children": [], "text": "LAB- 0327-24.0" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="24%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="24%"/> <col align="left" valign="top" width="12%"/> <col align="left" valign="top" width="28%"/> <col align="left" valign="top" width="2%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="5">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="2">Revised Feb 2019    </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">MEDICATION GUIDE<br/>CHANTIX<span class="Sup">®</span> (CHANT-iks)<br/>(varenicline) <br/>Tablets</span> </p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What is the most important information I should know about CHANTIX?</span> </p> <p>When you try to quit smoking, with or without CHANTIX, you may have symptoms that may be due to nicotine withdrawal, including:</p> </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>urge to smoke</li> <li>depressed mood</li> <li>trouble sleeping</li> <li>irritability</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>frustration</li> <li>anger</li> <li>feeling anxious</li> <li>difficulty concentrating</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>restlessness</li> <li>decreased heart rate</li> <li>increased appetite</li> <li>weight gain</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First">Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.</p> <p>Some people have had serious side effects while taking CHANTIX to help them quit smoking, including:</p> <p> <span class="Bold">New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depressed mood, or suicidal thoughts or actions</span>. 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.</p> <p> <span class="Bold">Stop taking CHANTIX and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms.</span> 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.</p> <p> <span class="Bold">Before taking CHANTIX,</span> 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.</p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What is CHANTIX?</span> </p> <p>CHANTIX is a prescription medicine to help people stop smoking.</p> <p>Quitting smoking can lower your chances of having lung disease, heart disease or getting certain types of cancer that are related to smoking.</p> <p>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.</p> <p>It is not known if CHANTIX is safe and effective when used with other stop smoking medicines.</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">Who should not take CHANTIX?</span> </p> <p>Do not take CHANTIX if you have had a serious allergic or skin reaction to CHANTIX. Symptoms may include:</p> <ul class="Disc"> <li>swelling of the face, mouth (tongue, lips, gums), throat or neck</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>trouble breathing</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>rash, with peeling skin</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>blisters in your mouth</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before taking CHANTIX?</span> </p> <p> <span class="Bold">See "<a href="#importantinfo">What is the most important information I should know about CHANTIX?</a>"</span> </p> <p> <span class="Bold">Before you take CHANTIX, tell your healthcare provider if you:</span> </p> <ul class="Disc"> <li>use other treatments to quit smoking. Using CHANTIX with a nicotine patch may cause nausea, vomiting, headache, dizziness, upset stomach, and tiredness to happen more often than if you just use a nicotine patch alone.</li> <li>have kidney problems or get kidney dialysis. Your healthcare provider may prescribe a lower dose of CHANTIX for you.</li> <li>have a history of seizures</li> <li>drink alcohol</li> <li>have heart or blood vessel problems</li> <li>have any other medical conditions</li> <li>are pregnant or plan to become pregnant.</li> <li>are breastfeeding. It is not known if CHANTIX passes into breast milk. If you breastfeed and take CHANTIX, monitor your baby for seizures as well as spitting up or vomiting more than normal.</li> </ul> <p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Your healthcare provider may need to change the dose of some of your medicines when you stop smoking.</p> <p>You should not use CHANTIX while using other medicines to quit smoking. Tell your healthcare provider if you use other treatments to quit smoking.</p> <p>Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">How should I take CHANTIX?</span> </p> <ul class="Disc"> <li>There are 3 ways that you can use CHANTIX to help you quit smoking. Talk to your healthcare provider about the following 3 ways to use CHANTIX:<ul class="Circle"> <li>Choose a <span class="Bold">quit date</span> when you will stop smoking. Start taking CHANTIX 1 week (7 days) before your <span class="Bold">quit date</span>. Take CHANTIX for 12 weeks.<br/> <span class="Bold">OR</span> </li> <li>Start taking CHANTIX before you choose a <span class="Bold">quit date.</span> Pick a date to quit smoking that is between days 8 and 35 of treatment. Take CHANTIX for 12 weeks.<br/> <span class="Bold">OR</span> </li> <li>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:</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule"> <p class="First">Weeks 1 through 4</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="4"> <p class="First">Reduce your smoking to reach one-half of your starting daily number of cigarettes.</p> <p>Example: If you usually smoke 20 cigarettes each day, reduce your smoking to 10 cigarettes each day during weeks 1 through 4.</p> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule"> <p class="First">Weeks 5 through 8</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="4"> <p class="First">Reduce your smoking to reach one-quarter of your starting daily number of cigarettes.</p> <p>Example: If you usually smoked 20 cigarettes each day, reduce your smoking to 5 cigarettes each day during weeks 5 through 8.</p> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule"> <p class="First">Weeks 9 through 12</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="4"> <p class="First">Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day).</p> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="6"> <dl> <dt> </dt> <dd>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.</dd> </dl>Starting CHANTIX before your <span class="Bold">quit date</span> gives CHANTIX time to build up in your body. You can keep smoking during this time. Take CHANTIX exactly as prescribed by your healthcare provider.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li>CHANTIX comes as a white tablet (0.5 mg) and a blue tablet (1 mg). You start with the white tablet and then usually go to the blue tablet. See the chart below for dosing instructions for adults.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule" colspan="2"> <p class="First">Day 1 to Day 3</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="3"> <ul class="Circle"> <li> <span class="Underline">White </span>tablet (0.5 mg)</li> <li>Take 1 tablet each day</li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule" colspan="2"> <p class="First">Day 4 to Day 7</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="3"> <ul class="Circle"> <li> <span class="Underline">White</span> tablet (0.5 mg)</li> <li>Take 1 in the morning and 1 in the evening</li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="left" class="Botrule Rrule Toprule" colspan="2"> <p class="First">Day 8 to end of treatment</p> </td><td align="left" class="Botrule Rrule Toprule" colspan="3"> <ul class="Circle"> <li> <span class="Underline">Blue</span> tablet (1 mg)</li> <li>Take 1 in the morning and 1 in the evening</li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li>Make sure that you try to stop smoking on your quit date. If you slip-up and smoke, try again. Some people need to take CHANTIX for a few weeks for CHANTIX to work best.</li> <li>Most people will take CHANTIX for up to 12 weeks. If you have completely quit smoking by 12 weeks, your healthcare provider may prescribe CHANTIX for another 12 weeks to help you stay cigarette-free.</li> <li>Take CHANTIX after eating and with a full glass (8 ounces) of water.</li> <li>This dosing schedule may not be right for everyone. Talk to your healthcare provider if you are having side effects such as nausea, strange dreams, or sleep problems. Your healthcare provider may want to reduce your dose.</li> <li>If you miss a dose of CHANTIX, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take your next dose at your regular time.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What should I avoid while taking CHANTIX?</span> </p> <ul class="Disc"> <li>Use caution when driving or operating machinery until you know how CHANTIX affects you. CHANTIX may make you feel sleepy, dizzy, or have trouble concentrating, making it hard to drive or perform other activities safely.</li> <li>Decrease the amount of alcoholic beverages that you drink during treatment with CHANTIX until you know if CHANTIX affects your ability to tolerate alcohol. Some people have experienced the following when drinking alcohol during treatment with CHANTIX:</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Circle"> <li>increased drunkenness (intoxication)</li> </ul> </td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li>unusual or sometimes aggressive behavior</li> <li>no memory of things that have happened</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What are the possible side effects of CHANTIX?</span> </p> <p> <span class="Bold">Serious side effects of CHANTIX may include:</span> </p> <ul class="Disc"> <li> <span class="Bold">See "<a href="#importantinfo">What is the most important information I should know about CHANTIX?</a>"</span> </li> <li> <span class="Bold">Seizures</span>. Some people have had seizures during treatment with CHANTIX. In most cases, the seizures have happened during the first month of treatment with CHANTIX. If you have a seizure during treatment with CHANTIX, stop taking CHANTIX and contact your healthcare provider right away.</li> <li> <span class="Bold">New or worse heart or blood vessel (cardiovascular) problems</span>, mostly in people, who already have cardiovascular problems. Tell your healthcare provider if you have any changes in symptoms during treatment with CHANTIX.<br/> <span class="Bold">Get emergency medical help right away if you have any of the following symptoms of a heart attack, including:</span> <ul class="Circle"> <li>chest discomfort (uncomfortable pressure, squeezing, fullness or pain) that lasts more than a few minutes, or that goes away and comes back</li> <li>pain or discomfort in one or both arms, back, neck, jaw or stomach</li> <li>shortness of breath, sweating, nausea, vomiting, or feeling lightheaded associated with chest discomfort</li> </ul> </li> <li> <span class="Bold">Sleepwalking</span> 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 healthcare provider if you start sleepwalking.</li> <li> <span class="Bold">Allergic reactions</span> can happen with CHANTIX. Some of these allergic reactions can be life-threatening.</li> <li> <span class="Bold">Serious skin reactions</span>, including rash, swelling, redness, and peeling of the skin. Some of these skin reactions can become life-threatening.</li> </ul> <p> <span class="Bold">Stop taking CHANTIX and get medical help right away if you have any of the following symptoms:</span> </p> <ul class="Circle"> <li>swelling of the face, mouth (tongue, lips, and gums), throat or neck</li> <li>trouble breathing</li> <li>rash with peeling skin</li> <li>blisters in your mouth</li> </ul> <p>The most common side effects of CHANTIX include:</p> <ul class="Disc"> <li>nausea</li> <li>sleep problems (trouble sleeping or vivid, unusual, or strange dreams)</li> <li>constipation</li> <li>gas</li> <li>vomiting</li> </ul> <p>Tell your healthcare provider about side effects that bother you or that do not go away.</p> <p>These are not all the side effects of CHANTIX. Ask your healthcare provider or pharmacist for more information.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">How should I store CHANTIX?</span> </p> <ul class="Disc"> <li>Store CHANTIX at room temperature, between 68°F to 77°F (20°C to 25°C).</li> <li> <span class="Bold">Keep CHANTIX and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">General information about the safe and effective use of CHANTIX</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CHANTIX for a condition for which it was not prescribed. Do not give your CHANTIX to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CHANTIX that is written for healthcare professionals.</p> <p>For more information about CHANTIX and tips on how to quit smoking, go to <span class="Underline">www.CHANTIX.com</span> or call 1-877-242-6849.</p> <p>If you are motivated to quit smoking and did not succeed during prior CHANTIX treatment for reasons other than side effects, or if you returned to smoking after treatment, speak with your healthcare provider about whether another course of CHANTIX therapy may be right for you.</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <p class="First"> <span class="Bold">What are the ingredients in CHANTIX?</span> </p> <p> <span class="Bold">Active ingredient:</span> varenicline tartrate</p> <p> <span class="Bold">Inactive ingredients:</span> microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry<span class="Sup">®</span> White (for 0.5 mg), Opadry<span class="Sup">®</span> Blue (for 1 mg), and Opadry<span class="Sup">®</span> Clear.</p> <p> <img alt="Logo" src="/dailymed/image.cfm?name=chantix-06.jpg&amp;setid=875351eb-1c25-44ad-9a37-799919216044"/></p> <p>LAB-0328-17.0</p> </td> </tr> <tr class="Last"> <td align="left" class="Lrule"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left" class="Rrule"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"24%\"/>\n<col align=\"left\" valign=\"top\" width=\"8%\"/>\n<col align=\"left\" valign=\"top\" width=\"24%\"/>\n<col align=\"left\" valign=\"top\" width=\"12%\"/>\n<col align=\"left\" valign=\"top\" width=\"28%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"5\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"2\">Revised Feb 2019    </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE<br/>CHANTIX<span class=\"Sup\">®</span> (CHANT-iks)<br/>(varenicline) <br/>Tablets</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about CHANTIX?</span>\n</p>\n<p>When you try to quit smoking, with or without CHANTIX, you may have symptoms that may be due to nicotine withdrawal, including:</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>urge to smoke</li>\n<li>depressed mood</li>\n<li>trouble sleeping</li>\n<li>irritability</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>frustration</li>\n<li>anger</li>\n<li>feeling anxious</li>\n<li>difficulty concentrating</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>restlessness</li>\n<li>decreased heart rate</li>\n<li>increased appetite</li>\n<li>weight gain</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.</p>\n<p>Some people have had serious side effects while taking CHANTIX to help them quit smoking, including:</p>\n<p>\n<span class=\"Bold\">New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depressed mood, or suicidal thoughts or actions</span>. 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.</p>\n<p>\n<span class=\"Bold\">Stop taking CHANTIX and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms.</span> 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.</p>\n<p>\n<span class=\"Bold\">Before taking CHANTIX,</span> 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.</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What is CHANTIX?</span>\n</p>\n<p>CHANTIX is a prescription medicine to help people stop smoking.</p>\n<p>Quitting smoking can lower your chances of having lung disease, heart disease or getting certain types of cancer that are related to smoking.</p>\n<p>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.</p>\n<p>It is not known if CHANTIX is safe and effective when used with other stop smoking medicines.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take CHANTIX?</span>\n</p>\n<p>Do not take CHANTIX if you have had a serious allergic or skin reaction to CHANTIX. Symptoms may include:</p>\n<ul class=\"Disc\">\n<li>swelling of the face, mouth (tongue, lips, gums), throat or neck</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>trouble breathing</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>rash, with peeling skin</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>blisters in your mouth</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before taking CHANTIX?</span>\n</p>\n<p>\n<span class=\"Bold\">See \"<a href=\"#importantinfo\">What is the most important information I should know about CHANTIX?</a>\"</span>\n</p>\n<p>\n<span class=\"Bold\">Before you take CHANTIX, tell your healthcare provider if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>use other treatments to quit smoking. Using CHANTIX with a nicotine patch may cause nausea, vomiting, headache, dizziness, upset stomach, and tiredness to happen more often than if you just use a nicotine patch alone.</li>\n<li>have kidney problems or get kidney dialysis. Your healthcare provider may prescribe a lower dose of CHANTIX for you.</li>\n<li>have a history of seizures</li>\n<li>drink alcohol</li>\n<li>have heart or blood vessel problems</li>\n<li>have any other medical conditions</li>\n<li>are pregnant or plan to become pregnant.</li>\n<li>are breastfeeding. It is not known if CHANTIX passes into breast milk. If you breastfeed and take CHANTIX, monitor your baby for seizures as well as spitting up or vomiting more than normal.</li>\n</ul>\n<p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Your healthcare provider may need to change the dose of some of your medicines when you stop smoking.</p>\n<p>You should not use CHANTIX while using other medicines to quit smoking. Tell your healthcare provider if you use other treatments to quit smoking.</p>\n<p>Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take CHANTIX?</span>\n</p>\n<ul class=\"Disc\">\n<li>There are 3 ways that you can use CHANTIX to help you quit smoking. Talk to your healthcare provider about the following 3 ways to use CHANTIX:<ul class=\"Circle\">\n<li>Choose a <span class=\"Bold\">quit date</span> when you will stop smoking. Start taking CHANTIX 1 week (7 days) before your <span class=\"Bold\">quit date</span>. Take CHANTIX for 12 weeks.<br/>\n<span class=\"Bold\">OR</span>\n</li>\n<li>Start taking CHANTIX before you choose a <span class=\"Bold\">quit date.</span> Pick a date to quit smoking that is between days 8 and 35 of treatment. Take CHANTIX for 12 weeks.<br/>\n<span class=\"Bold\">OR</span>\n</li>\n<li>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:</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\">\n<p class=\"First\">Weeks 1 through 4</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">Reduce your smoking to reach one-half of your starting daily number of cigarettes.</p>\n<p>Example: If you usually smoke 20 cigarettes each day, reduce your smoking to 10 cigarettes each day during weeks 1 through 4.</p>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\">\n<p class=\"First\">Weeks 5 through 8</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">Reduce your smoking to reach one-quarter of your starting daily number of cigarettes.</p>\n<p>Example: If you usually smoked 20 cigarettes each day, reduce your smoking to 5 cigarettes each day during weeks 5 through 8.</p>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\">\n<p class=\"First\">Weeks 9 through 12</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"4\">\n<p class=\"First\">Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day).</p>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"6\">\n<dl>\n<dt> </dt>\n<dd>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.</dd>\n</dl>Starting CHANTIX before your <span class=\"Bold\">quit date</span> gives CHANTIX time to build up in your body. You can keep smoking during this time. Take CHANTIX exactly as prescribed by your healthcare provider.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>CHANTIX comes as a white tablet (0.5 mg) and a blue tablet (1 mg). You start with the white tablet and then usually go to the blue tablet. See the chart below for dosing instructions for adults.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">Day 1 to Day 3</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"3\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Underline\">White </span>tablet (0.5 mg)</li>\n<li>Take 1 tablet each day</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">Day 4 to Day 7</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"3\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Underline\">White</span> tablet (0.5 mg)</li>\n<li>Take 1 in the morning and 1 in the evening</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">Day 8 to end of treatment</p>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" colspan=\"3\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Underline\">Blue</span> tablet (1 mg)</li>\n<li>Take 1 in the morning and 1 in the evening</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>Make sure that you try to stop smoking on your quit date. If you slip-up and smoke, try again. Some people need to take CHANTIX for a few weeks for CHANTIX to work best.</li>\n<li>Most people will take CHANTIX for up to 12 weeks. If you have completely quit smoking by 12 weeks, your healthcare provider may prescribe CHANTIX for another 12 weeks to help you stay cigarette-free.</li>\n<li>Take CHANTIX after eating and with a full glass (8 ounces) of water.</li>\n<li>This dosing schedule may not be right for everyone. Talk to your healthcare provider if you are having side effects such as nausea, strange dreams, or sleep problems. Your healthcare provider may want to reduce your dose.</li>\n<li>If you miss a dose of CHANTIX, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take your next dose at your regular time.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking CHANTIX?</span>\n</p>\n<ul class=\"Disc\">\n<li>Use caution when driving or operating machinery until you know how CHANTIX affects you. CHANTIX may make you feel sleepy, dizzy, or have trouble concentrating, making it hard to drive or perform other activities safely.</li>\n<li>Decrease the amount of alcoholic beverages that you drink during treatment with CHANTIX until you know if CHANTIX affects your ability to tolerate alcohol. Some people have experienced the following when drinking alcohol during treatment with CHANTIX:</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>increased drunkenness (intoxication)</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>unusual or sometimes aggressive behavior</li>\n<li>no memory of things that have happened</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of CHANTIX?</span>\n</p>\n<p>\n<span class=\"Bold\">Serious side effects of CHANTIX may include:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">See \"<a href=\"#importantinfo\">What is the most important information I should know about CHANTIX?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Seizures</span>. Some people have had seizures during treatment with CHANTIX. In most cases, the seizures have happened during the first month of treatment with CHANTIX. If you have a seizure during treatment with CHANTIX, stop taking CHANTIX and contact your healthcare provider right away.</li>\n<li>\n<span class=\"Bold\">New or worse heart or blood vessel (cardiovascular) problems</span>, mostly in people, who already have cardiovascular problems. Tell your healthcare provider if you have any changes in symptoms during treatment with CHANTIX.<br/>\n<span class=\"Bold\">Get emergency medical help right away if you have any of the following symptoms of a heart attack, including:</span>\n<ul class=\"Circle\">\n<li>chest discomfort (uncomfortable pressure, squeezing, fullness or pain) that lasts more than a few minutes, or that goes away and comes back</li>\n<li>pain or discomfort in one or both arms, back, neck, jaw or stomach</li>\n<li>shortness of breath, sweating, nausea, vomiting, or feeling lightheaded associated with chest discomfort</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Sleepwalking</span> 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 healthcare provider if you start sleepwalking.</li>\n<li>\n<span class=\"Bold\">Allergic reactions</span> can happen with CHANTIX. Some of these allergic reactions can be life-threatening.</li>\n<li>\n<span class=\"Bold\">Serious skin reactions</span>, including rash, swelling, redness, and peeling of the skin. Some of these skin reactions can become life-threatening.</li>\n</ul>\n<p>\n<span class=\"Bold\">Stop taking CHANTIX and get medical help right away if you have any of the following symptoms:</span>\n</p>\n<ul class=\"Circle\">\n<li>swelling of the face, mouth (tongue, lips, and gums), throat or neck</li>\n<li>trouble breathing</li>\n<li>rash with peeling skin</li>\n<li>blisters in your mouth</li>\n</ul>\n<p>The most common side effects of CHANTIX include:</p>\n<ul class=\"Disc\">\n<li>nausea</li>\n<li>sleep problems (trouble sleeping or vivid, unusual, or strange dreams)</li>\n<li>constipation</li>\n<li>gas</li>\n<li>vomiting</li>\n</ul>\n<p>Tell your healthcare provider about side effects that bother you or that do not go away.</p>\n<p>These are not all the side effects of CHANTIX. Ask your healthcare provider or pharmacist for more information.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store CHANTIX?</span>\n</p>\n<ul class=\"Disc\">\n<li>Store CHANTIX at room temperature, between 68°F to 77°F (20°C to 25°C).</li>\n<li>\n<span class=\"Bold\">Keep CHANTIX and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of CHANTIX</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CHANTIX for a condition for which it was not prescribed. Do not give your CHANTIX to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CHANTIX that is written for healthcare professionals.</p>\n<p>For more information about CHANTIX and tips on how to quit smoking, go to <span class=\"Underline\">www.CHANTIX.com</span> or call 1-877-242-6849.</p>\n<p>If you are motivated to quit smoking and did not succeed during prior CHANTIX treatment for reasons other than side effects, or if you returned to smoking after treatment, speak with your healthcare provider about whether another course of CHANTIX therapy may be right for you.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in CHANTIX?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> varenicline tartrate</p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry<span class=\"Sup\">®</span> White (for 0.5 mg), Opadry<span class=\"Sup\">®</span> Blue (for 1 mg), and Opadry<span class=\"Sup\">®</span> Clear.</p>\n<p>\n<img alt=\"Logo\" src=\"/dailymed/image.cfm?name=chantix-06.jpg&amp;setid=875351eb-1c25-44ad-9a37-799919216044\"/></p>\n<p>LAB-0328-17.0</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n</tbody>\n</table></div>" }

Varenicline tablets are indicated for use as an aid to smoking cessation treatment.

{ "type": "p", "children": [], "text": "\nVarenicline tablets are indicated for use as an aid to smoking cessation treatment." }

Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.

The patient should set a date to stop smoking. Begin varenicline tablets dosing one week before this date. Alternatively, the patient can begin varenicline tablets dosing and then quit smoking between days 8 and 35 of treatment.

Varenicline tablets should be taken orally after eating and with a full glass of water.

The recommended dose of varenicline tablets is 1 mg twice daily following a 1-week titration as follows:

<div class="scrollingtable"><table class="Noautorules" width="398"> <col width="199"/> <col width="199"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> Days 1 to 3:<br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> 0.5 mg once daily<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Days 4 to 7:<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 0.5 mg twice daily<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Day 8 to end of treatment:<br/> </td><td align="left" class="Botrule Rrule" valign="top"> 1 mg twice daily<br/> </td> </tr> </tbody> </table></div>

Patients should be treated with varenicline tablets for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline tablets is recommended to further increase the likelihood of long-term abstinence.

For patients who are sure that they are not able or willing to quit abruptly, consider a gradual approach to quitting smoking with varenicline tablets. Patients should begin varenicline tablets dosing and reduce smoking by 50% from baseline within the first four weeks, by an additional 50% in the next four weeks, and continue reducing with the goal of reaching complete abstinence by 12 weeks. Continue varenicline tablets treatment for an additional 12 weeks, for a total of 24 weeks of treatment. Encourage patients to attempt quitting sooner if they feel ready [see Clinical Studies (14.5)].

Patients who are motivated to quit, and who did not succeed in stopping smoking during prior varenicline tablets therapy for reasons other than intolerability due to adverse events or who relapsed after treatment, should be encouraged to make another attempt with varenicline tablets once factors contributing to the failed attempt have been identified and addressed.

Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of varenicline tablets.

Patients with Impaired Renal Function

No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance less than 30 mL per min), the recommended starting dose of varenicline tablets is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Elderly and Patients with Impaired Hepatic Function

No dosage adjustment is necessary for patients with hepatic impairment. 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 [see Use in Specific Populations (8.5)].

Varenicline Tablets: 0.5 mg (white to off white, round, biconvex-coated tablets, debossed with "T" on one side and "2" on the other side) and 1 mg (yellow, round, biconvex-coated tablets, debossed with "T" on one side and "1" on the other side).

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Varenicline tablets are contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to varenicline tablets.

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Serious neuropsychiatric adverse events have been reported in patients being treated with varenicline tablets [see Adverse Reactions (6.2)]. 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 varenicline tablets 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 neuropsychiatric adverse events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)]. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking varenicline tablets 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 varenicline tablets were reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The neuropsychiatric safety of varenicline tablets 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, varenicline tablets were not associated with an 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 varenicline tablets, 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 varenicline tablets -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 varenicline tablets -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 [see Clinical Studies (14.10)].

During clinical trials and the postmarketing experience, there have been reports of seizures in patients treated with varenicline tablets. Some patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy. Weigh this potential risk against the potential benefits before prescribing varenicline tablets in patients with a history of seizures or other factors that can lower the seizure threshold. Advise patients to discontinue varenicline tablets and contact a healthcare provider immediately if they experience a seizure while on treatment [see Adverse Reactions (6.2)].

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking varenicline tablets until they know whether varenicline tablets affect their tolerance for alcohol [see Adverse Reactions (6.2)].

There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking varenicline tablets. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how varenicline tablets may affect them.

A comprehensive evaluation of cardiovascular (CV) risk with varenicline tablets 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 varenicline tablets 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 varenicline tablets compared to placebo. All-cause and CV mortality was lower in patients treated with varenicline tablets [see Clinical Studies (14.8)]. This study was included in a meta-analysis of 15 varenicline tablets 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 varenicline tablets. 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 [see Clinical Studies (14.10)].

Cases of somnambulism have been reported in patients taking varenicline tablets. Some cases described harmful behavior to self, others, or property. Instruct patients to discontinue varenicline tablets and notify their healthcare provider if they experience somnambulism [see Adverse Reactions (6.2)].

There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline tablets [see Adverse Reactions (6.2), Patient Counseling Information (17)]. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue varenicline tablets and immediately seek medical care if they experience these symptoms.

There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using varenicline tablets [see Adverse Reactions (6.2)]. As these skin reactions can be life-threatening, instruct patients to stop taking varenicline tablets and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.

Nausea was the most common adverse reaction reported with varenicline tablets treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking varenicline tablets 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with varenicline tablets 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.

Because clinical trials are conducted under widely varying conditions, the adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the premarketing development of varenicline tablets, over 4500 subjects were exposed to varenicline tablets, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less.

The most common adverse event associated with varenicline tablets treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen [see Warnings and Precautions (5.9)].

Table 1 shows the adverse events for varenicline tablets and placebo in the 12- week fixed dose premarketing studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).

MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the varenicline tablets 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥ 1% of varenicline tablets patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once.

<div class="scrollingtable"><table class="Noautorules" width="623"> <caption> <span> Table 1: Common Treatment Emergent AEs (%) in the Fixed-Dose, Placebo-Controlled Studies (HLGTs &gt;5% of Patients in the 1 mg BID Varenicline Tablets Group and More Commonly than Placebo and PT ≥ 1% in the 1 mg BID Varenicline Tablets Group, and 1 mg BID Varenicline Tablets at Least 0.5% More than Placebo)</span> </caption> <col width="245"/> <col width="132"/> <col width="127"/> <col width="119"/> <tfoot> <tr> <td align="left" colspan="4"> <p class="First Footnote">* Includes PTs Abdominal (pain, pain upper, pain lower, discomfort, tenderness, distension) and Stomach discomfort</p> </td> </tr> <tr> <td align="left" colspan="4"> <p class="First Footnote">** Includes PTs Insomnia/Initial insomnia/Middle insomnia/Early morning awakening</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> SYSTEM ORGAN CLASS</span> <br/> <span class="Bold"> High Level Group Term</span> <br/> <span class="Bold"> Preferred Term</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 0.5 mg BID</span> <br/> <span class="Bold"> N=129</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> 1 mg BID</span> <br/> <span class="Bold"> N=821</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> <br/> <span class="Bold"> N=805</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> GASTROINTESTINAL (GI)<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> GI Signs and Symptoms<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 16<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 30<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abdominal Pain *<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Flatulence<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dyspepsia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> GI Motility/Defecation<br/> Conditions<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Constipation<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Gastroesophageal reflux<br/> disease<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Salivary Gland Conditions<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dry mouth<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> PSYCHIATRIC DISORDERS<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Sleep<br/> Disorder/Disturbances<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia **<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 19<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 18<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abnormal dreams<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Sleep disorder<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nightmare<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> NERVOUS SYSTEM<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headaches<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 19<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 15<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Neurological Disorders<br/> NEC<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dysgeusia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Lethargy<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> GENERAL DISORDERS<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> General Disorders NEC<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Fatigue/Malaise/Asthenia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> RESPIR/THORACIC/MEDIAST<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Respiratory Disorders NEC<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rhinorrhea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dyspnea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Upper Respiratory Tract<br/> Disorder<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> SKIN/SUBCUTANEOUS TISSUE<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Epidermal and Dermal<br/> Conditions<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rash<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Pruritis<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> METABOLISM &amp; NUTRITION<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Appetite/General Nutrition<br/> Disorders<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Increased appetite<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Decreased appetite/<br/> Anorexia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1<br/> </td> </tr> </tbody> </table></div>

The overall pattern and frequency of adverse events during the longer-term premarketing trials was similar to those described in Table 1, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with varenicline tablets 1 mg twice daily in a one year study, compared to 8% of placebo-treated patients).

Following is a list of treatment-emergent adverse events reported by patients treated with varenicline tablets during all premarketing clinical trials and updated based on pooled data from 18 placebo-controlled pre- and postmarketing studies, including approximately 5,000 patients treated with varenicline. Adverse events were categorized using MedDRA, Version 16.0. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.

Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.

Cardiac Disorders. Infrequent: angina pectoris, myocardial infarction, palpitations, tachycardia. Rare: acute coronary syndrome, arrhythmia, atrial fibrillation, bradycardia, cardiac flutter, cor pulmonale, coronary artery disease, ventricular extrasystoles.

Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.

Endocrine Disorders. Infrequent: thyroid gland disorders.

Eye Disorders. Infrequent: conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment. Rare: blindness transient, cataract subcapsular, dry eye, night blindness, ocular vascular disorder, photophobia, vitreous floaters.

Gastrointestinal Disorders. Frequent: diarrhea, toothache. Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute.

General Disorders and Administration Site Conditions. Frequent: chest pain. Infrequent: chest discomfort, chills, edema, influenza-like illness, pyrexia.

Hepatobiliary Disorders. Rare: gall bladder disorder.

Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal. Rare: muscle enzyme increased, urine analysis abnormal.

Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hypoglycemia. Rare: hyperlipidemia, hypokalemia.

Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, myalgia. Infrequent: arthritis, muscle cramp, musculoskeletal pain. Rare: myositis, osteoporosis.

Nervous System Disorders. Frequent: disturbance in attention, dizziness. Infrequent: amnesia, convulsion, migraine, parosmia, syncope, tremor. Rare: balance disorder, cerebrovascular accident, dysarthria, mental impairment, multiple sclerosis, VIIth nerve paralysis, nystagmus, psychomotor hyperactivity, psychomotor skills impaired, restless legs syndrome, sensory disturbance, transient ischemic attack, visual field defect.

Psychiatric Disorders. Infrequent: dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, disorientation, euphoric mood.

Renal and Urinary Disorders. Infrequent: nocturia, pollakiuria, urine abnormality. Rare: nephrolithiasis, polyuria, renal failure acute, urethral syndrome, urinary retention.

Reproductive System and Breast Disorders. Frequent: menstrual disorder. Infrequent: erectile dysfunction. Rare: sexual dysfunction.

Respiratory, Thoracic and Mediastinal Disorders. Frequent: respiratory disorders. Infrequent: asthma, epistaxis, rhinitis allergic, upper respiratory tract inflammation. Rare: pleurisy, pulmonary embolism.

Skin and Subcutaneous Tissue Disorders. Infrequent: acne, dry skin, eczema, erythema, hyperhidrosis, urticaria. Rare: photosensitivity reaction, psoriasis.

Vascular Disorders. Infrequent: hot flush. Rare: thrombosis.

Varenicline tablets have 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 varenicline tablets 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, (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 or willing to quit abruptly and who were instructed to quit gradually ("gradual approach to quitting smoking trial").

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 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%).

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.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 2: Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency &gt;1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease </span> </caption> <col width="378"/> <col width="162"/> <col width="84"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">*some procedures were part of management of nonfatal MI and hospitalization for angina</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> <span class="Bold"> N=353</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=350</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adverse Events ≥1% in either treatment group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">       Up to 30 days after treatment</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Angina pectoris<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3.7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.0<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Chest pain<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Peripheral edema<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hypertension<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Palpitations<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.6<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adjudicated Cardiovascular Mortality (up to 52 weeks)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in either treatment group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">       Up to 30 days after treatment</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nonfatal MI<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.1<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hospitalization for angina pectoris<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.6<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">       Beyond 30 days after treatment and up to 52 weeks</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Need for coronary revascularization*<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hospitalization for angina pectoris<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> New diagnosis of peripheral vascular disease (PVD)<br/> or admission for a PVD procedure<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.6<br/> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="590"> <caption> <span> Table 3: Common Treatment Emergent AEs (%) in the Trial of Patients with Stable Schizophrenia or Schizoaffective Disorder </span> </caption> <col width="316"/> <col width="149"/> <col width="125"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> <span class="Bold"> N=84</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=43</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adverse Events ≥10% in the varenicline group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 24<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 14<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 19<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Psychiatric Adverse Events ≥5% and at a higher rate than in the placebo group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> </tbody> </table></div>

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%).

<div class="scrollingtable"><table class="Noautorules" width="590"> <caption> <span> Table 4: Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder </span> </caption> <col width="316"/> <col width="149"/> <col width="125"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> <span class="Bold"> N=256</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=269</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adverse Events ≥10% in either treatment group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 27<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 17<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abnormal dreams<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Psychiatric Adverse Events ≥2% in any treatment group and not included above</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Depressed mood disorders and disturbances<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anxiety<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Agitation<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Tension<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Hostility<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Restlessness<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 5: Treatment Emergent Common AEs (%) in the Trial of Patients without or with a History of Psychiatric Disorder </span> </caption> <col width="354"/> <col width="144"/> <col width="126"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Adverse Events ≥10% in the varenicline group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">       Entire study population, </span> N<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1982<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1979<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 25<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Psychiatric Adverse Events ≥2% in any treatment group</span> <br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">       Non-psychiatric cohort, N</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 975<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 982<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abnormal dreams<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Agitation<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anxiety<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Depressed mood<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Sleep disorder<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">       Psychiatric cohort, N</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1007<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 997<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abnormal dreams<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Agitation<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anxiety<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Depressed mood<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Depression<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nervousness<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Sleep disorder<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2<br/> </td> </tr> </tbody> </table></div>

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.

The following adverse events have been reported during post-approval use of varenicline tablets. 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 tablets [see Warnings and Precautions (5.1)].

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

There have been postmarketing reports of patients experiencing increased intoxicating effects of alcohol while taking varenicline tablets. 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 tablets [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 tablets. 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 tablets.

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

Safety and efficacy of varenicline tablets 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.

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

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 US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 tablets 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.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 6: Summary of Primary and Secondary Outcomes for Three Birth Cohorts </span> </caption> <col width="156"/> <col width="156"/> <col width="156"/> <col width="156"/> <tfoot> <tr> <td align="left" colspan="4"> <p class="First Footnote">*Included only live births in the cohorts. Prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]).</p> </td> </tr> <tr> <td align="left" colspan="4"> <p class="First Footnote">**There was a lag in death data in Denmark, so the cohorts were smaller.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Outcome</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Cohort</span> <br/> <span class="Bold"> (n=335)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Smoking Cohort</span> <br/> <span class="Bold"> (n=78,412)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Non-Smoking Cohort</span> <br/> <span class="Bold"> (n=806,438)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Major congenital malformation*<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12 / 334 (3.6%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3,382 / 78,028 (4.3%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 33,950 /804,020 (4.2%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Stillbirth<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1 (0.3%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 384 (0.5%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2,418 (0.3%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Small for gestational age<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 42 (12.5%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13,433 (17.1%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 73,135 (9.1%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Preterm birth<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 25 (7.5%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6,173 (7.9%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 46,732 (5.8%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Premature rupture of membranes<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12 (3.6%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4,246 (5.4%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 30,641 (3.8%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Sudden infant death syndrome**<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0/307 (0.0%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 51/71,720 (0.1%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 58/755,939 (&lt;0.1%)<br/> </td> </tr> </tbody> </table></div>

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.

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 [see Data]. 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 varenicline tablets to an infant during lactation; however the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for varenicline tablets and any potential adverse effects on the breastfed child from varenicline tablets 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 to 22% of maternal serum concentrations.

Varenicline 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 to 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 ≤ 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.

A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 to 75 years) 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 [see Dosage and Administration (2.2)].

No dosage adjustment is recommended for elderly patients.

Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Varenicline is not a controlled substance.

Humans

Fewer than 1 out of 1,000 patients reported euphoria in clinical trials with varenicline tablets. At higher doses (greater than 2 mg), varenicline tablets produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of varenicline tablets was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction.

In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers.

Animals

Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self- administration.

In case of overdose, standard supportive measures should be instituted as required.

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Varenicline has been shown to be dialyzed in patients with end-stage renal disease [see Clinical Pharmacology (12.3)], however, there is no experience in dialysis following overdose.

{ "type": "p", "children": [], "text": "Varenicline has been shown to be dialyzed in patients with end-stage renal disease [see Clinical Pharmacology (12.3)], however, there is no experience in dialysis following overdose." }

Varenicline tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.

{ "type": "p", "children": [], "text": "\nVarenicline tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α4β2 nicotinic acetylcholine receptor subtypes." }

Varenicline, as the tartrate salt, is a powder which is a white to light brown color powder with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano 6H-pyrazino[2,3 h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is freely soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 • C4H6O6. The chemical structure is:

{ "type": "p", "children": [], "text": "Varenicline, as the tartrate salt, is a powder which is a white to light brown color powder with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano 6H-pyrazino[2,3 h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is freely soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 • C4H6O6. The chemical structure is:" }

Varenicline tablets are supplied for oral administration in two strengths: 0.5 mg white to off white, round, biconvex-coated tablets, debossed with "T" on one side and "2" on the other side  and 1 mg yellow, round, biconvex-coated tablets, debossed with "T" on one side and "1" on the other side. Each 0.5 mg varenicline tablet contains 0.855 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1 mg varenicline tablet contains 1.710 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, magnesium stearate, maltodextrin, talc and titanium dioxide. The 1 mg tablet also contains iron oxide yellow.

{ "type": "p", "children": [], "text": "\nVarenicline tablets are supplied for oral administration in two strengths: 0.5 mg white to off white, round, biconvex-coated tablets, debossed with \"T\" on one side and \"2\" on the other side  and 1 mg yellow, round, biconvex-coated tablets, debossed with \"T\" on one side and \"1\" on the other side. Each 0.5 mg varenicline tablet contains 0.855 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1 mg varenicline tablet contains 1.710 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, magnesium stearate, maltodextrin, talc and titanium dioxide. The 1 mg tablet also contains iron oxide yellow." }

Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of varenicline tablets in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3,500-fold α7, >20,000-fold α1βγδ), or to non  nicotinic receptors and transporters (>2,000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

Absorption

Maximum plasma concentrations of varenicline occur typically within 3 to 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%.

Food Effect

Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

Distribution

Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.

Elimination

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

Metabolism

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.

Excretion

Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.

Specific Populations

There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Age: Geriatric Patients

A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 to 75 years) for 7 consecutive days was similar to that of younger subjects.

Age: Pediatric Patients

Varenicline tablets are not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated [see Use in Specific Populations (8.4)].

Renal Impairment

Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily [see Dosage and Administration (2.2), Use in Specific Populations (8.6)]. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis [see Overdosage (10)].

Hepatic Impairment

Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.

Drug-Drug Interactions

In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.

In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin [see below]) are unlikely to be affected by varenicline.

In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may not necessitate a dose adjustment of varenicline tablets as the increase in systemic exposure to varenicline tablets is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline tablets [see Clinical Pharmacology (12.3)]; therefore, a dose adjustment of varenicline tablets would not be required.

Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions have been identified.

Metformin

When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.

Cimetidine

Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.

Digoxin

Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.

Warfarin

Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics [see Drug Interactions (7.2)].

Use with Other Drugs for Smoking Cessation

Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers [see Drug Interactions (7.1)].

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 adverse reactions was greater for the combination than for NRT alone [see Drug Interactions (7.1)].

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 (MRHD) 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 MRHD exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the MRHD 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 MRHD exposure based on AUC at 1 mg twice daily).

Maternal toxicity, characterized by a decrease in body weight gain, was observed at 15 mg/kg/day. 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. 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 MRHD exposure based on AUC at 1 mg twice daily).

Study 1

This was a six-week dose-ranging study comparing varenicline tablets to placebo. This study provided initial evidence that varenicline tablets at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.

Study 2

This study of 627 patients compared varenicline tablets 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one-week titration) and then were followed for 40 weeks post-treatment. Varenicline tablets were given in two divided doses daily. Each dose of varenicline tablets was given in two different regimens, with and without initial dose-titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.

Forty-five percent of patients receiving varenicline tablets 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.

Study 3

This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of varenicline tablets or placebo. After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.

Of the patients treated with varenicline tablets, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the varenicline tablets group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.

Study 4 and Study 5

These identical double-blind studies compared varenicline tablets 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The varenicline tablets dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.

In Study 4, patients treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the varenicline tablets group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.

Similarly in Study 5, patients treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the varenicline tablets group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.

Figure 1: Continuous Abstinence, Weeks 9 through 12

<div class="scrollingtable"><table class="Noautorules" width="575"> <caption> <span> Table 7: Continuous Abstinence, Weeks 9 through 12 (95% confidence interval) </span> </caption> <col width="84"/> <col width="102"/> <col width="102"/> <col width="93"/> <col width="96"/> <col width="98"/> <tfoot> <tr> <td align="left" colspan="6"> <p class="First Footnote">BID=twice daily</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> 0.5 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> Flexible</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Bupropion SR</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 45%<br/> (39%, 51%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 51%<br/> (44%, 57%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12%<br/> (6%, 18%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 3<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 40%<br/> (32%, 48%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 12%<br/> (7%, 17%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 4<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 44%<br/> (38%, 49%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 30%<br/> (25%, 35%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 17%<br/> (13%, 22%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 5<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 44%<br/> (38%, 49%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 30%<br/> (25%, 35%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 18%<br/> (14%, 22%)<br/> </td> </tr> </tbody> </table></div>

Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale "urge to smoke" item, varenicline tablets reduced urge to smoke compared to placebo.

Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, varenicline tablets -treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo (Figure 2, Table 8).

Figure 2: Continuous Abstinence, Weeks 9 through 52

<div class="scrollingtable"><table class="Noautorules" width="643"> <caption> <span> Table 8: Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) Across Different Studies </span> </caption> <col width="87"/> <col width="112"/> <col width="112"/> <col width="112"/> <col width="106"/> <col width="113"/> <tfoot> <tr> <td align="left" colspan="6"> <p class="First Footnote">BID=twice daily</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets 0.5 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets Flexible</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Bupropion SR</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 2<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 19%<br/> (14%, 24%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 23%<br/> (18%, 28%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> (1%, 8%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 3<br/> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 22%<br/> (16%, 29%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 8%<br/> (3%, 12%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 4<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 21%<br/> (17%, 26%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 16%<br/> (12%, 20%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8%<br/> (5%, 11%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Study 5<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 22%<br/> (17%, 26%)<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 14%<br/> (11%, 18%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10%<br/> (7%, 13%)<br/> </td> </tr> </tbody> </table></div>

Study 6

This study assessed the effect of an additional 12 weeks of varenicline tablets therapy on the likelihood of long-term abstinence. Patients in this study (N=1927) were treated with open-label varenicline tablets 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (N= 1210) were then randomized to double-blind treatment with varenicline tablets (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.

The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with varenicline tablets (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (varenicline tablets 54% versus placebo 39%).

In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of varenicline tablets; post- varenicline tablets follow-up begins at Week 13 for the placebo group and Week 25 for the varenicline tablets group. The y-axis represents the percentage of patients who had been abstinent for the last week of varenicline tablets treatment and remained abstinent at the given timepoint.

Figure 3: Continuous Abstinence Rate during Nontreatment Follow-Up

Varenicline tablets were evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to varenicline tablets 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post- treatment. Patients treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).

Varenicline tablets were evaluated in a 52-week double-blind placebo-controlled study of 1,510 subjects who were not able or willing to quit smoking within four weeks, but were willing to gradually reduce their smoking over a 12 week period before quitting. Subjects were randomized to either varenicline tablets 1 mg twice daily (N=760) or placebo (N=750) for 24 weeks and followed up post-treatment through week 52. Subjects were instructed to reduce the number of cigarettes smoked by at least 50 percent by the end of the first four weeks of treatment, followed by a further 50 percent reduction from week four to week eight of treatment, with the goal of reaching complete abstinence by 12 weeks. After the initial 12-week reduction phase, subjects continued treatment for another 12 weeks. Subjects treated with varenicline tablets had a significantly higher Continuous Abstinence Rate compared with placebo at weeks 15 through 24 (32% vs. 7%) and weeks 15 through 52 (24% vs. 6%).

Varenicline tablets were evaluated in a double-blind, placebo-controlled trial of patients who had made a previous attempt to quit smoking with varenicline tablets, and either did not succeed in quitting or relapsed after treatment. Subjects were randomized 1:1 to varenicline tablets 1 mg twice daily (N=249) or placebo (N=245) for 12 weeks of treatment and followed for 40 weeks post-treatment. Patients included in this study had taken varenicline tablets for a smoking-cessation attempt in the past (for a total treatment duration of a minimum of two weeks), at least three months prior to study entry, and had been smoking for at least four weeks.

Patients treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (45%) compared to patients treated with placebo (12%) and from weeks 9 through 52 (20%) compared to subjects treated with placebo (3%).

<div class="scrollingtable"><table class="Noautorules" width="605"> <caption> <span> Table 9: Continuous Abstinence (95% confidence interval), Re-Treatment Study </span> </caption> <col width="121"/> <col width="121"/> <col width="121"/> <col width="121"/> <col width="121"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> Weeks 9 through 12</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> Weeks 9 through 52</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Retreatment<br/> Study<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 45%<br/> (39%, 51%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12%<br/> (8%, 16%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20%<br/> (15%, 25%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> (1%, 5%)<br/> </td> </tr> </tbody> </table></div>

BID = twice daily

Varenicline tablets were evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 ≥ 50% of predicted normal value. Subjects were randomized to varenicline tablets 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).

<div class="scrollingtable"><table class="Noautorules" width="605"> <caption> <span> Table 10: Continuous Abstinence (95% confidence interval), Studies in Patients with Chronic Obstructive Pulmonary Disease (COPD) </span> </caption> <col width="121"/> <col width="121"/> <col width="121"/> <col width="121"/> <col width="121"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 12</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 52</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule"><span class="Bold"> V</span><span class="Bold"> arenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> COPD Study<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 41%<br/> (34%, 47%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9%<br/> (6%, 13%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 19%<br/> (14%, 24%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6%<br/> (3%, 9%)<br/> </td> </tr> </tbody> </table></div>

BID = twice daily

Varenicline tablets were evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to varenicline tablets 1 mg twice daily (N=353) or placebo (N=350) for a treatment period of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).

<div class="scrollingtable"><table class="Noautorules" width="610"> <caption> <span> Table 11:Continuous Abstinence (95% confidence interval), Studies in Patients with Cardiovascular Disease (CVD) </span> </caption> <col width="122"/> <col width="122"/> <col width="122"/> <col width="122"/> <col width="122"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 12</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 52</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> CVD Study <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 47%<br/> (42%, 53%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 14%<br/> (11%, 18%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20%<br/> (16%, 24%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7%<br/> (5%, 10%)<br/> </td> </tr> </tbody> </table></div>

BID = twice daily

In this study, all-cause and CV mortality was lower in patients treated with varenicline tablets, but certain nonfatal CV events occurred more frequently in patients treated with varenicline tablets than in patients treated with placebo [see Warnings and Precautions (5.5), Adverse Reactions (6.1)]. Table 12 below shows mortality and the incidence of selected nonfatal serious CV events occurring more frequently in the varenicline tablets arm compared to the placebo arm. These events were adjudicated by an independent blinded committee. Nonfatal serious CV events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one CV event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.

<div class="scrollingtable"><table class="Noautorules" width="590"> <caption> <span> Table 12: Mortality and Adjudicated Nonfatal Serious Cardiovascular Events in the Placebo-Controlled Varenicline Tablets Trial in Patients with Stable Cardiovascular Disease </span> </caption> <col width="387"/> <col width="105"/> <col width="98"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Mortality and Cardiovascular Events</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> (N=353)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> (N=350)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">Mortality (Cardiovascular and All-cause up to 52 weeks)</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Cardiovascular<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1 (0.3)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 (0.6)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> All-cause<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 (0.6)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 (1.4)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">Nonfatal Cardiovascular Events (rate on </span></span><span class="Bold"><span class="Italics">Varenicline Tablets</span></span><span class="Bold"><span class="Italics">&gt; Placebo)</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics"><span class="Underline">Up to 30 days after treatment</span></span> <br/> </td><td align="left" class="Botrule Rrule" valign="top"> <br/> </td><td align="left" class="Botrule Rrule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">            Nonfatal myocardial infarction<br/> </td><td align="center" class="Botrule Rrule"> 4 (1.1)<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.3)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">            Nonfatal Stroke<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.6)<br/> </td><td align="center" class="Botrule Rrule"> 0 (0)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics"><span class="Underline">Beyond 30 days after treatment and up to 52 weeks</span></span> <br/> </td><td align="center" class="Botrule Rrule"> <br/> </td><td align="center" class="Botrule Rrule"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">           Nonfatal myocardial infarction<br/> </td><td align="center" class="Botrule Rrule"> 3 (0.8)<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.6)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">           Need for coronary revascularization<br/> </td><td align="center" class="Botrule Rrule"> 7 (2.0)<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.6)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">           Hospitalization for angina pectoris<br/> </td><td align="center" class="Botrule Rrule"> 6 (1.7)<br/> </td><td align="center" class="Botrule Rrule"> 4 (1.1)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">           Transient ischemia attack<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.3)<br/> </td><td align="center" class="Botrule Rrule"> 0 (0)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">           New diagnosis of peripheral vascular disease (PVD) or        admission for a PVD procedure<br/> </td><td align="center" class="Botrule Rrule"> 5 (1.4)<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.6)<br/> </td> </tr> </tbody> </table></div>

Following the CVD study, a meta-analysis of 15 clinical trials of ≥12 weeks treatment duration, including 7002 patients (4190 varenicline tablets, 2812 placebo), was conducted to systematically assess the CV safety of varenicline tablets. The study in patients with stable CV disease described above was included in the meta-analysis. There were lower rates of all-cause mortality (varenicline tablets 6 [0.14%]; placebo 7 [0.25%]) and CV mortality (varenicline tablets 2 [0.05%]; placebo 2 [0.07%]) in the varenicline tablets arms compared with the placebo arms in the meta-analysis.

The key CV safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as CV death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred in the trials included in the meta-analysis, as described in Table 13. These events occurred primarily in patients with known CV disease.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 13: Number of MACE cases, Hazard Ratio and Rate Difference in a Meta-Analysis of 15 Clinical Trials Comparing Varenicline Tablets to Placebo* </span> </caption> <col width="330"/> <col width="186"/> <col width="108"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">*Includes MACE occurring up to 30 days post-treatment.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> N=4190</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=2812</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"><span class="Italics">MACE cases, n (%)</span></span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13 (0.31%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6 (0.21%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Patient-years of exposure<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1316<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 839<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">Hazard Ratio (95% CI)</span></span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 1.95 (0.79, 4.82)<br/> </td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"><span class="Bold"><span class="Italics">Rate Difference per 1,000 patient-years (95% CI)</span></span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 6.30 (-2.40, 15.10)<br/> </td><td class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

The meta-analysis showed that exposure to varenicline tablets resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up to 30 days after treatment; this is equivalent to an estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV endpoints in patients on varenicline tablets relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.

Additionally, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension, [see Warnings and Precautions (5.5), Adverse Reactions (6.1), Clinical Studies (14.10)].

Varenicline tablets were evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 18 to 75 years with major depressive disorder without psychotic features (DSM-IV TR). If on medication, subjects were to be on a stable antidepressant regimen for at least two months. If not on medication, subjects were to have experienced a major depressive episode in the past 2 years, which was successfully treated. Subjects were randomized to varenicline tablets 1 mg twice daily (N=256) or placebo (N=269) for a treatment of 12 weeks and then followed for 40 weeks post-treatment. Subjects treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (36%) compared to subjects treated with placebo (16%) and from week 9 through 52 (20%) compared to subjects treated with placebo (10%).

<div class="scrollingtable"><table class="Noautorules" width="625"> <caption> <span> Table 14: Continuous Abstinence (95% confidence interval), Study in Patients with Major Depressive Disorder (MDD) </span> </caption> <col width="125"/> <col width="125"/> <col width="125"/> <col width="125"/> <col width="125"/> <tfoot> <tr> <td align="left" colspan="5"> <p class="First Footnote">BID = twice daily</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 12</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Weeks 9 through 52</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> MDD Study<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 36%<br/> (30%, 42%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 16%<br/> (11%, 20%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20%<br/> (15%, 25%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10%<br/> (7%, 14%)<br/> </td> </tr> </tbody> </table></div>

Varenicline tablets were evaluated in a randomized, double-blind, active and placebo-controlled trial that included subjects without a history of psychiatric disorder (non-psychiatric cohort, N=3912) and with a history of psychiatric disorder (psychiatric cohort, N=4003). Subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to varenicline tablets 1 mg BID, bupropion SR 150 mg BID, NRT patch 21 mg/day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. [See Warnings and Precautions (5.1)]

A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse events included the following NPS adverse events: anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, irritability, suicidal ideation, suicidal behavior or completed suicide.

As shown in Table 15, the use of varenicline tablets, bupropion, and NRT in the non-psychiatric cohort was not associated with an increased risk of clinically significant NPS adverse events compared with placebo. Similarly, in the non-psychiatric cohort, the use of varenicline tablets was not associated with an increased risk of clinically significant NPS adverse events in the composite safety endpoint compared with bupropion or NRT.

<div class="scrollingtable"><table class="Noautorules" width="568"> <caption> <span> Table 15: Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients without a History of Psychiatric Disorder </span> </caption> <col width="180"/> <col width="97"/> <col width="101"/> <col width="96"/> <col width="94"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets (N=975)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Bupropion</span> <br/> <span class="Bold"> (N=968)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> NRT</span> <br/> <span class="Bold"> (N=987)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo (N=982)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Clinically Significant NPS<br/> </td><td align="center" class="Botrule Rrule"> 30 (3.1)<br/> </td><td align="center" class="Botrule Rrule"> 34 (3.5)<br/> </td><td align="center" class="Botrule Rrule"> 33 (3.3)<br/> </td><td align="center" class="Botrule Rrule"> 40 (4.1)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Serious NPS<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.1)<br/> </td><td align="center" class="Botrule Rrule"> 5 (0.5)<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.1)<br/> </td><td align="center" class="Botrule Rrule"> 4 (0.4)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Psychiatric Hospitalizations<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.1)<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.2)<br/> </td><td align="center" class="Botrule Rrule"> 0 (0.0)<br/> </td><td align="center" class="Botrule Rrule"> 1 (0.1)<br/> </td> </tr> </tbody> </table></div>

As shown in Table 16, there were more clinically significant NPS adverse events reported in patients in the psychiatric cohort in each treatment group compared with the non-psychiatric cohort. 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 varenicline tablets, 2.2% (-0.5, 4.9) for bupropion, and 0.4% (-2.2, 3.0) for NRT transdermal nicotine.

<div class="scrollingtable"><table class="Noautorules" width="565"> <caption> <span> Table 16: Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group Among Patients with a History of Psychiatric Disorder </span> </caption> <col width="180"/> <col width="96"/> <col width="100"/> <col width="95"/> <col width="94"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold">  (N=1007)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Bupropion</span> <br/> <span class="Bold"> (N=1004)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> NRT (N=995)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo (N=997)</span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Clinically Significant NPS<br/> </td><td align="center" class="Botrule Rrule"> 123 (12.2)<br/> </td><td align="center" class="Botrule Rrule"> 118 (11.8)<br/> </td><td align="center" class="Botrule Rrule"> 98 (9.8)<br/> </td><td align="center" class="Botrule Rrule"> 95 (9.5)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Serious NPS<br/> </td><td align="center" class="Botrule Rrule"> 6 (0.6)<br/> </td><td align="center" class="Botrule Rrule"> 8 (0.8)<br/> </td><td align="center" class="Botrule Rrule"> 4 (0.4)<br/> </td><td align="center" class="Botrule Rrule"> 6 (0.6)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Psychiatric hospitalizations<br/> </td><td align="center" class="Botrule Rrule"> 5 (0.5)<br/> </td><td align="center" class="Botrule Rrule"> 8 (0.8)<br/> </td><td align="center" class="Botrule Rrule"> 4 (0.4)<br/> </td><td align="center" class="Botrule Rrule"> 2 (0.2)<br/> </td> </tr> </tbody> </table></div>

There was one completed suicide, which occurred during treatment in a patient treated with placebo in the non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort.

In both cohorts, subjects treated with varenicline tablets had a superior rate of CO-confirmed abstinence during weeks 9 through 12 and 9 through 24 compared to subjects treated with bupropion, nicotine patch and placebo.

<div class="scrollingtable"><table class="Noautorules" width="623"> <caption> <span> Table 17: Continuous Abstinence (95% confidence interval), Study in Patients with or without a History of Psychiatric Disorder </span> </caption> <col width="129"/> <col width="125"/> <col width="137"/> <col width="113"/> <col width="119"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> 1 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Bupropion SR</span> <br/> <span class="Bold"> 150 mg BID</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> NRT</span> <br/> <span class="Bold"> 21 mg/day with taper</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5"><span class="Bold"> Weeks 9 through 12</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Non-Psychiatric<br/> Cohort<br/> </td><td align="center" class="Botrule Rrule"> 38%<br/> (35%, 41%)<br/> </td><td align="center" class="Botrule Rrule"> 26%<br/> (23%, 29%)<br/> </td><td align="center" class="Botrule Rrule"> 26%<br/> (24%, 29%)<br/> </td><td align="center" class="Botrule Rrule"> 14%<br/> (12%, 16%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Psychiatric Cohort<br/> </td><td align="center" class="Botrule Rrule"> 29%<br/> (26%, 32%)<br/> </td><td align="center" class="Botrule Rrule"> 19%<br/> (17%, 22%)<br/> </td><td align="center" class="Botrule Rrule"> 20%<br/> (18%, 23%)<br/> </td><td align="center" class="Botrule Rrule"> 11%<br/> (10%, 14%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5"><span class="Bold"> Weeks 9 through 24</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Non-Psychiatric<br/> Cohort<br/> </td><td align="center" class="Botrule Rrule"> 25%<br/> (23%, 28%)<br/> </td><td align="center" class="Botrule Rrule"> 19%<br/> (16%, 21%)<br/> </td><td align="center" class="Botrule Rrule"> 18%<br/> (16%, 21%)<br/> </td><td align="center" class="Botrule Rrule"> 11%<br/> (9%, 13%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Psychiatric Cohort<br/> </td><td align="center" class="Botrule Rrule"> 18%<br/> (16%, 21%)<br/> </td><td align="center" class="Botrule Rrule"> 14%<br/> (12%, 16%)<br/> </td><td align="center" class="Botrule Rrule"> 13%<br/> (11%, 15%)<br/> </td><td align="center" class="Botrule Rrule"> 8%<br/> (7%, 10%)<br/> </td> </tr> </tbody> </table></div>

BID = twice daily

Cardiovascular Outcome Analysis

To obtain another source of data regarding the CV risk of varenicline tablets, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension. In the parent study (N=8027), subjects aged 18-75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to varenicline tablets 1 mg BID, bupropion SR 150 mg BID, nicotine replacement therapy (NRT) patch 21 mg/day or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment. The extension study enrolled 4590 (57.2%) of the 8027 subjects who were randomized and treated in the parent study and followed them for additional 28 weeks. Of all treated subjects, 1743 (21.7%) had a medium CV risk and 640 (8.0%) had a high CV risk, as defined by Framingham score. Note that one site from the parent study was excluded in the assessment of CV safety and two sites were excluded in the assessment of neuropsychiatric safety.

The primary CV endpoint was the time to major adverse CV event (MACE), defined as CV death, nonfatal myocardial infarction or nonfatal stroke during treatment.

Deaths and CV events were adjudicated by a blinded, independent committee. Table 18 below shows the incidence of MACE and Hazard Ratios compared to placebo for all randomized subjects exposed to at least 1 partial dose of study treatment in the parent study.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 18: The Incidence of MACE and Hazard Ratios in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder </span> </caption> <col width="294"/> <col width="96"/> <col width="84"/> <col width="84"/> <col width="66"/> <tfoot> <tr> <td align="left" colspan="5"> <p class="First Footnote">[IR] indicates incidence rate per 1000 person-years</p> </td> </tr> <tr> <td align="left" colspan="5"> <p class="First Footnote">*during treatment in the parent neuropsychiatric safety study</p> </td> </tr> <tr> <td align="left" colspan="5"> <p class="First Footnote">**either the end of the extension study or the end of parent neuropsychiatric safety study for those subjects not enrolled into the extension study</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Varenicline Tablets</span> <br/> <span class="Bold"> N=2006</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Bupropion</span> <br/> <span class="Bold"> N=1997</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> NRT</span> <br/> <span class="Bold"> N=2017</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=2007</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">During treatment*</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> MACE, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1 [2.4]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 [4.9]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1 [2.4]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 [9.8]<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Hazard Ratio (95% CI)</span> <br/> <span class="Italics">vs. placebo</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.24<br/> (0.03, 2.18)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.49<br/> (0.09, 2.69)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.24<br/> (0.03, 2.18)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Through end of study**</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> MACE, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3 [2.1]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9 [6.3]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6 [4.3]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 8 [5.7]<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Hazard Ratio (95% CI)</span> <br/> <span class="Italics">vs. placebo</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.36<br/> (0.10, 1.36)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.09<br/> (0.42, 2.83)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.74<br/> (0.26, 2.13)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> </td> </tr> </tbody> </table></div>

For this study, MACE+ was defined as any MACE or a new onset or worsening peripheral vascular disease (PVD) requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina. Incidence rates of MACE+ and all-cause mortality for all randomized subjects exposed to at least 1 partial dose of study treatment in the parent study are shown for all treatment groups during treatment, and through end of study in the Table 19 below.

<div class="scrollingtable"><table class="Noautorules" width="624"> <caption> <span> Table 19: The Incidence of MACE+ and All-Cause Death in the Cardiovascular Safety Assessment Trial in Subjects without or with a History of Psychiatric Disorder </span> </caption> <col width="234"/> <col width="126"/> <col width="96"/> <col width="84"/> <col width="84"/> <tfoot> <tr> <td align="left" colspan="5"> <p class="First Footnote">[IR] indicates incidence rate per 1000 person-years</p> </td> </tr> <tr> <td align="left" colspan="5"> <p class="First Footnote">*during treatment in the parent neuropsychiatric safety study</p> </td> </tr> <tr> <td align="left" colspan="5"> <p class="First Footnote">**either the end of the extension study or the end of the parent neuropsychiatric safety study for those subjects not enrolled into the extension study</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Varenicline Tablets </span> <br/> <span class="Bold"> N=2006</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Bupropion</span> <br/> <span class="Bold"> N=1997</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> NRT</span> <br/> <span class="Bold"> N=2017</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> N=2007</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">During treatment*</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> MACE+, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 [12.1]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 [9.9]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 [4.8]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5 [12.2]<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> All-cause deaths, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 [4.9]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 [4.9]<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Through end of study**</span></span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> MACE+, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10 [6.9]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 15 [10.5]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10 [7.1]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12 [8.6]<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> All-cause deaths, n [IR]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2 [1.4]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 [2.8]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3 [2.1]<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 [2.9]<br/> </td> </tr> </tbody> </table></div>

The number of subjects who experienced MACE, MACE+ and all-cause death was similar or lower among patients treated with varenicline tablets than patients treated with placebo. The number of events observed overall was too low to distinguish meaningful differences between the treatment arms.

Varenicline tablets are supplied for oral administration in two strengths: 0.5 mg white to off white, round, biconvex-coated tablets, debossed with "T" on one side and "2" on the other side and 1 mg yellow, round, biconvex-coated tablets, debossed with "T" on one side and "1" on the other side. Varenicline tablets are supplied in the following package configurations:

{ "type": "p", "children": [], "text": "\nVarenicline tablets are supplied for oral administration in two strengths: 0.5 mg white to off white, round, biconvex-coated tablets, debossed with \"T\" on one side and \"2\" on the other side and 1 mg yellow, round, biconvex-coated tablets, debossed with \"T\" on one side and \"1\" on the other side. Varenicline tablets are supplied in the following package configurations:" }

<div class="scrollingtable"><table class="Noautorules" width="623"> <col width="69"/> <col width="375"/> <col width="179"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Description</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> NDC</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="4"> Packs<br/> </td><td align="left" class="Botrule Rrule"> Starting 4-week card: 0.5 mg x 11 Tablets and 1 mg x 42 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -125-11<br/> </td> </tr> <tr> <td align="left" class="Botrule Rrule"> Continuing 4-week card: 1 mg x 56 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -126-11<br/> </td> </tr> <tr> <td align="left" class="Botrule Rrule"> Starting Month Box: 0.5 mg x 11 Tablets and 1 mg x 42 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -125-13<br/> </td> </tr> <tr> <td align="left" class="Botrule Rrule"> Continuing Month Box: 1 mg x 56 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -126-13<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2"> Bottles<br/> </td><td align="left" class="Botrule Rrule"> 0.5 mg - Bottle of 56 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -127-49<br/> </td> </tr> <tr> <td align="left" class="Botrule Rrule"> 1 mg - Bottle of 56 Tablets<br/> </td><td align="center" class="Botrule Rrule"> NDC 70748 -128-49<br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"623\">\n<col width=\"69\"/>\n<col width=\"375\"/>\n<col width=\"179\"/>\n<tbody class=\"Headless\">\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\"> Description</span>\n<br/>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\"> NDC</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" rowspan=\"4\"> Packs<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\"> Starting 4-week card: 0.5 mg x 11 Tablets and 1 mg x 42 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -125-11<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"> Continuing 4-week card: 1 mg x 56 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -126-11<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"> Starting Month Box: 0.5 mg x 11 Tablets and 1 mg x 42 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -125-13<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"> Continuing Month Box: 1 mg x 56 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -126-13<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" rowspan=\"2\"> Bottles<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\"> 0.5 mg - Bottle of 56 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -127-49<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\"> 1 mg - Bottle of 56 Tablets<br/>\n</td><td align=\"center\" class=\"Botrule Rrule\"> NDC 70748 -128-49<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) (see USP Controlled Room Temperature).

{ "type": "p", "children": [], "text": "\nStore at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) (see USP Controlled Room Temperature)." }

See FDA-approved patient labeling (Medication Guide)

{ "type": "p", "children": [], "text": "\nSee FDA-approved patient labeling (Medication Guide) \n" }

Initiate Treatment and Continue to Attempt to Quit if Lapse

{ "type": "p", "children": [], "text": "\nInitiate Treatment and Continue to Attempt to Quit if Lapse\n" }

Instruct patients to set a date to quit smoking and to initiate varenicline tablets treatment one week before the quit date. Alternatively, the patient can begin varenicline tablets dosing and then set a date to quit smoking between days 8 and 35 of treatment. Encourage patients to continue to attempt to quit if they have early lapses after quit day [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Instruct patients to set a date to quit smoking and to initiate varenicline tablets treatment one week before the quit date. Alternatively, the patient can begin varenicline tablets dosing and then set a date to quit smoking between days 8 and 35 of treatment. Encourage patients to continue to attempt to quit if they have early lapses after quit day [see Dosage and Administration (2.1)].\n" }

For patients who are sure that they are not able or willing to quit abruptly, a gradual approach to quitting smoking with varenicline tablets may be considered. Patients should begin varenicline tablets 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 [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "For patients who are sure that they are not able or willing to quit abruptly, a gradual approach to quitting smoking with varenicline tablets may be considered. Patients should begin varenicline tablets 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 [see Dosage and Administration (2.1)].\n" }

Encourage patients who are motivated to quit and who did not succeed in stopping smoking during prior varenicline tablets therapy for reasons other than intolerability due to adverse events, or who relapsed after treatment to make another attempt with varenicline tablets once factors contributing to the failed attempt have been identified and addressed [see Dosage and Administration (2.1), Clinical Studies (14.6)].

{ "type": "p", "children": [], "text": "Encourage patients who are motivated to quit and who did not succeed in stopping smoking during prior varenicline tablets therapy for reasons other than intolerability due to adverse events, or who relapsed after treatment to make another attempt with varenicline tablets once factors contributing to the failed attempt have been identified and addressed [see Dosage and Administration (2.1), Clinical Studies (14.6)].\n" }

How to Take

{ "type": "p", "children": [], "text": "\nHow to Take\n" }

Advise patients that varenicline tablets should be taken orally after eating, and with a full glass of water [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Advise patients that varenicline tablets should be taken orally after eating, and with a full glass of water [see Dosage and Administration (2.1)].\n" }

Starting Week Dosage

{ "type": "p", "children": [], "text": "\nStarting Week Dosage\n" }

Instruct patients on how to titrate varenicline tablets, beginning at a dose of 0.5 mg/day. 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 [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Instruct patients on how to titrate varenicline tablets, beginning at a dose of 0.5 mg/day. 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 [see Dosage and Administration (2.1)].\n" }

Continuing Weeks Dosage

{ "type": "p", "children": [], "text": "\nContinuing Weeks Dosage\n" }

Advise patients 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 [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Advise patients 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 [see Dosage and Administration (2.1)].\n" }

Dosage Adjustment for varenicline tablets or Other Drugs

{ "type": "p", "children": [], "text": "\nDosage Adjustment for varenicline tablets or Other Drugs\n" }

Inform patients that nausea and insomnia are side effects of varenicline tablets and are usually transient; however, advise patients that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered.

{ "type": "p", "children": [], "text": "Inform patients that nausea and insomnia are side effects of varenicline tablets and are usually transient; however, advise patients that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered." }

Inform patients that some drugs may require dose adjustment after quitting smoking [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Inform patients that some drugs may require dose adjustment after quitting smoking [see Dosage and Administration (2.1)].\n" }

Counseling and Support

{ "type": "p", "children": [], "text": "\nCounseling and Support\n" }

Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking [see Dosage and Administration (2.1)].\n" }

Neuropsychiatric Adverse Events

{ "type": "p", "children": [], "text": "\nNeuropsychiatric Adverse Events\n" }

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 varenicline tablets. Instruct patients to discontinue varenicline tablets and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "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 varenicline tablets. Instruct patients to discontinue varenicline tablets and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].\n" }

History of Psychiatric Illness

{ "type": "p", "children": [], "text": "\nHistory of Psychiatric Illness\n" }

Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.

{ "type": "p", "children": [], "text": "Encourage patients to reveal any history of psychiatric illness prior to initiating treatment." }

Nicotine Withdrawal

{ "type": "p", "children": [], "text": "\nNicotine Withdrawal\n" }

Inform patients that quitting smoking, with or without varenicline tablets, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of pre-existing psychiatric illness.

{ "type": "p", "children": [], "text": "Inform patients that quitting smoking, with or without varenicline tablets, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of pre-existing psychiatric illness." }

Seizures

{ "type": "p", "children": [], "text": "\nSeizures\n" }

Encourage patients to report any history of seizures or other factors that can lower seizure threshold. Instruct patients to discontinue varenicline tablets and contact a healthcare provider immediately if they experience a seizure while on treatment [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Encourage patients to report any history of seizures or other factors that can lower seizure threshold. Instruct patients to discontinue varenicline tablets and contact a healthcare provider immediately if they experience a seizure while on treatment [see Warnings and Precautions (5.2)].\n" }

Interaction with Alcohol

{ "type": "p", "children": [], "text": "\nInteraction with Alcohol\n" }

Advise patients to reduce the amount of alcohol they consume while taking varenicline tablets until they know whether varenicline tablets affect their tolerance for alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Advise patients to reduce the amount of alcohol they consume while taking varenicline tablets until they know whether varenicline tablets affect their tolerance for alcohol [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].\n" }

Driving or Operating Machinery

{ "type": "p", "children": [], "text": "\nDriving or Operating Machinery\n" }

Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them [see Warnings and Precautions (5.4)].\n" }

Cardiovascular Events

{ "type": "p", "children": [], "text": "\nCardiovascular Events\n" }

Patients should be instructed to notify their healthcare providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "Patients should be instructed to notify their healthcare providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].\n" }

Somnambulism

{ "type": "p", "children": [], "text": "\nSomnambulism\n" }

Patients should be instructed to discontinue varenicline tablets and notify their healthcare providers if they experience somnambulism [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Patients should be instructed to discontinue varenicline tablets and notify their healthcare providers if they experience somnambulism [see Warnings and Precautions (5.6)]. \n" }

Angioedema

{ "type": "p", "children": [], "text": "\nAngioedema\n" }

Inform patients that there have been reports of angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue varenicline tablets and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients that there have been reports of angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue varenicline tablets and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].\n" }

Serious Skin Reactions

{ "type": "p", "children": [], "text": "\nSerious Skin Reactions\n" }

Inform patients that serious skin reactions, such as Stevens-Johnson Syndrome and erythema multiforme, were reported by some patients taking varenicline tablets. Advise patients to stop taking varenicline tablets at the first sign of rash with mucosal lesions or skin reaction and contact a healthcare provider immediately [see Warnings and Precautions (5.8), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients that serious skin reactions, such as Stevens-Johnson Syndrome and erythema multiforme, were reported by some patients taking varenicline tablets. Advise patients to stop taking varenicline tablets at the first sign of rash with mucosal lesions or skin reaction and contact a healthcare provider immediately [see Warnings and Precautions (5.8), Adverse Reactions (6.2)].\n" }

Vivid, Unusual, or Strange Dreams

{ "type": "p", "children": [], "text": "\nVivid, Unusual, or Strange Dreams\n" }

Inform patients that they may experience vivid, unusual or strange dreams during treatment with varenicline tablets.

{ "type": "p", "children": [], "text": "Inform patients that they may experience vivid, unusual or strange dreams during treatment with varenicline tablets." }

Pregnancy and Lactation

{ "type": "p", "children": [], "text": "\nPregnancy and Lactation\n" }

Patients who are pregnant or breastfeeding or planning to become pregnant should be advised of: the risks of smoking to a pregnant mother and her developing baby, the potential risks of varenicline tablets use during pregnancy and breastfeeding, and the benefits of smoking cessation with and without varenicline tablets. Advise breastfeeding women to monitor the infant for seizures and vomiting [see Use in Specific Populations (8.1 and 8.2)].

{ "type": "p", "children": [], "text": "Patients who are pregnant or breastfeeding or planning to become pregnant should be advised of: the risks of smoking to a pregnant mother and her developing baby, the potential risks of varenicline tablets use during pregnancy and breastfeeding, and the benefits of smoking cessation with and without varenicline tablets. Advise breastfeeding women to monitor the infant for seizures and vomiting [see Use in Specific Populations (8.1 and 8.2)].\n" }

Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:" }

Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc.\n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108 " }

United States.

{ "type": "p", "children": [], "text": "United States." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Pithampur (M. P.), 454 775

{ "type": "p", "children": [], "text": "Pithampur (M. P.), 454 775" }

India

{ "type": "p", "children": [], "text": "India" }

Revised: December 2024

{ "type": "p", "children": [], "text": "\nRevised: December 2024" }

MEDICATION GUIDE

{ "type": "p", "children": [], "text": "\nMEDICATION GUIDE\n" }

Varenicline (va-ren-i-cline) Tablets

{ "type": "p", "children": [], "text": "\nVarenicline (va-ren-i-cline) Tablets\n" }

What is the most important information I should know about varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about varenicline tablets?\n" }

When you try to quit smoking, with or without varenicline tablets, you may have symptoms that may be due to nicotine withdrawal, including:

{ "type": "p", "children": [], "text": "When you try to quit smoking, with or without varenicline tablets, you may have symptoms that may be due to nicotine withdrawal, including:" }

{ "type": "ul", "children": [ "  urge to smoke", "  frustration", "  restlessness", "  depressed mood", "  anger", "  decreased heart rate", "  trouble sleeping", "  feeling anxious", "  increased appetite", "  irritability", "  difficulty concentrating", "  weight gain" ], "text": "" }

Some people have even experienced suicidal thoughts when trying to quit smoking without medication.

{ "type": "p", "children": [], "text": "\nSome people have even experienced suicidal thoughts when trying to quit smoking without medication. " }

Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.

{ "type": "p", "children": [], "text": "Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression." }

Some people have had serious side effects while taking varenicline tablets to help them quit smoking, including:

{ "type": "p", "children": [], "text": "Some people have had serious side effects while taking varenicline tablets 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 varenicline tablets, and others developed them after several weeks of treatment, or after stopping varenicline tablets. These symptoms happened more often in people who had a history of mental health problems before taking varenicline tablets, than in people without a history of mental health problems.

{ "type": "p", "children": [], "text": "\nNew 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 varenicline tablets, and others developed them after several weeks of treatment, or after stopping varenicline tablets. These symptoms happened more often in people who had a history of mental health problems before taking varenicline tablets, than in people without a history of mental health problems." }

Stop taking varenicline tablets 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 varenicline tablets. In many people, these symptoms went away after stopping varenicline tablets, but in some people symptoms continued after stopping varenicline tablets. It is important for you to follow-up with your healthcare provider until your symptoms go away.

{ "type": "p", "children": [], "text": "\nStop taking varenicline tablets 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 varenicline tablets. In many people, these symptoms went away after stopping varenicline tablets, but in some people symptoms continued after stopping varenicline tablets. It is important for you to follow-up with your healthcare provider until your symptoms go away." }

Before taking varenicline tablets, 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 varenicline tablets.

{ "type": "p", "children": [], "text": "\nBefore taking varenicline tablets, 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 varenicline tablets." }

What are varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat are varenicline tablets?\n" }

Varenicline tablets are prescription medicine to help people stop smoking.

{ "type": "p", "children": [], "text": "Varenicline tablets are 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.

{ "type": "p", "children": [], "text": "Quitting smoking can lower your chances of having lung disease, heart disease or getting certain types of cancer that are related to smoking." }

Varenicline tablets have not been shown to be effective in children 16 years of age and under. Varenicline tablets should not be used in children 16 years of age and under.

{ "type": "p", "children": [], "text": "Varenicline tablets have not been shown to be effective in children 16 years of age and under. Varenicline tablets should not be used in children 16 years of age and under. " }

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

{ "type": "p", "children": [], "text": "It is not known if varenicline tablets are safe and effective when used with other stop smoking medicines." }

Who should not take varenicline tablets?

{ "type": "p", "children": [], "text": "\nWho should not take varenicline tablets?\n" }

Do not take varenicline tablets if you have had a serious allergic or skin reaction to varenicline tablets. Symptoms may include:

{ "type": "p", "children": [], "text": "Do not take varenicline tablets if you have had a serious allergic or skin reaction to varenicline tablets. Symptoms may include:" }

{ "type": "ul", "children": [ "  swelling of the face, mouth (tongue, lips, gums), throat or neck", "  trouble breathing", "  rash, with peeling skin", "  blisters in your mouth" ], "text": "" }

What should I tell my healthcare provider before taking varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before taking varenicline tablets?\n" }

See "What is the most important information I should know about varenicline tablets?"

{ "type": "p", "children": [], "text": "\nSee \"What is the most important information I should know about varenicline tablets?\"\n" }

Before you take varenicline tablets, tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "\nBefore you take varenicline tablets, tell your healthcare provider if you:\n" }

{ "type": "ul", "children": [ "use other treatments to quit smoking. Using varenicline tablets with a nicotine patch may cause nausea, vomiting, headache, dizziness, upset stomach, and tiredness to happen more often than if you just use a nicotine patch alone.", "have kidney problems or get kidney dialysis. Your healthcare provider may prescribe a lower dose of varenicline tablets for you.", "have a history of seizures", "drink alcohol", "have heart or blood vessel problems", "have any other medical conditions", "are pregnant or plan to become pregnant.", "are breastfeeding. It is not known if varenicline passes into breast milk. If you breastfeed and take varenicline tablets, monitor your baby for seizures as well as spitting up or vomiting more than normal." ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Your healthcare provider may need to change the dose of some of your medicines when you stop smoking.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Your healthcare provider may need to change the dose of some of your medicines when you stop smoking." }

You should not use varenicline tablets while using other medicines to quit smoking. Tell your healthcare provider if you use other treatments to quit smoking.

{ "type": "p", "children": [], "text": "You should not use varenicline tablets while using other medicines to quit smoking. Tell your healthcare provider if you use other treatments to quit smoking." }

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine." }

How should I take varenicline tablets?

{ "type": "p", "children": [], "text": "\nHow should I take varenicline tablets?\n" }

{ "type": "ul", "children": [ "There are 3 ways that you can use varenicline tablets to help you quit smoking. Talk to your healthcare provider about the following 3 ways to use varenicline tablets:\nChoose a quit date when you will stop smoking. Start taking varenicline tablets 1 week (7 days) before your quit date . Take varenicline tablets for 12 weeks. OR\n\nStart taking varenicline tablets before you choose a quit date . Pick a date to quit smoking that is between days 8 and 35 of treatment. Take varenicline tablets for 12 weeks. OR\n\nIf you are sure that you are not able or willing to quit smoking right away, start taking varenicline tablets and reduce smoking during the first 12 weeks of treatment, as follows:\n\n" ], "text": "" }

<div class="scrollingtable"><table width="548"> <col width="191"/> <col width="357"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> Weeks 1 through 4<br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> Reduce your smoking to reach one-half of your starting daily number of cigarettes.<br/> Example: If you usually smoke 20 cigarettes each day, reduce your smoking to 10 cigarettes each day during weeks 1 through 4.<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Weeks 5 through 8<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Reduce your smoking to reach one-quarter of your starting daily number of cigarettes.<br/> Example: If you usually smoked 20 cigarettes each day, reduce your smoking to 5 cigarettes each day during weeks 5 through 8.<br/> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"> Weeks 9 through 12<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day).<br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"548\">\n<col width=\"191\"/>\n<col width=\"357\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> Weeks 1 through 4<br/>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\"> Reduce your smoking to reach one-half of your starting daily number of cigarettes.<br/> Example: If you usually smoke 20 cigarettes each day, reduce your smoking to 10 cigarettes each day during weeks 1 through 4.<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Weeks 5 through 8<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Reduce your smoking to reach one-quarter of your starting daily number of cigarettes.<br/> Example: If you usually smoked 20 cigarettes each day, reduce your smoking to 5 cigarettes each day during weeks 5 through 8.<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Weeks 9 through 12<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day).<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Aim to quit by the end of the 12th week of treatment, or sooner if you feel ready. Continue to take varenicline tablets for another 12 weeks, for a total of 24 weeks of treatment.

{ "type": "p", "children": [], "text": "\nAim to quit by the end of the 12th week of treatment, or sooner if you feel ready. Continue to take varenicline tablets for another 12 weeks, for a total of 24 weeks of treatment." }

Starting varenicline tablets before your quit date gives varenicline tablets time to build up in your body. You can keep smoking during this time. Take varenicline tablets exactly as prescribed by your healthcare provider.

{ "type": "p", "children": [], "text": "Starting varenicline tablets before your quit date gives varenicline tablets time to build up in your body. You can keep smoking during this time. Take varenicline tablets exactly as prescribed by your healthcare provider." }

{ "type": "ul", "children": [ "Varenicline tablets come as a white tablet (0.5 mg) and a yellow tablet (1 mg). You start with the white tablet and then usually go to the yellow tablet. See the chart below for dosing instructions for adults." ], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="544"> <caption> <span></span> </caption> <col width="250"/> <col width="294"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> Day 1 to Day 3<br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"> o   White tablet (0.5 mg)<br/> o   Take 1 tablet each day<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Day 4 to Day 7<br/> </td><td align="left" class="Botrule Rrule" valign="top"> o   White tablet (0.5 mg)<br/> o   Take 1 in the morning and 1 in the evening<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Day 8 to end of treatment<br/> </td><td align="left" class="Botrule Rrule" valign="top"> o   Yellow tablet (1 mg)<br/> o   Take 1 in the morning and 1 in the evening<br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"544\">\n<caption>\n<span></span>\n</caption>\n<col width=\"250\"/>\n<col width=\"294\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> Day 1 to Day 3<br/>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\"> o   White tablet (0.5 mg)<br/> o   Take 1 tablet each day<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Day 4 to Day 7<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> o   White tablet (0.5 mg)<br/> o   Take 1 in the morning and 1 in the evening<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Day 8 to end of treatment<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> o   Yellow tablet (1 mg)<br/> o   Take 1 in the morning and 1 in the evening<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "ul", "children": [ "Make sure that you try to stop smoking on your quit date. If you slip-up and smoke, try again. Some people need to take varenicline tablets for a few weeks for varenicline tablets to work best.", "Most people will take varenicline tablets for up to 12 weeks. If you have completely quit smoking by 12 weeks, your healthcare provider may prescribe varenicline tablets for another 12 weeks to help you stay cigarette-free.", "Take varenicline tablets after eating and with a full glass (8 ounces) of water.", "This dosing schedule may not be right for everyone. Talk to your healthcare provider if you are having side effects such as nausea, strange dreams, or sleep problems. Your healthcare provider may want to reduce your dose.", "If you miss a dose of varenicline tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take your next dose at your regular time." ], "text": "" }

What should I avoid while taking varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking varenicline tablets?\n" }

{ "type": "ul", "children": [ "Use caution when driving or operating machinery until you know how varenicline tablets affect you. Varenicline tablets may make you feel sleepy, dizzy, or have trouble concentrating, making it hard to drive or perform other activities safely.", "Decrease the amount of alcoholic beverages that you drink during treatment with varenicline tablets until you know if varenicline tablets affect your ability to tolerate alcohol. Some people have experienced the following when drinking alcohol during treatment with varenicline tablets:\nincreased drunkenness (intoxication)\nunusual or sometimes aggressive behavior\nno memory of things that have happened\n\n" ], "text": "" }

What are the possible side effects of varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of varenicline tablets? \n" }

Serious side effects of varenicline tablets may include:

{ "type": "p", "children": [], "text": "\nSerious side effects of varenicline tablets may include:\n" }

{ "type": "ul", "children": [ "\nSee \"What is the most important information I should know about varenicline tablets?\"\n", "\nSeizures. Some people have had seizures during treatment with varenicline tablets. In most cases, the seizures have happened during the first month of treatment with varenicline tablets. If you have a seizure during treatment with varenicline tablets, stop taking varenicline tablets and contact your healthcare provider right away.", "\nNew or worse heart or blood vessel (cardiovascular) problems, mostly in people, who already have cardiovascular problems. Tell your healthcare provider if you have any changes in symptoms during treatment with varenicline tablets." ], "text": "" }

Get emergency medical help right away if you have any of the following symptoms of a heart attack, including:

{ "type": "p", "children": [], "text": "\nGet emergency medical help right away if you have any of the following symptoms of a heart attack, including:\n" }

{ "type": "ul", "children": [ "chest discomfort (uncomfortable pressure, squeezing, fullness or pain) that lasts more than a few minutes, or that goes away and comes back", "pain or discomfort in one or both arms, back, neck, jaw or stomach", "shortness of breath, sweating, nausea, vomiting, or feeling lightheaded associated with chest discomfort" ], "text": "" }

{ "type": "ul", "children": [ "\nSleepwalking can happen with varenicline tablets, and can sometimes lead to behavior that is harmful to you or other people, or to property. Stop taking varenicline tablets and tell your healthcare provider if you start sleepwalking.", "\nAllergic reactions can happen with varenicline tablets. Some of these allergic reactions can be life-threatening.", "\nSerious skin reactions, including rash, swelling, redness, and peeling of the skin. Some of these skin reactions can become life-threatening." ], "text": "" }

Stop taking varenicline tablets and get medical help right away if you have any of the following symptoms:

{ "type": "p", "children": [], "text": "\nStop taking varenicline tablets and get medical help right away if you have any of the following symptoms:\n" }

{ "type": "ul", "children": [ "swelling of the face, mouth (tongue, lips, and gums), throat or neck", "trouble breathing", "rash with peeling skin", "blisters in your mouth" ], "text": "" }

The most common side effects of varenicline tablets include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of varenicline tablets include:" }

{ "type": "ul", "children": [ "nausea", "sleep problems (trouble sleeping or vivid, unusual, or strange dreams)", "constipation", "gas", "vomiting" ], "text": "" }

Tell your healthcare provider about side effects that bother you or that do not go away.

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These are not all the side effects of varenicline tablets. Ask your healthcare provider or pharmacist for more information.

{ "type": "p", "children": [], "text": "These are not all the side effects of varenicline tablets. Ask your healthcare provider or pharmacist for more information." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561." }

How should I store varenicline tablets?

{ "type": "p", "children": [], "text": "\nHow should I store varenicline tablets?\n" }

{ "type": "ul", "children": [ "Store varenicline tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC)", "\nKeep varenicline tablets and all medicines out of the reach of children.\n" ], "text": "" }

General information about the safe and effective use of varenicline tablets

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Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use varenicline tablets for a condition for which it was not prescribed. Do not give your varenicline tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about varenicline tablets that is written for healthcare professionals.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use varenicline tablets for a condition for which it was not prescribed. Do not give your varenicline tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about varenicline tablets that is written for healthcare professionals." }

If you are motivated to quit smoking and did not succeed during prior varenicline tablets treatment for reasons other than side effects, or if you returned to smoking after treatment, speak with your healthcare provider about whether another course of varenicline tablets therapy may be right for you.

{ "type": "p", "children": [], "text": "If you are motivated to quit smoking and did not succeed during prior varenicline tablets treatment for reasons other than side effects, or if you returned to smoking after treatment, speak with your healthcare provider about whether another course of varenicline tablets therapy may be right for you." }

What are the ingredients in varenicline tablets?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in varenicline tablets? \n" }

Active ingredient: varenicline tartrate

{ "type": "p", "children": [], "text": "\nActive ingredient: varenicline tartrate" }

Inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, magnesium stearate, maltodextrin, talc and titanium dioxide. The 1 mg tablet also contains iron oxide yellow.

{ "type": "p", "children": [], "text": "\nInactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, magnesium stearate, maltodextrin, talc and titanium dioxide. The 1 mg tablet also contains iron oxide yellow." }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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Manufactured for:

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Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nLupin Pharmaceuticals, Inc.\n" }

Naples, FL 34108

{ "type": "p", "children": [], "text": "Naples, FL 34108 " }

United States.

{ "type": "p", "children": [], "text": "United States." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Lupin Limited

{ "type": "p", "children": [], "text": "\nLupin Limited\n" }

Pithampur (M.P.) 454 775

{ "type": "p", "children": [], "text": "Pithampur (M.P.) 454 775" }

India

{ "type": "p", "children": [], "text": "India" }

Revised: December 2024                                                            ID#: 277243 / 277244                                                                               

{ "type": "p", "children": [], "text": "\nRevised: December 2024                                                            ID#: 277243 / 277244                                                                               " }

Varenicline Tablets

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0.5 mg

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NDC 70748-127-49

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Bottle Label -0.5 mg - 56s Tablets

{ "type": "p", "children": [], "text": "Bottle Label -0.5 mg - 56s Tablets " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Varenicline Tablets

{ "type": "p", "children": [], "text": "\nVarenicline Tablets " }

1 mg

{ "type": "p", "children": [], "text": "1 mg" }

NDC 70748-128-49

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Bottle Label -1 mg - 56s Tablets

{ "type": "p", "children": [], "text": "Bottle Label -1 mg - 56s Tablets " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Varenicline Tablets

{ "type": "p", "children": [], "text": "\nVarenicline Tablets " }

NDC 70748-125-11

{ "type": "p", "children": [], "text": "NDC 70748-125-11" }

Starting 4-Week Pack-Wallet Label

{ "type": "p", "children": [], "text": "Starting 4-Week Pack-Wallet Label " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Varenicline Tablets

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NDC 70748-125-11

{ "type": "p", "children": [], "text": "NDC 70748-125-11" }

Starting 4-Week Pack-Pouch Label

{ "type": "p", "children": [], "text": "Starting 4-Week Pack-Pouch Label " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Varenicline Tablets

{ "type": "p", "children": [], "text": "\nVarenicline Tablets " }

NDC 70748-125-13

{ "type": "p", "children": [], "text": "NDC 70748-125-13" }

Starting Month Box-Carton (with Pouch) Label

{ "type": "p", "children": [], "text": "Starting Month Box-Carton (with Pouch) Label " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }