Анализ сайта chantix.com
Основное Готовность: 90%
Домен
chantix.com
Состояние доменного имени
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Проверяем корректность доменного имени и наличие технических проблем на уровне домена.
Домен второго уровня идеален для продвижения.
Отличный запоминающийся домен.
Ответ сервера
200 Успешный ответ
HTTP-код ответа и цепочка редиректов
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Код 200 — страница доступна. Коды 3xx — редиректы (цепочки замедляют загрузку и размывают ссылочный вес). Коды 4xx/5xx — ошибки, поисковик не сможет проиндексировать страницу.
Сервер настроен корректно.
Цепочка редиректов:
http://chantix.com
301 MovedPermanently
https://labeling.pfizer.com/ShowLabeling.aspx?id=557
200 OK
Безопасность
Сайт безопасен
Использование HTTPS и SSL-сертификат
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HTTPS — обязательный стандарт. Google и Яндекс отдают предпочтение защищённым сайтам. Отсутствие SSL или просроченный сертификат ведут к предупреждениям в браузере и снижению позиций.
Не настроен HSTS (Strict-Transport-Security) — рекомендуется включить.
На сайте работает защищенный протокол ssl и сайт открывается по https.
Ssl-сертификат действителен до 06.11.2026 17:30:07.
HTTP автоматически перенаправляется на HTTPS.
Поздравляем! Сайт не содержится в реестре РКН.
Кодировка
utf-8
Кодировка символов страницы
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Стандарт — UTF-8. Неправильная кодировка вызывает нечитаемые символы и мешает поисковику корректно распознать текст страницы.
Указана кодировка на странице utf-8.
Язык
Атрибут lang в HTML-теге
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Атрибут lang (<html lang="ru">) сообщает поисковикам и браузерам, на каком языке написана страница. Помогает при ранжировании в региональном поиске.
Язык страницы не указан. Рекомендуется явно указать язык документа!
Скорость загрузки
~1,39сек
Время отклика сервера (TTFB)
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Time To First Byte — время до получения первого байта от сервера. Норма до 200 мс. Медленный отклик ухудшает пользовательский опыт и ранжирование: Яндекс и Google учитывают скорость страниц.
Скорость загрузки сайта 1,39сек превышает 1 секунду. Желательно улучшить работу сайта!
Объем документа
207Кб
Размер HTML-кода страницы
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Слишком большой HTML замедляет парсинг браузером и сканирование поисковым роботом. Рекомендуется не более 200 Кб.
Объем html-документа 207Кб оптимален.
Структура html-документа корректна.
Ресурсы
Ресурсы: 2
Внешние ресурсы страницы (CSS, JS, изображения)
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Количество и тип подключённых ресурсов влияют на скорость загрузки. Большое число запросов увеличивает время рендеринга страницы.
В одном из файлов ресурсов встречается путь без https. Все подгружаемые файлы ресурсов должны открываться по защищенному протоколу ssl/https!
Кол-во файлов ресурсов 2 достаточно.
Показать полный список ресурсов
| Тип | Название | Значение |
|---|---|---|
| stylesheet | text/css | /spl.css |
| js | text/javascript | http://www.accessdata.fda.gov/spl/stylesheet/spl.js |
Серверные заголовки
Кол-во: 6
HTTP-заголовки ответа сервера
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Заголовки сервера передают браузеру и поисковику служебную информацию: кеширование, безопасность (CSP, HSTS), сжатие (gzip). Правильная настройка ускоряет загрузку и повышает защищённость.
Найдены серверные заголовки 6шт. Подробнее про серверные заголовки.
Показать полный список серверных заголовков
| Ключ | Значение |
|---|---|
| Cache-Control | private |
| X-AspNet-Version | 4.0.30319 |
| X-Frame-Options | DENY |
| traceresponse | 00-f59f631bf6500e2fea9c5d8c38d36f10-55cdf1e0a3e58359-01 |
| x-dt-tracestate | 10f479a3-4e8ccd0c@dt |
| Date | Tue, 25 Aug 2026 07:21:26 GMT |
CMS
Не определена
Система управления сайтом (движок)
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CMS — это движок, на котором работает сайт (WordPress, 1C-Bitrix, Tilda и др.). Знание CMS помогает понять возможности SEO-оптимизации и подобрать подходящие инструменты. «Не определена» — вероятно, самописный сайт или нестандартная сборка.
CMS не определена. Вероятно, сайт самописный либо движок надёжно скрыт. Это не ошибка.
Веб-сервер
Microsoft-IIS
Программное обеспечение сервера
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Веб-сервер — это ПО, которое отдаёт страницы посетителям (nginx, Apache, IIS, LiteSpeed и др.). Определяется по серверным заголовкам ответа (Server, X-Powered-By и т.п.). «Не определён» — сервер намеренно скрывает эти заголовки, это нормальная практика безопасности.
Сайт работает на веб-сервере Microsoft-IIS.
Мета-теги Готовность: 12%
Title
Заголовок страницы в браузере и поисковой выдаче
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Title — главный SEO-заголовок страницы. Влияет на CTR в поиске и ранжирование. Оптимальная длина: 50–70 символов. Ключевые слова — ближе к началу.
Пропишите тег title!
Description
Описание страницы в поисковой выдаче (сниппет)
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Meta Description — текст под заголовком в выдаче. Напрямую на позиции не влияет, но влияет на CTR. Оптимальная длина: 120–160 символов.
Установите мета-тег description!
Keywords
Список ключевых слов страницы (устаревший тег)
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Meta Keywords не учитывается Яндексом и Google для ранжирования с 2009–2012 годов. Заполнение не обязательно, но не вредит. Конкурент может использовать содержимое для анализа.
Установите мета-тег keywords!
Канонический Url
Указывает поисковику основную версию страницы
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Canonical (rel=canonical) предотвращает проблему дублей страниц. Должен точно совпадать с URL проверяемой страницы. Неправильный canonical может передать ссылочный вес на другую страницу.
Рекомендуем прописать канонический Url.
Robots
Ошибок нет
Директивы для поисковых роботов на уровне страницы
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Meta Robots управляет индексацией конкретной страницы: index/noindex — индексировать ли, follow/nofollow — следовать ли по ссылкам. Noindex полностью исключает страницу из поиска.
Meta-тег robots не указан. Страница свободна для индексации.
Адаптивность
Настройка масштабирования на мобильных устройствах
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Тег viewport (<meta name="viewport">) сообщает браузеру, как масштабировать страницу на мобильных. Стандарт: width=device-width, initial-scale=1. Отсутствие — признак отсутствия мобильной версии.
Meta-тег viewport не указан. Страница не адаптивная.
Разметка OpenGraph
Не найдено
Мета-теги для красивых превью в соцсетях
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OpenGraph (og:title, og:description, og:image) управляет тем, как страница выглядит при репосте в социальных сетях и мессенджерах. Отсутствие OG-тегов — невзрачный превью при шеринге.
Разметка OpenGraph не задана. Страница не оптимизирована под социальные сети. Мета-теги с разметкой Og помогают социальным роботам лучше структурировать Ваш сайт.
Все мета-теги
Кол-во: 4
Полный список мета-тегов страницы
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Таблица всех meta-тегов, включая нестандартные. Позволяет найти опечатки, дубли и лишние теги.
Найдены мета-теги 4шт. Мета-теги не видимы для человека и предназначены для обмена информацией между веб-страницей и поисковыми системами, браузерами и другими веб-службами. С ними роботы 🤖 и устройства ведут себя более ожидаемо.
Показать полный список мета-тегов
| Тип | Название | Значение |
|---|---|---|
| name | documentId | 166a0560-2999-4e1f-a6fd-826a767f0776 |
| name | documentSetId | f0ff4f27-5185-4881-a749-c6b7a0ca5696 |
| name | documentVersionNumber | 47 |
| name | documentEffectiveTime | 20250922 |
Оптимизация Готовность: 60%
Структура
Ошибок нет
Семантические HTML-элементы страницы
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Проверяет наличие основных структурных элементов: nav, header, footer, main. Корректная семантическая структура помогает поисковику понять архитектуру страницы.
Структура документа корректна (теги <html> и <body> присутствуют по одному на документ).
Контент
Есть ошибки
Объём и качество текстового содержимого
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Анализирует объём полезного текста на странице. Слишком мало — страница может считаться малополезной. Слишком много — ухудшается читаемость и восприятие.
Слова из title 0 встречаются в тексте редко. Добавьте в контент страницы слова из тега <title>!
Абзацев с текстом 815 достаточно.
Среднее число слов в абзаце 16 достаточно.
Кол-во знаков контента 104549 на странице оптимально.
Кол-во слов 16052 на странице оптимально.
Заголовки
Ошибок нет
Иерархия заголовков H1–H6
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H1 должен быть один и содержать ключевой запрос. H2–H6 описывают подразделы. Пропуск уровней (H1 → H3) и несколько H1 — типичные ошибки, снижающие понятность страницы для поисковика.
На странице присутствуют заголовки <h1> 42. Это прекрасно.
На странице присутствуют заголовки <h2> 70. Это хорошо.
Тошнота
17,26
Насколько одно слово доминирует в тексте
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Классическая тошнота = √(частота самого повторяющегося слова). Норма до 7–8: текст воспринимается естественно. Выше — поисковик может счесть страницу переспамленной.
Тошнота превышает норму 5. Измените текст страницы!
Академич. тошнота
28,41%
Насколько текст перенасыщен ключевыми словами
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Академическая тошнота = (частота слова / общее количество слов) × 100%. Показывает долю конкретного слова в тексте. Норма 5–15%.
Академическая тошнота превышает норму 5-15%. Измените текст страницы!
Семантическое ядро
20
Наиболее часто встречающиеся слова на странице
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Топ слов по частоте использования. Показывает, какие слова доминируют в тексте с точки зрения поисковика.
Контент страницы содержит осмысленный текст и слова.
Показать список слов
| Слово | Кол-во | Частота |
|---|---|---|
| chantix | 298 | 1,86% |
| patients | 241 | 1,50% |
| treatment | 110 | 0,69% |
| varenicline | 107 | 0,67% |
| placebo | 101 | 0,63% |
| smoking | 100 | 0,62% |
| events | 91 | 0,57% |
| adverse | 82 | 0,51% |
| subjects | 61 | 0,38% |
| treated | 61 | 0,38% |
| during | 57 | 0,36% |
| studies | 55 | 0,34% |
| through | 52 | 0,32% |
| reactions | 48 | 0,30% |
| compared | 47 | 0,29% |
| clinical | 45 | 0,28% |
| healthcare | 42 | 0,26% |
| should | 39 | 0,24% |
| cardiovascular | 39 | 0,24% |
| psychiatric | 37 | 0,23% |
Индексация Готовность: 80%
Индексирование
Ошибок нет
Разрешено ли индексирование страницы
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Проверяет, не закрыта ли страница от индексации через robots.txt, meta robots или X-Robots-Tag. Страница, закрытая от индексации, не появится в поисковой выдаче.
Анкоров на странице 198 оптимально. Поисковые роботы обязательно проиндексируют сайт.
Robots.txt
Найден корректный robots.txt
Файл управления сканированием сайта роботами
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Robots.txt указывает поисковым роботам, какие страницы сканировать, а какие — нет. Ошибки в файле могут случайно закрыть важные разделы от индексации.
Robots.txt настроен корректно. Размер файла: 212904 байт. Загружен за: 1сек.
Проверяемая страница не запрещена в robots.txt.
Robots.txt доступен по постоянному адресу
Цепочка редиректов для файла robots.txt:
http://chantix.com/robots.txt
301 MovedPermanently
https://labeling.pfizer.com/ShowLabeling.aspx?id=557
200 OK
Показать содержимое robots.txt
<!DOCTYPE html PUBLIC "-"><html><head><META http-equiv="Content-Type" content="text/html; charset=UTF-8"><meta content="166a0560-2999-4e1f-a6fd-826a767f0776" name="documentId"><meta content="f0ff4f27-5185-4881-a749-c6b7a0ca5696" name="documentSetId"><meta content="47" name="documentVersionNumber"><meta content="20250922" name="documentEffectiveTime"><link href="/spl.css" type="text/css" rel="stylesheet"><script charset="utf-8" type="text/javascript" src="http://www.accessdata.fda.gov/spl/stylesheet/spl.js">/* */</script></head><body id="spl" class="spl" onload="if(typeof convertToTwoColumns == "function")convertToTwoColumns();"><div class="DocumentTitle"><p class="DocumentTitle"><strong>CHANTIX- varenicline tartrate tablet, film coated </strong><br><strong>CHANTIX- varenicline tartrate </strong><br>Pfizer Laboratories Div Pfizer Inc<br></p><p>----------</p></div><div class="Highlights" id="Highlights"><table style="table-layout:fixed" width="100%" cellpadding="5" cellspacing="5"><tr><td valign="top" align="left" width="50%"><div></div></td><td valign="top" align="left" width="50%"><div><h1>HIGHLIGHTS OF PRESCRIBING INFORMATION</h1><div class="HighlightsDisclaimer">These highlights do not include all the information needed to use CHANTIX safely and effectively. See full prescribing information for CHANTIX. <br><br>CHANTIX<span class="Sup">®</span> (varenicline) tablets, for oral use <br>Initial U.S. Approval: 2006</div><div></div><div class="HighlightSection"><h1 class="Highlights"><span>INDICATIONS AND USAGE</span></h1><div><p class="Highlighta">CHANTIX is a nicotinic receptor partial agonist indicated for use as an aid to smoking-cessation treatment. (<a href="#S1">1</a> and <a href="#S2.1">2.1</a>) </p></div></div><div class="HighlightSection"><h1 class="Highlights"><span>DOSAGE AND ADMINISTRATION</span></h1><div><dl><dt>•</dt><dd>Begin CHANTIX dosing one week before the date set by the patient to stop smoking. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Starting Week: 0.5 mg once daily on days 1–3 and 0.5 mg twice daily on days 4–7. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>An additional 12 weeks of treatment is recommended for successful quitters to increase likelihood of long-term abstinence. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Consider a gradual approach to quitting smoking with CHANTIX for patients who are sure that they are not able or willing to quit abruptly. 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 treatment for an additional 12 weeks, for a total of 24 weeks. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Severe Renal Impairment (estimated creatinine clearance less than 30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum of 0.5 mg daily may be given if tolerated. (<a href="#S2.2">2.2</a>)</dd><dt>•</dt><dd>Consider dose reduction for patients who cannot tolerate adverse effects. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Another attempt at treatment is recommended for those who fail to stop smoking or relapse when factors contributing to the failed attempt have been addressed. (<a href="#S2.1">2.1</a>)</dd><dt>•</dt><dd>Provide patients with appropriate educational materials and counseling to support the quit attempt. (<a href="#S2.1">2.1</a>)</dd></dl></div><div></div><div><div></div><div></div></div></div><div class="HighlightSection"><h1 class="Highlights"><span>DOSAGE FORMS AND STRENGTHS</span></h1><div><p class="Highlighta">Tablets: 0.5 mg and 1 mg (<a href="#S3">3</a>) </p></div></div><div class="HighlightSection"><h1 class="Highlights"><span>CONTRAINDICATIONS</span></h1><div><p class="Highlighta">History of serious hypersensitivity or skin reactions to CHANTIX. (<a href="#S4">4</a>) </p></div></div><div class="HighlightSection"><h1 class="Highlights"><span>WARNINGS AND PRECAUTIONS</span></h1><div><dl><dt>•</dt><dd><span class="Underline">Neuropsychiatric Adverse Events:</span> Postmarketing reports of serious or clinically significant neuropsychiatric adverse events 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. Observe patients attempting to quit smoking with CHANTIX for the occurrence of such symptoms and instruct them to discontinue CHANTIX and contact a healthcare provider if they experience such adverse events. (<a href="#S5.1">5.1</a>)</dd><dt>•</dt><dd><span class="Underline">Seizures</span>: New or worsening seizures have been observed in patients taking CHANTIX. CHANTIX should be used cautiously in patients with a history of seizures or other factors that can lower the seizure threshold. (<a href="#S5.2">5.2</a>)</dd><dt>•</dt><dd><span class="Underline">Interaction with Alcohol</span>: Increased effects of alcohol have been reported. Instruct patients to reduce the amount of alcohol they consume until they know whether CHANTIX affects them. (<a href="#S5.3">5.3</a>)</dd><dt>•</dt><dd><span class="Underline">Accidental Injury</span>: Accidental injuries (e.g., traffic accidents) have been reported. Instruct patients to use caution driving or operating machinery until they know how CHANTIX may affect them. (<a href="#S5.4">5.4</a>)</dd><dt>•</dt><dd><span class="Underline">Cardiovascular Events</span>: Patients with underlying cardiovascular (CV) disease may be at increased risk of CV events; however, these concerns must be balanced with the health benefits of smoking cessation. 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 myocardial infarction (MI) or stroke. (<a href="#S5.5">5.5</a> and <a href="#S6.1">6.1</a>)</dd><dt>•</dt><dd><span class="Underline">Somnambulism</span>: 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. (<a href="#S5.6">5.6</a> and <a href="#S6.2">6.2</a>)</dd><dt>•</dt><dd><span class="Underline">Angioedema and Hypersensitivity Reactions</span>: Such reactions, including angioedema, infrequently life-threatening, have been reported. Instruct patients to discontinue CHANTIX and immediately seek medical care if symptoms occur. (<a href="#S5.7">5.7</a> and <a href="#S6.2">6.2</a>)</dd><dt>•</dt><dd><span class="Underline">Serious Skin Reactions</span>: Rare, potentially life-threatening skin reactions have been reported. Instruct patients to discontinue CHANTIX and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions. (<a href="#S5.8">5.8</a> and <a href="#S6.2">6.2</a>)</dd><dt>•</dt><dd><span class="Underline">Nausea</span>: Nausea is the most common adverse reaction (up to 30% incidence rate). Dose reduction may be helpful. (<a href="#S5.9">5.9</a>)</dd></dl></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div></div><div class="HighlightSection"><h1 class="Highlights"><span>ADVERSE REACTIONS</span></h1><div><p class="Highlighta">Most common adverse reactions (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting. (<a href="#S6">6</a>)<br><br> </p><p class="Highlighta"><span class="Bold">To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or <a href="http://www.fda.gov/medwatch">www.fda.gov/medwatch</a>.</span> </p></div><div></div><div></div></div><div class="HighlightSection"><h1 class="Highlights"><span>DRUG INTERACTIONS</span></h1><div><dl><dt>•</dt><dd><span class="Underline">Other Smoking-Cessation Therapies:</span> Safety and efficacy in combination with other smoking-cessation therapies has not been established. Coadministration of varenicline and transdermal nicotine resulted in a high rate of discontinuation due to adverse events. (<a href="#S7.1">7.1</a>)</dd><dt>•</dt><dd><span class="Underline">Effect of Smoking Cessation on Other Drugs:</span> Pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) may be altered, necessitating dose adjustment. (<a href="#S7.2">7.2</a>)</dd></dl></div><div><div></div><div></div></div><div></div></div><div><div><div></div><div><div></div></div><div><div></div><div></div></div></div><div><div></div><div></div><div></div></div><div></div><div></div></div><div><div></div><div><div></div><div></div></div></div><div></div><div></div><div><div></div><div><div><div></div></div><div></div><div><div></div><div></div></div><div><div></div><div></div><div></div><div></div></div><div><div></div><div></div><div></div><div></div><div><div></div><div></div></div></div></div></div><div><div><div></div><div></div><div></div></div></div><div><div><div></div><div></div><div></div><div></div></div><div></div><div><div></div></div><div></div><div></div><div></div><div></div><div></div><div></div><div><div></div></div></div><div><div></div></div><div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div><div></div></div><div></div><div></div><div></div><div></div><div></div><div></div><p class="HighlightsSeeReference">See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.</p><p class="HighlightsRevision">Revised: 6/2025</p></div></td></tr></table></div><div class="Index" id="Index"><table style="table-layout:fixed" width="100%" cellpadding="5" cellspacing="5"><tr><td valign="top" align="left" width="50%"><div></div></td><td valign="top" align="left" width="50%"><div><h1 class="Colspan">FULL PRESCRIBING INFORMATION: CONTENTS<a name="footnote-reference-content" href="#footnote-content">*</a></h1><h1><a href="#section-1" class="toc">1 INDICATIONS AND USAGE</a></h1><h1><a href="#section-2" class="toc">2 DOSAGE AND ADMINISTRATION</a></h1><h2><a href="#section-2.1" class="toc">2.1 Recommended Dosage for Adults</a></h2><h2><a href="#section-2.2" class="toc">2.2 Dosage in Special Populations</a></h2><h1><a href="#section-3" class="toc">3 DOSAGE FORMS AND STRENGTHS</a></h1><h1><a href="#section-4" class="toc">4 CONTRAINDICATIONS</a></h1><h1><a href="#section-5" class="toc">5 WARNINGS AND PRECAUTIONS</a></h1><h2><a href="#section-5.1" class="toc">5.1 Neuropsychiatric Adverse Events including Suicidality</a></h2><h2><a href="#section-5.2" class="toc">5.2 Seizures</a></h2><h2><a href="#section-5.3" class="toc">5.3 Interaction with Alcohol</a></h2><h2><a href="#section-5.4" class="toc">5.4 Accidental Injury</a></h2><h2><a href="#section-5.5" class="toc">5.5 Cardiovascular Events</a></h2><h2><a href="#section-5.6" class="toc">5.6 Somnambulism</a></h2><h2><a href="#section-5.7" class="toc">5.7 Angioedema and Hypersensitivity Reactions</a></h2><h2><a href="#section-5.8" class="toc">5.8 Serious Skin Reactions</a></h2><h2><a href="#section-5.9" class="toc">5.9 Nausea</a></h2><h1><a href="#section-6" class="toc">6 ADVERSE REACTIONS</a></h1><h2><a href="#section-6.1" class="toc">6.1 Clinical Trials Experience</a></h2><h2><a href="#section-6.2" class="toc">6.2 Postmarketing Experience</a></h2><h1><a href="#section-7" class="toc">7 DRUG INTERACTIONS</a></h1><h2><a href="#section-7.1" class="toc">7.1 Use with Other Drugs for Smoking Cessation</a></h2><h2><a href="#section-7.2" class="toc">7.2 Effect of Smoking Cessation on Other Drugs</a></h2><h1><a href="#section-8" class="toc">8 USE IN SPECIFIC POPULATIONS</a></h1><h2><a href="#section-8.1" class="toc">8.1 Pregnancy</a></h2><h2><a href="#section-8.2" class="toc">8.2 Lactation</a></h2><h2><a href="#section-8.3" class="toc">8.4 Pediatric Use</a></h2><h2><a href="#section-8.4" class="toc">8.5 Geriatric Use</a></h2><h2><a href="#section-8.5" class="toc">8.6 Renal Impairment</a></h2><h1><a href="#section-9" class="toc">9 DRUG ABUSE AND DEPENDENCE</a></h1><h2><a href="#section-9.1" class="toc">9.1 Controlled Substance</a></h2><h2><a href="#section-9.2" class="toc">9.3 Dependence</a></h2><h1><a href="#section-10" class="toc">10 OVERDOSAGE</a></h1><h1><a href="#section-11" class="toc">11 DESCRIPTION</a></h1><h1><a href="#section-12" class="toc">12 CLINICAL PHARMACOLOGY</a></h1><h2><a href="#section-12.1" class="toc">12.1 Mechanism of Action</a></h2><h2><a href="#section-12.2" class="toc">12.3 Pharmacokinetics</a></h2><h1><a href="#section-13" class="toc">13 NONCLINICAL TOXICOLOGY</a></h1><h2><a href="#section-13.1" class="toc">13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility</a></h2><h1><a href="#section-14" class="toc">14 CLINICAL STUDIES</a></h1><h2><a href="#section-14.1" class="toc">14.1 Initiation of Abstinence</a></h2><h2><a href="#section-14.2" class="toc">14.2 Urge to Smoke</a></h2><h2><a href="#section-14.3" class="toc">14.3 Long-Term Abstinence</a></h2><h2><a href="#section-14.4" class="toc">14.4 Alternative Instructions for Setting a Quit Date</a></h2><h2><a href="#section-14.5" class="toc">14.5 Gradual Approach to Quitting Smoking</a></h2><h2><a href="#section-14.6" class="toc">14.6 Re-Treatment Study</a></h2><h2><a href="#section-14.7" class="toc">14.7 Subjects with Chronic Obstructive Pulmonary Disease</a></h2><h2><a href="#section-14.8" class="toc">14.8 Subjects with Cardiovascular Disease and Other Cardiovascular Analyses</a></h2><h2><a href="#section-14.9" class="toc">14.9 Subjects with Major Depressive Disorder</a></h2><h2><a href="#section-14.10" class="toc">14.10 Postmarketing Neuropsychiatric Safety Outcome Trial</a></h2><h1><a href="#section-15" class="toc">16 HOW SUPPLIED/STORAGE AND HANDLING</a></h1><h1><a href="#section-16" class="toc">17 PATIENT COUNSELING INFORMATION</a></h1><dl class="Footnote"><dt><a name="footnote-content" href="#footnote-reference-content">*</a></dt><dd>Sections or subsections omitted from the full prescribing information are not listed.</dd></dl></div></td></tr></table></div><div class="Contents"><h1>FULL PRESCRIBING INFORMATION</h1><div class="Section" data-sectionCode="48780-1"><a name="section-1"></a><p></p></div><div class="Section" data-sectionCode="34067-9"><a name="S1"></a><a name="section-1"></a><p></p><h1>1 INDICATIONS AND USAGE</h1><p class="First">CHANTIX is indicated for use as an aid to smoking-cessation treatment.</p></div><div class="Section" data-sectionCode="34068-7"><a name="S2"></a><a name="section-2"></a><p></p><h1>2 DOSAGE AND ADMINISTRATION</h1><div class="Section" data-sectionCode="42229-5"><a name="S2.1"></a><a name="section-2.1"></a><p></p><h2>2.1 Recommended Dosage for Adults</h2><p class="First">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.</p><p>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.</p><p>CHANTIX should be taken orally after eating and with a full glass of water.</p><p>The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:</p><table width="50%"><col width="30%"><col width="28%"><tbody class="Headless"><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="middle"><p class="First">Days 1 – 3:</p></td><td class="Botrule Rrule Toprule" valign="middle"><p class="First">0.5 mg once daily</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="middle"><p class="First">Days 4 – 7:</p></td><td class="Botrule Rrule" valign="middle"><p class="First">0.5 mg twice daily</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="middle"><p class="First">Day 8 – end of treatment:</p></td><td class="Botrule Rrule" valign="middle"><p class="First">1 mg twice daily</p></td></tr></tbody></table><p>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.</p><p>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<span class="Italics"> [see <a href="#S14.5">Clinical Studies (14.5)</a>].</span></p><p>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.</p><p>Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S2.2"></a><a name="section-2.2"></a><p></p><h2>2.2 Dosage in Special Populations</h2><div class="Section" data-sectionCode="42229-5"><a name="ID_b19b68c9-8464-428e-a929-ce6dfebc5691"></a><a name="section-2.2.1"></a><p></p><p class="First"><span class="Underline">Patients with Impaired Renal Function</span></p><p>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 <span class="Italics">[see <a href="#S8.6">Use in Specific Populations (8.6)</a>, <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_4c598654-bdd6-4c3d-88bb-8dd34e1a7ec6"></a><a name="section-2.2.2"></a><p></p><p class="First"><span class="Underline">Elderly and Patients with Impaired Hepatic Function</span></p><p>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 <span class="Italics">[see <a href="#S8.5">Use in Specific Populations (8.5)</a>]</span>.</p></div></div></div><div class="Section" data-sectionCode="43678-2"><a name="S3"></a><a name="section-3"></a><p></p><h1>3 DOSAGE FORMS AND STRENGTHS</h1><p class="First">Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "<span class="Italics">Pfizer</span>" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "<span class="Italics">Pfizer</span>" on one side and "CHX 1.0" on the other side).</p></div><div class="Section" data-sectionCode="34070-3"><a name="S4"></a><a name="section-4"></a><p></p><h1>4 CONTRAINDICATIONS</h1><p class="First">CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.</p></div><div class="Section" data-sectionCode="43685-7"><a name="S5"></a><a name="section-5"></a><p></p><h1>5 WARNINGS AND PRECAUTIONS</h1><div class="Section" data-sectionCode="42229-5"><a name="S5.1"></a><a name="section-5.1"></a><p></p><h2>5.1 Neuropsychiatric Adverse Events including Suicidality</h2><p class="First">Serious neuropsychiatric adverse events have been reported in patients being treated with CHANTIX<span class="Italics"> [see <a href="#S6.2">Adverse Reactions (6.2)</a>]</span>. 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.</p><p>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 <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3)</a>, <a href="#S6.2">Adverse Reactions (6.2)</a>].</span> 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.</p><p>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 <span class="Italics">[see <a href="#S14.10">Clinical Studies (14.10)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.2"></a><a name="section-5.2"></a><p></p><h2>5.2 Seizures</h2><p class="First">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 <span class="Italics">[see <a href="#S6.2">Adverse Reactions (6.2)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.3"></a><a name="section-5.3"></a><p></p><h2>5.3 Interaction with Alcohol</h2><p class="First">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 <span class="Italics">[see <a href="#S6.2">Adverse Reactions (6.2)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.4"></a><a name="section-5.4"></a><p></p><h2>5.4 Accidental Injury</h2><p class="First">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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.5"></a><a name="section-5.5"></a><p></p><h2>5.5 Cardiovascular Events</h2><p class="First">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 <span class="Italics">[see <a href="#S14.8">Clinical Studies (14.8)</a>]</span>. 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<span class="Italics"> [see <a href="#S14.10">Clinical Studies (14.10)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.6"></a><a name="section-5.6"></a><p></p><h2>5.6 Somnambulism</h2><p class="First">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 <span class="Italics">[see <a href="#S6.2">Adverse Reactions (6.2)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.7"></a><a name="section-5.7"></a><p></p><h2>5.7 Angioedema and Hypersensitivity Reactions</h2><p class="First">There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX <span class="Italics">[see <a href="#S6.2">Adverse Reactions (6.2)</a>, <a href="#S17">Patient Counseling Information (17)</a>]</span>. 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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.8"></a><a name="section-5.8"></a><p></p><h2>5.8 Serious Skin Reactions</h2><p class="First">There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX <span class="Italics">[see <a href="#S6.2">Adverse Reactions (6.2)</a>].</span> 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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S5.9"></a><a name="section-5.9"></a><p></p><h2>5.9 Nausea</h2><p class="First">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.</p></div></div><div class="Section" data-sectionCode="34084-4"><a name="S6"></a><a name="section-6"></a><p></p><h1>6 ADVERSE REACTIONS</h1><p class="First">The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:</p><dl><dt>•</dt><dd>Neuropsychiatric Adverse Events including Suicidality <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>]</span></dd><dt>•</dt><dd>Seizures <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2)</a>]</span></dd><dt>•</dt><dd>Interaction with Alcohol <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3)</a>]</span></dd><dt>•</dt><dd>Accidental Injury <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>]</span></dd><dt>•</dt><dd>Cardiovascular Events <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>]</span></dd><dt>•</dt><dd>Somnambulism <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6)</a>]</span></dd><dt>•</dt><dd>Angioedema and Hypersensitivity Reactions <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>]</span></dd><dt>•</dt><dd>Serious Skin Reactions <span class="Italics">[see <a href="#S5.8">Warnings and Precautions (5.8)</a>]</span></dd></dl><p>In the placebo-controlled premarketing studies, the most common adverse events associated with CHANTIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.</p><p>The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of three months' treatment. In this group, the discontinuation rates that are higher than placebo for the most common adverse events in CHANTIX-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).</p><p>Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness.</p><div class="Section" data-sectionCode="90374-0"><a name="S6.1"></a><a name="section-6.1"></a><p></p><h2>6.1 Clinical Trials Experience</h2><p class="First">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.</p><p>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.</p><p>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 <span class="Italics">[see <a href="#S5.9">Warnings and Precautions (5.9)</a>]</span>.</p><p>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).</p><p>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.</p><a name="_RefID0ENUAG"></a><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 width="33%"><col width="18%"><col width="18%"><col width="17%"><thead><tr class="First"><th class="Lrule Rrule Toprule" align="left" valign="top"><span class="Bold">SYSTEM ORGAN CLASS</span><br><span class="Bold">High Level Group Term</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">0.5 mg BID</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"><span class="Bold">Preferred Term</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=129</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=821</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=805</span></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="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">GASTROINTESTINAL (GI)</p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> GI Signs and Symptoms</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Nausea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">16</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">30</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Abdominal Pain <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Flatulence</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Dyspepsia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Vomiting</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> GI Motility/Defecation Conditions</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Constipation</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Gastroesophageal reflux disease</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Salivary Gland Conditions</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Dry mouth</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">PSYCHIATRIC DISORDERS</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Sleep Disorder/Disturbances</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Insomnia <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">19</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">18</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">13</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Abnormal dreams</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">13</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Sleep disorder</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nightmare</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">NERVOUS SYSTEM</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Headaches</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Headache</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">19</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">15</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">13</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Neurological Disorders NEC</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Dysgeusia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Somnolence</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Lethargy</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">GENERAL DISORDERS</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> General Disorders NEC</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Fatigue/Malaise/Asthenia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">RESPIR/THORACIC/MEDIAST</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Respiratory Disorders NEC</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Rhinorrhea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Dyspnea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Upper Respiratory Tract Disorder</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">SKIN/SUBCUTANEOUS TISSUE</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Epidermal and Dermal Conditions</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Rash</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Pruritis</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">METABOLISM and NUTRITION</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Appetite/General Nutrition Disorders</p></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 class="Botrule Lrule Rrule" valign="top"><p class="First"> Increased appetite</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Decreased appetite/Anorexia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1</p></td></tr></tbody></table><p>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).</p><p>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.</p><p><span class="Underline">Blood and Lymphatic System Disorders</span>. <span class="Italics">Infrequent: </span>anemia, lymphadenopathy. <span class="Italics">Rare: </span>leukocytosis, splenomegaly, thrombocytopenia.</p><p><span class="Underline">Cardiac Disorders</span>. <span class="Italics">Infrequent: </span>angina pectoris, myocardial infarction, palpitations, tachycardia. <span class="Italics">Rare:</span> acute coronary syndrome, arrhythmia, atrial fibrillation, bradycardia, cardiac flutter, cor pulmonale, coronary artery disease, ventricular extrasystoles.</p><p><span class="Underline">Ear and Labyrinth Disorders</span>. <span class="Italics">Infrequent: </span>tinnitus, vertigo. <span class="Italics">Rare: </span>deafness, Meniere's disease.</p><p><span class="Underline">Endocrine Disorders</span>. <span class="Italics">Infrequent: </span>thyroid gland disorders.</p><p><span class="Underline">Eye Disorders</span>. <span class="Italics">Infrequent: </span>conjunctivitis, eye irritation, eye pain, vision blurred, visual impairment. <span class="Italics">Rare: </span>blindness transient, cataract subcapsular, dry eye, night blindness, ocular vascular disorder, photophobia, vitreous floaters.</p><p><span class="Underline">Gastrointestinal Disorders</span>. <span class="Italics">Frequent: </span>diarrhea, toothache<span class="Italics">. Infrequent: </span>dysphagia, eructation, gastritis, gastrointestinal hemorrhage, mouth ulceration. <span class="Italics">Rare: </span>enterocolitis, esophagitis, gastric ulcer, intestinal obstruction, pancreatitis acute.</p><p><span class="Underline">General Disorders and Administration Site Conditions</span>. <span class="Italics">Frequent: </span>chest pain. <span class="Italics">Infrequent:</span> chest discomfort, chills, edema, influenza-like illness, pyrexia.</p><p><span class="Underline">Hepatobiliary Disorders</span>. <span class="Italics">Rare: </span>gall bladder disorder.</p><p><span class="Underline">Investigations</span>. <span class="Italics">Frequent:</span> liver function test abnormal, weight increased. <span class="Italics">Infrequent:</span> electrocardiogram abnormal. <span class="Italics">Rare:</span> muscle enzyme increased, urine analysis abnormal.</p><p><span class="Underline">Metabolism and Nutrition Disorders</span>. <span class="Italics">Infrequent: </span>diabetes mellitus, hypoglycemia. <span class="Italics">Rare: </span>hyperlipidemia, hypokalemia.</p><p><span class="Underline">Musculoskeletal and Connective Tissue Disorders</span>. <span class="Italics">Frequent</span>: arthralgia, back pain, myalgia. <span class="Italics">Infrequent: </span>arthritis, muscle cramp, musculoskeletal pain. <span class="Italics">Rare: </span>myositis, osteoporosis.</p><p><span class="Underline">Nervous System Disorders</span>. <span class="Italics">Frequent:</span> disturbance in attention, dizziness. <span class="Italics">Infrequent: </span>amnesia, convulsion, migraine, parosmia, syncope, tremor. <span class="Italics">Rare: </span>balance disorder, cerebrovascular accident, dysarthria, mental impairment, multiple sclerosis, VII<span class="Sup">th</span> nerve paralysis, nystagmus, psychomotor hyperactivity, psychomotor skills impaired, restless legs syndrome, sensory disturbance, transient ischemic attack, visual field defect.</p><p><span class="Underline">Psychiatric Disorders</span>. <span class="Italics">Infrequent:</span> dissociation, libido decreased, mood swings, thinking abnormal. <span class="Italics">Rare: </span>bradyphrenia, disorientation, euphoric mood.</p><p><span class="Underline">Renal and Urinary Disorders</span>. <span class="Italics">Infrequent:</span> nocturia, pollakiuria, urine abnormality. <span class="Italics">Rare:</span> nephrolithiasis, polyuria, renal failure acute, urethral syndrome, urinary retention.</p><p><span class="Underline">Reproductive System and Breast Disorders</span>. <span class="Italics">Frequent: </span>menstrual disorder. <span class="Italics">Infrequent: </span>erectile dysfunction. <span class="Italics">Rare:</span> sexual dysfunction.</p><p><span class="Underline">Respiratory, Thoracic and Mediastinal Disorders. </span><span class="Italics">Frequent:</span> respiratory disorders. <span class="Italics">Infrequent: </span>asthma, epistaxis, rhinitis allergic, upper respiratory tract inflammation. <span class="Italics">Rare: </span>pleurisy, pulmonary embolism.</p><p><span class="Underline">Skin and Subcutaneous Tissue Disorders</span>. <span class="Italics">Infrequent: </span>acne, dry skin, eczema, erythema, hyperhidrosis, urticaria. <span class="Italics">Rare: </span>photosensitivity reaction, psoriasis.</p><p><span class="Underline">Vascular Disorders</span>. <span class="Italics">Infrequent:</span> hot flush. <span class="Italics">Rare:</span> thrombosis.</p><p>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").</p><p>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%).</p><p>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.</p><a name="_RefID0EAJBG"></a><table width="75%"><caption><span>Table 2. Cardiovascular Mortality and Nonfatal Cardiovascular Events (%) with a Frequency >1% in Either Treatment Group in the Trial of Patients with Stable Cardiovascular Disease</span></caption><col width="47%"><col width="20%"><col width="19%"><thead><tr class="First"><th class="Lrule Rrule Toprule" align="left" valign="top"></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=353</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=350</span></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="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First"><span class="Bold">Adverse Events ≥1% in either treatment group</span></p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics">Up to 30 days after treatment</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Angina pectoris</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3.7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.0</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Chest pain</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Peripheral edema</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.1</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Hypertension</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Palpitations</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.6</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.1</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"><span class="Bold">Adjudicated Cardiovascular Mortality (up to 52 weeks)</span></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"><span class="Bold">Adjudicated Nonfatal Serious Cardiovascular Events ≥1% in either treatment group</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics">Up to 30 days after treatment</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nonfatal MI</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.1</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Hospitalization for angina pectoris</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.6</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.1</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics">Beyond 30 days after treatment and up to 52 weeks</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Need for coronary revascularization<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2.0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Hospitalization for angina pectoris</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.1</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.6</p></td></tr></tbody></table><p>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.</p><a name="_RefID0ETOBG"></a><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 width="47%"><col width="20%"><col width="19%"><thead><tr class="First"><th class="Lrule Rrule Toprule" align="left" valign="top"></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=84</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=43</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First"><span class="Bold">Adverse Events ≥10% in the varenicline group</span></p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nausea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">24</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">14</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Headache</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">19</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Vomiting</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"><span class="Bold">Psychiatric Adverse Events ≥5% and at a higher rate than in the placebo group</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Insomnia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr></tbody></table><p>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%).</p><a name="_RefID0EJRBG"></a><table width="75%"><caption><span>Table 4. Common Treatment Emergent AEs (%) in the Trial of Patients with Major Depressive Disorder</span></caption><col width="47%"><col width="20%"><col width="19%"><thead><tr class="First"><th class="Lrule Rrule Toprule" align="left" valign="top"></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=256</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">N=269</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First"><span class="Bold">Adverse Events ≥10% in either treatment group</span></p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nausea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">27</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Headache</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">17</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Abnormal dreams</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Insomnia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Irritability</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"><span class="Bold">Psychiatric Adverse Events ≥2% in any treatment group and not included above</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Depressed mood disorders and disturbances</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Anxiety</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Agitation</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Tension</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Hostility</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.4</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Restlessness</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr></tbody></table><p>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.</p><a name="_RefID0EXVBG"></a><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 width="47%"><col width="20%"><col width="19%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First"><span class="Bold">Adverse Events ≥10% in the varenicline group</span></p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Bold">Entire study population,</span> N</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1982</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1979</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nausea</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">25</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Headache</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">12</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"><span class="Bold">Psychiatric Adverse Events ≥2% in any treatment group</span></p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Bold">Non-psychiatric cohort, N</span></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">975</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">982</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Abnormal dreams</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Agitation</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Anxiety</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Depressed mood</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Insomnia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Irritability</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Sleep disorder</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Bold">Psychiatric cohort, N</span></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1007</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">997</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Abnormal dreams</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">12</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Agitation</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Anxiety</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Depressed mood</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Depression</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Insomnia</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Irritability</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">7</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nervousness</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Sleep disorder</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2</p></td></tr></tbody></table><p>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.</p></div><div class="Section" data-sectionCode="90375-7"><a name="S6.2"></a><a name="section-6.2"></a><p></p><h2>6.2 Postmarketing Experience</h2><p class="First">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.</p><p>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 <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>]</span>.</p><p>There have been postmarketing reports of new or worsening seizures in patients treated with CHANTIX <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2)</a>].</span></p><p>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 <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a> and <a href="#S5.3">(5.3)</a>]</span>.</p><p>There have been reports of hypersensitivity reactions, including angioedema <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>]</span>.</p><p>There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking CHANTIX <span class="Italics">[see <a href="#S5.8">Warnings and Precautions (5.8)</a>]</span>.</p><p>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 <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>]</span>.</p><p>There have been reports of hyperglycemia in patients following initiation of CHANTIX.</p><p>There have been reports of somnambulism, some resulting in harmful behavior to self, others, or property in patients treated with CHANTIX <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6)</a>]</span>.</p></div></div><div class="Section" data-sectionCode="34073-7"><a name="S7"></a><a name="section-7"></a><p></p><h1>7 DRUG INTERACTIONS</h1><p class="First">Based on varenicline characteristics and clinical experience to date, CHANTIX has no clinically meaningful pharmacokinetic drug interactions <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></p><div class="Section" data-sectionCode="42229-5"><a name="S7.1"></a><a name="section-7.1"></a><p></p><h2>7.1 Use with Other Drugs for Smoking Cessation</h2><p class="First">Safety and efficacy of CHANTIX in combination with other smoking cessation therapies have not been studied.</p><div class="Section" data-sectionCode="42229-5"><a name="ID_8d7fa8c5-4584-48ae-858f-caaebcae14f4"></a><a name="section-7.1.1"></a><p></p><p class="First"><span class="Underline">Bupropion</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_c5503f99-3886-46f8-918b-b3d85593e6c2"></a><a name="section-7.1.2"></a><p></p><p class="First"><span class="Underline">Nicotine replacement therapy (NRT</span>)</p><p>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.</p></div></div><div class="Section" data-sectionCode="42229-5"><a name="S7.2"></a><a name="section-7.2"></a><p></p><h2>7.2 Effect of Smoking Cessation on Other Drugs</h2><p class="First">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.</p></div></div><div class="Section" data-sectionCode="43684-0"><a name="S8"></a><a name="section-8"></a><p></p><h1>8 USE IN SPECIFIC POPULATIONS</h1><p class="First"> </p><div class="Section" data-sectionCode="42228-7"><a name="S8.1"></a><a name="section-8.1"></a><p></p><h2>8.1 Pregnancy</h2><p class="First"> </p><div class="Section" data-sectionCode="42229-5"><a name="ID_5a4ea7bc-fb75-4f06-9fd5-76bac2a14ded"></a><a name="section-8.1.1"></a><p></p><p class="First"><span class="Underline">Risk Summary</span></p><p>Available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke <span class="Italics">[see <a href="#refdata">Data</a>].</span> Smoking during pregnancy is associated with maternal, fetal, and neonatal risks <span class="Italics">(see <a href="#refclinicalconsiderations">Clinical Considerations</a>)</span>. 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 <span class="Italics">[see <a href="#refdata">Data</a>]</span>.</p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="clinical"></a><a name="section-8.1.2"></a><p></p><p class="First"><a name="refclinicalconsiderations"></a><span class="Underline">Clinical Considerations</span></p><div class="Section" data-sectionCode="42229-5"><a name="ID_5d2dd7dd-fd2f-4a5e-b61e-3a6530e4758a"></a><a name="section-8.1.2.1"></a><p></p><p class="First"><span class="Italics">Disease-Associated Maternal and/or Embryo/Fetal Risk</span></p><p>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.</p></div></div><div class="Section" data-sectionCode="42229-5"><a name="data"></a><a name="section-8.1.3"></a><p></p><p class="First"><a name="refdata"></a><span class="Underline">Data</span></p><div class="Section" data-sectionCode="42229-5"><a name="ID_95019827-7629-4121-8a89-a5c75932d0fa"></a><a name="section-8.1.3.1"></a><p></p><p class="First"><span class="Italics">Human Data</span></p><p>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.</p><a name="_RefID0ESGAI"></a><table width="75%"><caption><span>Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts</span></caption><col width="25%"><col width="19%"><col width="19%"><col width="23%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="center" valign="top"><span class="Bold">Outcome</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Varenicline Cohort</span><br><span class="Bold">(n=335)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Smoking Cohort</span><br><span class="Bold">(n=78,412)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Non-Smoking Cohort</span><br><span class="Bold">(n=806,438)</span></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="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Major congenital malformation<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">12 / 334 (3.6%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">3,382 / 78,028 (4.3%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">33,950 /804,020 (4.2%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Stillbirth</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 (0.3%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">384 (0.5%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2,418 (0.3%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Small for gestational age</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">42 (12.5%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">13,433 (17.1%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">73,135 (9.1%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Preterm birth</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">25 (7.5%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6,173 (7.9%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">46,732 (5.8%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Premature rupture of membranes</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">12 (3.6%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4,246 (5.4%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">30,641 (3.8%)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Sudden infant death syndrome<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0/307 (0.0%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">51/71,720 (0.1%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">58/755,939 (<0.1%)</p></td></tr></tbody></table><p>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.</p><p>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.</p><p>Overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy. </p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_f7b21848-c057-4fcd-883e-64e72be975d6"></a><a name="section-8.1.3.2"></a><p></p><p class="First"><span class="Italics">Animal Data</span></p><p>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.</p><p>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.</p></div></div></div><div class="Section" data-sectionCode="77290-5"><a name="S8.2"></a><a name="section-8.2"></a><p></p><h2>8.2 Lactation</h2><p class="First"> </p><div class="Section" data-sectionCode="42229-5"><a name="ID_2e104608-c834-49ea-98d5-8ec41c1828c8"></a><a name="section-8.2.1"></a><p></p><p class="First"><span class="Underline">Risk Summary</span></p><p>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 <span class="Italics">[see <a href="#refdata2">Data</a>]</span>. 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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_c0c1a492-9259-4228-90cd-fdda6243e9e7"></a><a name="section-8.2.2"></a><p></p><p class="First"><span class="Underline">Clinical Considerations</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="data2"></a><a name="section-8.2.3"></a><p></p><p class="First"><a name="refdata2"></a><span class="Underline">Data</span></p><p>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.</p></div></div><div class="Section" data-sectionCode="34081-0"><a name="S8.4"></a><a name="section-8.3"></a><p></p><h2>8.4 Pediatric Use</h2><p class="First">CHANTIX is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated.</p><p>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.</p><p>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.</p></div><div class="Section" data-sectionCode="34082-8"><a name="S8.5"></a><a name="section-8.4"></a><p></p><h2>8.5 Geriatric Use</h2><p class="First">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.</p><p>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 <span class="Italics">[see <a href="#S2.2">Dosage and Administration (2.2)</a>]</span>.</p><p>No dosage adjustment is recommended for elderly patients.</p></div><div class="Section" data-sectionCode="88828-9"><a name="S8.6"></a><a name="section-8.5"></a><p></p><h2>8.6 Renal Impairment</h2><p class="First">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 <span class="Italics">[see <a href="#S2.2">Dosage and Administration (2.2)</a>, <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></p></div></div><div class="Section" data-sectionCode="42227-9"><a name="S9"></a><a name="section-9"></a><p></p><h1>9 DRUG ABUSE AND DEPENDENCE</h1><p class="First"> </p><div class="Section" data-sectionCode="34085-1"><a name="S9.1"></a><a name="section-9.1"></a><p></p><h2>9.1 Controlled Substance</h2><p class="First">Varenicline is not a controlled substance.</p></div><div class="Section" data-sectionCode="34087-7"><a name="S9.3"></a><a name="section-9.2"></a><p></p><h2>9.3 Dependence</h2><p class="First"> </p><div class="Section" data-sectionCode="42229-5"><a name="ID_e545ee24-6c7a-4b49-af22-dc787f143a85"></a><a name="section-9.2.1"></a><p></p><p class="First"><span class="Underline">Humans</span></p><p>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.</p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_5ffa8378-7ac2-4839-a142-6f5949efd1d3"></a><a name="section-9.2.2"></a><p></p><p class="First"><span class="Underline">Animals</span></p><p>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.</p></div></div></div><div class="Section" data-sectionCode="34088-5"><a name="S10"></a><a name="section-10"></a><p></p><h1>10 OVERDOSAGE</h1><p class="First">In case of overdose, standard supportive measures should be instituted as required.</p><p>Varenicline has been shown to be dialyzed in patients with end-stage renal disease <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>], </span>however, there is no experience in dialysis following overdose.</p></div><div class="Section" data-sectionCode="34089-3"><a name="S11"></a><a name="section-11"></a><p></p><h1>11 DESCRIPTION</h1><p class="First">CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial nicotinic agonist selective for α<span class="Sub">4</span>β<span class="Sub">2 </span>nicotinic acetylcholine receptor subtypes.</p><p>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-6<span class="Italics">H</span>-pyrazino[2,3- h][3]benzazepine, (2<span class="Italics">R</span>,3<span class="Italics">R</span>)-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 C<span class="Sub">13</span>H<span class="Sub">13</span>N<span class="Sub">3</span> ∙ C<span class="Sub">4</span>H<span class="Sub">6</span>O<span class="Sub">6</span>. The chemical structure is:</p><div class="Figure"><a name="id2357"></a><img src="ImageHandler.ashx?id=22016" alt="Chemical Structure"></div><p>CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "<span class="Italics">Pfizer</span>" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "<span class="Italics">Pfizer</span>" 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.</p></div><div class="Section" data-sectionCode="34090-1"><a name="S12"></a><a name="section-12"></a><p></p><h1>12 CLINICAL PHARMACOLOGY</h1><p class="First"> </p><div class="Section" data-sectionCode="43679-0"><a name="S12.1"></a><a name="section-12.1"></a><p></p><h2>12.1 Mechanism of Action</h2><p class="First">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.</p><p>Electrophysiology studies <span class="Italics">in vitro</span> and neurochemical studies <span class="Italics">in vivo </span>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.</p></div><div class="Section" data-sectionCode="43682-4"><a name="S12.3"></a><a name="section-12.2"></a><p></p><h2>12.3 Pharmacokinetics</h2><p class="First"> </p><div class="Section" data-sectionCode="42229-5"><a name="ID_66980776-543e-46dc-8149-be3ddcf0147c"></a><a name="section-12.2.1"></a><p></p><p class="First"><span class="Underline">Absorption</span></p><p>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.</p><p>In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%.</p><div class="Section" data-sectionCode="42229-5"><a name="ID_f990850b-ae78-49a9-8dbc-f699841177af"></a><a name="section-12.2.1.1"></a><p></p><p class="First"><span class="Italics">Food Effect</span></p><p>Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.</p></div></div><div class="Section" data-sectionCode="42229-5"><a name="ID_489ae9dc-06cf-4a84-a6d0-30ea2fbd4e7a"></a><a name="section-12.2.2"></a><p></p><p class="First"><span class="Underline">Distribution</span></p><p>Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_a9fbb7c0-1eb3-4193-bdb8-3ed4aecd3669"></a><a name="section-12.2.3"></a><p></p><p class="First"><span class="Underline">Elimination</span></p><p>The elimination half-life of varenicline is approximately 24 hours.</p><div class="Section" data-sectionCode="42229-5"><a name="ID_dc106240-26e1-4c95-9df7-eb1fe2aee11b"></a><a name="section-12.2.3.1"></a><p></p><p class="First"><span class="Italics">Metabolism</span></p><p>Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_bf935fa0-b38a-4884-8020-81d882f3c112"></a><a name="section-12.2.3.2"></a><p></p><p class="First"><span class="Italics">Excretion</span></p><p>Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.</p></div></div><div class="Section" data-sectionCode="42229-5"><a name="ID_bdc12528-ca99-4911-8d32-db4fd948a85b"></a><a name="section-12.2.4"></a><p></p><p class="First"><span class="Underline">Specific Populations</span></p><p>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.</p><div class="Section" data-sectionCode="42229-5"><a name="ID_30b3393f-d711-4bff-a5eb-4081aa7e6900"></a><a name="section-12.2.4.1"></a><p></p><p class="First"><span class="Italics">Age: Geriatric Patients</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_978918e9-37c5-4a1a-805a-ec10b436efa8"></a><a name="section-12.2.4.2"></a><p></p><p class="First"><span class="Italics">Age: Pediatric Patients</span></p><p>CHANTIX is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated <span class="Italics">[see <a href="#S8.4">Use in Specific Populations (8.4)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_aed63690-d54f-4e59-8277-b74b57b5f850"></a><a name="section-12.2.4.3"></a><p></p><p class="First"><span class="Italics">Renal Impairment</span></p><p>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 <span class="Italics">[see <a href="#S2.2">Dosage and Administration (2.2)</a>, <a href="#S8.6">Use in Specific Populations (8.6)</a>]</span>. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis <span class="Italics">[see <a href="#S10">Overdosage (10)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_dc46d1b0-5b27-4b03-9b65-dd5d71989310"></a><a name="section-12.2.4.4"></a><p></p><p class="First"><span class="Italics">Hepatic Impairment</span></p><p>Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.</p></div></div><div class="Section" data-sectionCode="42229-5"><a name="ID_d8acd7d0-83de-41cd-9110-da8e09d962e4"></a><a name="section-12.2.5"></a><p></p><p class="First"><span class="Underline">Drug-Drug Interactions</span></p><p><span class="Italics">In vitro </span>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 <span class="Italics">in vitro</span>, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.</p><p><span class="Italics">In vitro </span>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 <span class="Italics">[see <a href="#refmetformin">below</a>]</span>) are unlikely to be affected by varenicline.</p><p><span class="Italics">In vitro </span>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 <span class="Italics">[see <a href="#refcimeditine">below</a>]</span>) 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 <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>; therefore, a dose adjustment of CHANTIX would not be required.</p><p>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.</p><div class="Section" data-sectionCode="42229-5"><a name="Metformin"></a><a name="section-12.2.5.1"></a><p></p><p class="First"><a name="refmetformin"></a><span class="Italics">Metformin</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="Cimetidine"></a><a name="section-12.2.5.2"></a><p></p><p class="First"><a name="refcimeditine"></a><span class="Italics">Cimetidine</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_31884c1e-bc90-46dd-953f-5a55f430d445"></a><a name="section-12.2.5.3"></a><p></p><p class="First"><span class="Italics">Digoxin</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_bc6023b5-baff-4f41-9adf-3d9cbec76b1f"></a><a name="section-12.2.5.4"></a><p></p><p class="First"><span class="Italics">Warfarin</span></p><p>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<span class="Italics"> [see <a href="#S7.2">Drug Interactions (7.2)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_fb99d00e-ac48-46be-bf8b-cf7c610af931"></a><a name="section-12.2.5.5"></a><p></p><p class="First"><span class="Italics">Use with Other Drugs for Smoking Cessation</span></p><div class="Section" data-sectionCode="42229-5"><a name="ID_64f84240-4e89-4488-b830-d14990cbb710"></a><a name="section-12.2.5.5.1"></a><p></p><p class="First">Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers <span class="Italics">[see <a href="#S7.1">Drug Interactions (7.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_4ce487af-c9e2-4e03-b829-6e2bdc31d84f"></a><a name="section-12.2.5.5.2"></a><p></p><p class="First">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 <span class="Italics">[see <a href="#S7.1">Drug Interactions (7.1)</a>]</span>.</p></div></div></div></div></div><div class="Section" data-sectionCode="43680-8"><a name="S13"></a><a name="section-13"></a><p></p><h1>13 NONCLINICAL TOXICOLOGY</h1><p class="First"> </p><div class="Section" data-sectionCode="34083-6"><a name="S13.1"></a><a name="section-13.1"></a><p></p><h2>13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility</h2><div class="Section" data-sectionCode="42229-5"><a name="ID_6f27468e-69e8-4acd-a0b8-2ac491d049f0"></a><a name="section-13.1.1"></a><p></p><p class="First"><span class="Underline">Carcinogenesis</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_804e7b83-8d18-4ae3-8c97-2d3bed66cd44"></a><a name="section-13.1.2"></a><p></p><p class="First"><span class="Underline">Mutagenesis</span></p><p>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 <span class="Italics">in vivo </span>in rat bone marrow and <span class="Italics">in vitro </span>in human lymphocytes.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_185061cc-060f-4293-b113-3235d6feb080"></a><a name="section-13.1.3"></a><p></p><p class="First"><span class="Underline">Impairment of Fertility</span></p><p>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).</p></div></div></div><div class="Section" data-sectionCode="34092-7"><a name="S14"></a><a name="section-14"></a><p></p><h1>14 CLINICAL STUDIES</h1><p class="First">The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (≥10 cigarettes per day) were treated with CHANTIX. In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO≤10 ppm) at weekly visits. Among the CHANTIX-treated patients enrolled in these studies, the completion rate was 65%. Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most patients enrolled in these trials were white (79–96%). All studies enrolled almost equal numbers of men and women. The average age of patients in these studies was 43 years. Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years. Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date.</p><p>Seven additional studies evaluated the efficacy of CHANTIX in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease <span class="Italics">[see <a href="#S14.7">Clinical Studies (14.7)</a>], </span>in patients instructed to select their quit date within days 8 and 35 of treatment <span class="Italics">[see <a href="#S14.4">Clinical Studies (14.4)</a>]</span>, patients with major depressive disorder<span class="Italics"> [see <a href="#S14.9">Clinical Studies (14.9)</a>], </span>patients who had made a previous attempt to quit smoking with CHANTIX, and either did not succeed in quitting or relapsed after treatment <span class="Italics">[see <a href="#S14.6">Clinical Studies (14.6)</a>],</span> in patients without or with a history of psychiatric disorder enrolled in a postmarketing neuropsychiatric safety outcome trial <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>, <a href="#S14.10">Clinical Studies (14.10)</a>]</span>, and in patients who were not able or willing to quit abruptly and were instructed to quit gradually <span class="Italics">[see <a href="#S14.5">Clinical studies (14.5)</a>]</span>.</p><p>In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each weekly treatment visit according to Agency for Healthcare Research and Quality guidelines.</p><div class="Section" data-sectionCode="42229-5"><a name="S14.1"></a><a name="section-14.1"></a><p></p><h2>14.1 Initiation of Abstinence</h2><div class="Section" data-sectionCode="42229-5"><a name="ID_bf1f5c56-6065-40c2-8bcf-cffb4f7e9e4c"></a><a name="section-14.1.1"></a><p></p><p class="First"><span class="Underline">Study 1</span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_c15ff497-fd35-40b1-911f-919167fbe66f"></a><a name="section-14.1.2"></a><p></p><p class="First"><span class="Underline">Study 2</span></p><p>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.</p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_4d321d4e-3426-4a26-a16f-165b750f6c30"></a><a name="section-14.1.3"></a><p></p><p class="First"><span class="Underline">Study 3</span></p><p>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.</p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_2a7c6ecc-bce9-4253-bddf-7b0e90e3f0d5"></a><a name="section-14.1.4"></a><p></p><p class="First"><span class="Underline">Study 4 and Study 5</span></p><p>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.</p><p>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.</p><p>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.</p><table class="Noautorules" width="100%"><col width="100%"><tbody class="Headless"><tr><td align="center" valign="top"><p class="First"><span class="Bold">Figure 1: Continuous Abstinence, Weeks 9 through 12</span></p></td></tr><tr><td valign="top"><a name="id2720"></a><img src="ImageHandler.ashx?id=22017" alt="Figure 1"></td></tr></tbody></table><a name="_RefID0EQIBI"></a><table width="75%"><caption><span>Table 7. Continuous Abstinence, Weeks 9 through 12 (95% confidence interval)</span></caption><col width="9%"><col width="16%"><col width="16%"><col width="16%"><col width="16%"><col width="14%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">0.5 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">Flexible</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion SR</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="6" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Study 2</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">45%<br>(39%, 51%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">51%<br>(44%, 57%)</p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">12%<br>(6%, 18%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 3</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">40%<br>(32%, 48%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">12%<br>(7%, 17%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 4</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">44%<br>(38%, 49%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">30%<br>(25%, 35%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">17%<br>(13%, 22%)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 5</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">44%<br>(38%, 49%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">30%<br>(25%, 35%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">18%<br>(14%, 22%)</p></td></tr></tbody></table></div></div><div class="Section" data-sectionCode="42229-5"><a name="S14.2"></a><a name="section-14.2"></a><p></p><h2>14.2 Urge to Smoke</h2><p class="First">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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S14.3"></a><a name="section-14.3"></a><p></p><h2>14.3 Long-Term Abstinence</h2><p class="First">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).</p><table class="Noautorules" width="100%"><col width="100%"><tbody class="Headless"><tr><td align="center" valign="top"><p class="First"><span class="Bold">Figure 2: Continuous Abstinence, Weeks 9 through 52</span></p></td></tr><tr><td valign="top"><a name="id2816"></a><img src="ImageHandler.ashx?id=22018" alt="Figure 2"></td></tr></tbody></table><a name="_RefID0EXOBI"></a><table width="75%"><caption><span>Table 8. Continuous Abstinence, Weeks 9 through 52 (95% confidence interval) Across Different Studies</span></caption><col width="12%"><col width="15%"><col width="15%"><col width="15%"><col width="15%"><col width="14%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">0.5 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">Flexible</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion SR</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="6" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Study 2</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">19%<br>(14%, 24%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">23%<br>(18%, 28%)</p></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">4%<br>(1%, 8%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 3</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">22%<br>(16%, 29%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8%<br>(3%, 12%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 4</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">21%<br>(17%, 26%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">16%<br>(12%, 20%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8%<br>(5%, 11%)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Study 5</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">22%<br>(17%, 26%)</p></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">14%<br>(11%, 18%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10%<br>(7%, 13%)</p></td></tr></tbody></table><div class="Section" data-sectionCode="42229-5"><a name="ID_089854cc-c053-4ba5-87bd-6e3ba93c56ee"></a><a name="section-14.3.1"></a><p></p><p class="First"><span class="Underline">Study 6</span></p><p>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.</p><p>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%).</p><p>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.</p><table class="Noautorules" width="100%"><col width="100%"><tbody class="Headless"><tr><td align="center" valign="top"><p class="First"><span class="Bold">Figure 3: Continuous Abstinence Rate during Nontreatment Follow-Up</span></p></td></tr><tr><td valign="top"><a name="id2902"></a><img src="ImageHandler.ashx?id=22019" alt="Figure 3"></td></tr></tbody></table></div></div><div class="Section" data-sectionCode="42229-5"><a name="S14.4"></a><a name="section-14.4"></a><p></p><h2>14.4 Alternative Instructions for Setting a Quit Date</h2><p class="First">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%).</p></div><div class="Section" data-sectionCode="42229-5"><a name="S14.5"></a><a name="section-14.5"></a><p></p><h2>14.5 Gradual Approach to Quitting Smoking</h2><p class="First">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%).</p></div><div class="Section" data-sectionCode="42229-5"><a name="S14.6"></a><a name="section-14.6"></a><p></p><h2>14.6 Re-Treatment Study</h2><p class="First">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.</p><p>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%).</p><a name="_RefID0EJWBI"></a><table width="75%"><caption><span>Table 9. Continuous Abstinence (95% confidence interval), Re-Treatment Study</span></caption><col width="14%"><col width="19%"><col width="18%"><col width="19%"><col width="18%"><thead><tr class="First"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 12</span></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 52</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First Last"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Re-treatment Study</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">45%<br>(39%, 51%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">12%<br>(8%, 16%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">20%<br>(15%, 25%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">3%<br>(1%, 5%)</p></td></tr></tbody></table></div><div class="Section" data-sectionCode="42229-5"><a name="S14.7"></a><a name="section-14.7"></a><p></p><h2>14.7 Subjects with Chronic Obstructive Pulmonary Disease</h2><p class="First">CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV<span class="Sub">1</span>/FVC <70% and FEV<span class="Sub">1 </span>≥ 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%).</p><a name="_RefID0ENZBI"></a><table width="75%"><caption><span>Table 10. Continuous Abstinence (95% confidence interval), Studies in Patients with Chronic Obstructive Pulmonary Disease (COPD)</span></caption><col width="14%"><col width="19%"><col width="18%"><col width="19%"><col width="18%"><thead><tr class="First"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 12</span></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 52</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First Last"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">COPD Study</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">41%<br>(34%, 47%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">9%<br>(6%, 13%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">19%<br>(14%, 24%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">6%<br>(3%, 9%)</p></td></tr></tbody></table></div><div class="Section" data-sectionCode="42229-5"><a name="S14.8"></a><a name="section-14.8"></a><p></p><h2>14.8 Subjects with Cardiovascular Disease and Other Cardiovascular Analyses</h2><p class="First">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%).</p><a name="_RefID0EM3BI"></a><table width="75%"><caption><span>Table 11. Continuous Abstinence (95% confidence interval), Studies in Patients with Cardiovascular Disease (CVD)</span></caption><col width="14%"><col width="19%"><col width="18%"><col width="19%"><col width="18%"><thead><tr class="First"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 12</span></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 52</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First Last"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">CVD Study</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">47%<br>(42%, 53%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">14%<br>(11%, 18%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">20%<br>(16%, 24%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">7%<br>(5%, 10%)</p></td></tr></tbody></table><p>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 <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>, <a href="#S6.1">Adverse Reactions (6.1)</a>]</span>. 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.</p><a name="_RefID0EI6BI"></a><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 width="34%"><col width="21%"><col width="20%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="center" valign="middle"><span class="Bold">Mortality and Cardiovascular Events</span></th><th class="Botrule Rrule Toprule" align="center" valign="middle"><span class="Bold">CHANTIX</span><br><span class="Bold">(N=353)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="middle"><span class="Bold">Placebo</span><br><span class="Bold">(N=350)</span><br><span class="Bold">n (%)</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"><p class="First"><span class="Bold"><span class="Italics">Mortality (Cardiovascular and All-cause up to 52 weeks)</span></span></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Cardiovascular</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">1 (0.3)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> All-cause</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">5 (1.4)</p></td></tr><tr><td class="Botrule Lrule Rrule" colspan="3" valign="top"><p class="First"> </p></td></tr><tr><td class="Botrule Lrule Rrule" colspan="3" valign="top"><p class="First"><span class="Bold"><span class="Italics">Nonfatal Cardiovascular Events (rate on CHANTIX > Placebo)</span></span></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics"><span class="Underline">Up to 30 days after treatment</span></span></p></td><td class="Botrule Rrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nonfatal myocardial infarction</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">4 (1.1)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">1 (0.3)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nonfatal Stroke</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">0 (0)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics"><span class="Underline">Beyond 30 days after treatment and up to 52 weeks</span></span></p></td><td class="Botrule Rrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Nonfatal myocardial infarction</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">3 (0.8)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Need for coronary revascularization</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">7 (2.0)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Hospitalization for angina pectoris</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">6 (1.7)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">4 (1.1)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> Transient ischemia attack</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">1 (0.3)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">0 (0)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> New diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">5 (1.4)</p></td><td class="Botrule Rrule" align="center" valign="middle"><p class="First">2 (0.6)</p></td></tr></tbody></table><p>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.</p><p>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.</p><a name="_RefID0E5DCI"></a><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 width="21%"><col width="26%"><col width="27%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">N=4190</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span><br><span class="Bold">N=2812</span></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="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First"><span class="Bold"><span class="Italics">MACE cases, n (%)</span></span></p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">13 (0.31%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">6 (0.21%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Patient-years of exposure</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1316</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">839</p></td></tr><tr><td class="Botrule Lrule Rrule" colspan="3" valign="top"><p class="First"><span class="Bold"><span class="Italics">Hazard Ratio (95% CI)</span></span></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.95 (0.79, 4.82)</p></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" colspan="3" valign="top"><p class="First"><span class="Bold"><span class="Italics">Rate Difference per 1,000 patient-years (95% CI)</span></span></p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6.30 (-2.40, 15.10)</p></td><td class="Botrule Rrule" valign="top"></td></tr></tbody></table><p>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.</p><p>Additionally, a cardiovascular endpoint analysis was added to the postmarketing neuropsychiatric safety outcome study along with a non-treatment extension, <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>, <a href="#S6.1">Adverse Reactions (6.1)</a>, <a href="#S14.10">Clinical Studies (14.10)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="S14.9"></a><a name="section-14.9"></a><p></p><h2>14.9 Subjects with Major Depressive Disorder</h2><p class="First">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%).</p><a name="_RefID0EMHCI"></a><table width="75%"><caption><span>Table 14. Continuous Abstinence (95% confidence interval), Study in Patients with Major Depressive Disorder (MDD)</span></caption><col width="14%"><col width="19%"><col width="18%"><col width="19%"><col width="18%"><thead><tr class="First"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 12</span></th><th class="Botrule Rrule Toprule" align="center" colspan="2" valign="top"><span class="Bold">Weeks 9 through 52</span></th></tr><tr class="Last"><th class="Botrule Lrule Rrule" align="left" valign="top"></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First Last"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">MDD Study</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">36%<br>(30%, 42%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">16%<br>(11%, 20%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">20%<br>(15%, 25%)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">10%<br>(7%, 14%)</p></td></tr></tbody></table></div><div class="Section" data-sectionCode="42229-5"><a name="S14.10"></a><a name="section-14.10"></a><p></p><h2>14.10 Postmarketing Neuropsychiatric Safety Outcome Trial</h2><p class="First">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. <span class="Italics">[See <a href="#S5.1">Warnings and Precautions (5.1)</a>] </span></p><p>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.</p><p>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.</p><a name="_RefID0EUKCI"></a><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 width="22%"><col width="17%"><col width="17%"><col width="16%"><col width="16%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">(N=975)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion</span><br><span class="Bold">(N=968)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NRT</span><br><span class="Bold">(N=987)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span><br><span class="Bold">(N=982)</span><br><span class="Bold">n (%)</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Clinically Significant NPS</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">30 (3.1)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">34 (3.5)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">33 (3.3)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">40 (4.1)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Serious NPS</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 (0.1)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5 (0.5)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 (0.1)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 (0.4)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Psychiatric Hospitalizations</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 (0.1)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 (0.2)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0 (0.0)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 (0.1)</p></td></tr></tbody></table><p>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.</p><a name="_RefID0EQNCI"></a><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 width="21%"><col width="17%"><col width="17%"><col width="16%"><col width="16%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">(N=1007)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion</span><br><span class="Bold">(N=1004)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NRT</span><br><span class="Bold">(N=995)</span><br><span class="Bold">n (%)</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span><br><span class="Bold">(N=997)</span><br><span class="Bold">n (%)</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Clinically Significant NPS</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">123 (12.2)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">118 (11.8)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">98 (9.8)</p></td><td class="Botrule Rrule Toprule" align="center" valign="top"><p class="First">95 (9.5)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Serious NPS</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6 (0.6)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8 (0.8)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 (0.4)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6 (0.6)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Psychiatric hospitalizations</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5 (0.5)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8 (0.8)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 (0.4)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 (0.2)</p></td></tr></tbody></table><p>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.</p><p>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.</p><a name="_RefID0ENQCI"></a><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 width="15%"><col width="19%"><col width="18%"><col width="17%"><col width="17%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">1 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion SR</span><br><span class="Bold">150 mg BID</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NRT</span><br><span class="Bold">21 mg/day with taper</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">BID = twice daily</td></tr></tfoot><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"><p class="First"><span class="Bold">Weeks 9 through 12</span></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Non-Psychiatric Cohort</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">38%<br>(35%, 41%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">26%<br>(23%, 29%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">26%<br>(24%, 29%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">14%<br>(12%, 16%)</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Psychiatric Cohort</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">29%<br>(26%, 32%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">19%<br>(17%, 22%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">20%<br>(18%, 23%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11%<br>(10%, 14%)</p></td></tr><tr><td class="Botrule Lrule Rrule" colspan="5" valign="top"><p class="First"><span class="Bold">Weeks 9 through 24</span></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">Non-Psychiatric Cohort</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">25%<br>(23%, 28%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">19%<br>(16%, 21%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">18%<br>(16%, 21%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">11%<br>(9%, 13%)</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">Psychiatric Cohort</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">18%<br>(16%, 21%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">14%<br>(12%, 16%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">13%<br>(11%, 15%)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8%<br>(7%, 10%)</p></td></tr></tbody></table><div class="Section" data-sectionCode="42229-5"><a name="ID_e7369539-5789-4e2e-8fc7-010e1dcd1b83"></a><a name="section-14.10.1"></a><p></p><p class="First"><span class="Underline">Cardiovascular Outcome Analysis</span></p><p>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.</p><p>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.</p><a name="_RefID0E4VCI"></a><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 width="16%"><col width="16%"><col width="16%"><col width="14%"><col width="14%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">N=2006</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion</span><br><span class="Bold">N=1997</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NRT</span><br><span class="Bold">N=2017</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span><br><span class="Bold">N=2007</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">[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="First"><td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"><p class="First"><span class="Bold"><span class="Italics">During treatment</span></span><a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">MACE, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 [2.4]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 [4.9]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1 [2.4]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 [9.8]</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics">Hazard Ratio (95% CI) vs. placebo</span></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.24<br>(0.03, 2.18)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.49<br>(0.09, 2.69)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.24<br>(0.03, 2.18)</p></td><td class="Botrule Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" colspan="5" valign="top"><p class="First"><span class="Bold"><span class="Italics">Through end of study</span></span><a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">MACE, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3 [2.1]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">9 [6.3]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">6 [4.3]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">8 [5.7]</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First"> <span class="Italics">Hazard Ratio (95% CI) vs. placebo</span></p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.36<br>(0.10, 1.36)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">1.09<br>(0.42, 2.83)</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0.74<br>(0.26, 2.13)</p></td><td class="Botrule Rrule" valign="top"></td></tr></tbody></table><p>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.</p><a name="_RefID0EM1CI"></a><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 width="16%"><col width="16%"><col width="15%"><col width="14%"><col width="14%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">CHANTIX</span><br><span class="Bold">N=2006</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Bupropion</span><br><span class="Bold">N=1997</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NRT</span><br><span class="Bold">N=2017</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Placebo</span><br><span class="Bold">N=2007</span></th></tr></thead><tfoot><tr class="First Last"><td align="left" colspan="5" valign="top">[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="First"><td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"><p class="First"><span class="Bold"><span class="Italics">During treatment</span></span><a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">MACE+, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5 [12.1]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 [9.9]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 [4.8]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">5 [12.2]</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">All-cause deaths, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 [4.9]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">0</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 [4.9]</p></td></tr><tr><td class="Botrule Lrule Rrule" colspan="5" valign="top"><p class="First"><span class="Bold"><span class="Italics">Through end of study</span></span><a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a></p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"><p class="First">MACE+, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10 [6.9]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">15 [10.5]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">10 [7.1]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">12 [8.6]</p></td></tr><tr class="Last"><td class="Botrule Lrule Rrule" valign="top"><p class="First">All-cause deaths, n [IR]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">2 [1.4]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 [2.8]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">3 [2.1]</p></td><td class="Botrule Rrule" align="center" valign="top"><p class="First">4 [2.9]</p></td></tr></tbody></table><p>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.</p></div></div></div><div class="Section" data-sectionCode="34069-5"><a name="S16"></a><a name="section-15"></a><p></p><h1>16 HOW SUPPLIED/STORAGE AND HANDLING</h1><p class="First">CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "<span class="Italics">Pfizer</span>" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "<span class="Italics">Pfizer</span>" on one side and "CHX 1.0" on the other side. CHANTIX is supplied in the following package configurations:</p><table width="65%"><col width="10%"><col width="47%"><col width="19%"><thead><tr class="First Last"><th class="Botrule Lrule Rrule Toprule" align="left" valign="top"></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">Description</span></th><th class="Botrule Rrule Toprule" align="center" valign="top"><span class="Bold">NDC</span></th></tr></thead><tbody><tr class="First"><td class="Botrule Lrule Rrule Toprule" valign="top"><p class="First">Packs</p></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Starting 4-week card: 0.5 mg × 11 tablets and 1 mg × 42 tablets</p></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">NDC 0069-0471-28</p></td></tr><tr><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"><p class="First">Continuing 4-week card: 1 mg × 56 tablets</p></td><td class="Botrule Rrule" valign="top"><p class="First">NDC 0069-0469-28</p></td></tr><tr><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><p class="First">Bottles</p></td><td class="Botrule Rrule" valign="top"><p class="First">0.5 mg - bottle of 56</p></td><td class="Botrule Rrule" valign="top"><p class="First">NDC 0069-0468-56</p></td></tr><tr class="Last"><td class="Botrule Rrule" valign="top"><p class="First">1 mg - bottle of 56</p></td><td class="Botrule Rrule" valign="top"><p class="First">NDC 0069-0469-56</p></td></tr></tbody></table><div class="Section" data-sectionCode="44425-7"><a name="ID_15d848d0-203e-47ca-8d91-44a4f9a0ff99"></a><a name="section-15.1"></a><p></p><p class="First">Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) (see USP Controlled Room Temperature).</p></div></div><div class="Section" data-sectionCode="34076-0"><a name="S17"></a><a name="section-16"></a><p></p><h1>17 PATIENT COUNSELING INFORMATION</h1><p class="First"><span class="Italics">See <a href="#medguide">FDA-approved patient labeling (Medication Guide)</a></span></p><div class="Section" data-sectionCode="42229-5"><a name="ID_81798e19-d020-4323-9998-cca266f03c67"></a><a name="section-16.1"></a><p></p><p class="First"><span class="Underline">Initiate Treatment and Continue to Attempt to Quit if Lapse</span></p><p>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 <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p><p>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 <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>]</span>.</p><p>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 <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>, <a href="#S14.6">Clinical Studies (14.6)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_aba86c1d-5310-4619-970e-7a49e2da2ed2"></a><a name="section-16.2"></a><p></p><p class="First"><span class="Underline">How to Take</span></p><p>Advise patients that CHANTIX should be taken orally after eating, and with a full glass of water<span class="Italics"> [see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_42d83a24-82e5-4096-aea4-8004ee22e733"></a><a name="section-16.3"></a><p></p><p class="First"><span class="Underline">Starting Week Dosage</span></p><p>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<span class="Italics"> [see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_177e2d12-029c-4d3d-8af4-33991b56fa86"></a><a name="section-16.4"></a><p></p><p class="First"><span class="Underline">Continuing Weeks Dosage</span></p><p>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<span class="Italics"> [see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_2571adc9-431c-452e-b698-495a4a5fdf91"></a><a name="section-16.5"></a><p></p><p class="First"><span class="Underline">Dosage Adjustment for CHANTIX or Other Drugs</span></p><p>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.</p><p>Inform patients that some drugs may require dose adjustment after quitting smoking <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_a505e72f-3892-4d80-9f46-50670069e5e2"></a><a name="section-16.6"></a><p></p><p class="First"><span class="Underline">Counseling and Support</span></p><p>Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_6243c29d-6cf9-479e-8de4-7fa8a9dd59e9"></a><a name="section-16.7"></a><p></p><p class="First"><span class="Underline">Neuropsychiatric Adverse Events </span></p><p>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 <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>, <a href="#S6.2">Adverse Reactions (6.2)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_dea062c4-bf7d-4a01-a86c-275e9621e41d"></a><a name="section-16.8"></a><p></p><p class="First"><span class="Underline">History of Psychiatric Illness</span></p><p>Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_5070ccc7-3d77-48d8-90f8-a4dd8686b9d4"></a><a name="section-16.9"></a><p></p><p class="First"><span class="Underline">Nicotine Withdrawal </span></p><p>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.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_036763b1-10d1-4dfd-90b0-a6d9f1ec448d"></a><a name="section-16.10"></a><p></p><p class="First"><span class="Underline">Seizures</span></p><p>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 <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_d27e24b1-3613-4c5e-912d-65f24856533e"></a><a name="section-16.11"></a><p></p><p class="First"><span class="Underline">Interaction with Alcohol</span></p><p>Advise patients to reduce the amount of alcohol they consume while taking CHANTIX until they know whether CHANTIX affects their tolerance for alcohol <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3)</a>, <a href="#S6.2">Adverse Reactions (6.2)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_0d455025-7d53-4d84-97ac-f03f61de2e3b"></a><a name="section-16.12"></a><p></p><p class="First"><span class="Underline">Driving or Operating Machinery</span></p><p>Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_2fda8ccc-ec94-42c5-8771-83ea6aa7f40c"></a><a name="section-16.13"></a><p></p><p class="First"><span class="Underline">Cardiovascular Events</span></p><p>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 <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>, <a href="#S6.1">Adverse Reactions (6.1)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_83a17666-4229-43b2-814d-aa820e3949b1"></a><a name="section-16.14"></a><p></p><p class="First"><span class="Underline">Somnambulism</span></p><p>Patients should be instructed to discontinue CHANTIX and notify their healthcare providers if they experience somnambulism <span class="Italics">[see <a href="#S5.6">Warnings and Precautions (5.6)</a>]</span>.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_b19c66d4-0db1-4766-a32b-3269cac46804"></a><a name="section-16.15"></a><p></p><p class="First"><span class="Underline">Angioedema </span></p><p>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 <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>, <a href="#S6.2">Adverse Reactions (6.2)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_bd3d1162-af89-4946-997a-49ed2b2351bd"></a><a name="section-16.16"></a><p></p><p class="First"><span class="Underline">Serious Skin Reactions</span></p><p>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 <span class="Italics">[see <a href="#S5.8">Warnings and Precautions (5.8)</a>, <a href="#S6.2">Adverse Reactions (6.2)</a>].</span></p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_d5a07c3b-4721-408f-8a28-9059f2e8701a"></a><a name="section-16.17"></a><p></p><p class="First"><span class="Underline">Vivid, Unusual, or Strange Dreams</span></p><p>Inform patients that they may experience vivid, unusual or strange dreams during treatment with CHANTIX.</p></div><div class="Section" data-sectionCode="42229-5"><a name="ID_adafa81d-cf93-4010-9c75-3cdb72a92291"></a><a name="section-16.18"></a><p></p><p class="First"><span class="Underline">Pregnancy and Lactation</span></p><p>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 <span class="Italics">[see <a href="#S8.1">Use in Specific Populations (8.1</a> and <a href="#S8.2">8.2)</a>]. </span></p></div></div><div class="Section" data-sectionCode="42229-5"><a name="ID_003d87ed-b94a-4d9c-9dbf-4adaf6373032"></a><a name="section-17"></a><p></p><p class="First">This product's label may have been updated. For full prescribing information, please visit <a href="http://www.pfizer.com">www.pfizer.com</a>.</p><div class="Figure"><a name="id3817"></a><img src="ImageHandler.ashx?id=22020" alt="Logo"></div><p>LAB-0327-26.0</p></div><div class="Section" data-sectionCode="42231-1"><a name="medguide"></a><a name="section-18"></a><p></p><table width="100%"><col width="3%"><col width="32%"><col width="32%"><col width="33%"><tfoot><tr class="First Last"><td align="left" colspan="4" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 6/2025</td></tr></tfoot><tbody class="Headless"><tr class="First"><td class="Botrule Lrule Rrule Toprule" align="center" colspan="4" valign="top"><p class="First"><span class="Bold">MEDICATION GUIDE</span><br><span class="Bold">CHANTIX<span class="Sup">®</span> (CHANT-iks)</span><br><span class="Bold">(varenicline)</span><br><span class="Bold">Tablets</span></p></td></tr><tr><td class="Lrule Rrule" colspan="4" valign="top"><p class="First"><a name="refimportantinfo"></a><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 class="Lrule" colspan="2" valign="top"><dl><dt>•</dt><dd>urge to smoke</dd><dt>•</dt><dd>depressed mood</dd><dt>•</dt><dd>trouble sleeping</dd><dt>•</dt><dd>irritability</dd></dl></td><td valign="top"><dl><dt>•</dt><dd>frustration</dd><dt>•</dt><dd>anger</dd><dt>•</dt><dd>feeling anxious</dd><dt>•</dt><dd>difficulty concentrating</dd></dl></td><td class="Rrule" valign="top"><dl><dt>•</dt><dd>restlessness</dd><dt>•</dt><dd>decreased heart rate</dd><dt>•</dt><dd>increased appetite</dd><dt>•</dt><dd>weight gain</dd></dl></td></tr><tr><td class="Botrule Lrule Rrule" colspan="4" valign="top"><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><td class="Botrule Lrule Rrule" colspan="4" valign="top"><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 class="Lrule Rrule" colspan="4" valign="top"><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><dl><dt>•</dt><dd>swelling of the face, mouth (tongue, lips, gums), throat or neck</dd></dl></td></tr><tr><td class="Botrule Lrule" colspan="2" valign="top"><dl><dt>•</dt><dd>trouble breathing</dd></dl></td><td class="Botrule" valign="top"><dl><dt>•</dt><dd>rash, with peeling skin</dd></dl></td><td class="Botrule Rrule" valign="top"><dl><dt>•</dt><dd>blisters in your mouth</dd></dl></td></tr><tr><td class="Botrule Lrule Rrule" colspan="4" valign="top"><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="#refimportantinfo">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><dl><dt>•</dt><dd>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.</dd><dt>•</dt><dd>have kidney problems or get kidney dialysis. Your healthcare provider may prescribe a lower dose of CHANTIX for you.</dd><dt>•</dt><dd>have a history of seizures.</dd><dt>•</dt><dd>drink alcohol.</dd><dt>•</dt><dd>have heart or blood vessel problems.</dd><dt>•</dt><dd>have any other medical conditions.</dd><dt>•</dt><dd>are pregnant or plan to become pregnant.</dd><dt>•</dt><dd>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.</dd></dl><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 class="Lrule Rrule" colspan="4" valign="top"><p class="First"><span class="Bold">How should I take CHANTIX?</span></p><dl><dt>•</dt><dd>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:<dl><dt>o</dt><dd>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></dd><dt>o</dt><dd>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></dd><dt>o</dt><dd>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:</dd></dl></dd></dl></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Weeks 1 through 4</p></td><td class="Botrule Rrule Toprule" valign="top"><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 class="Rrule" valign="top"></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Weeks 5 through 8</p></td><td class="Botrule Rrule Toprule" valign="top"><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 class="Rrule" valign="top"></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Weeks 9 through 12</p></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Keep reducing your smoking until you are no longer smoking (you reach zero cigarettes each day).</p></td><td class="Rrule" valign="top"></td></tr><tr><td class="Lrule" valign="top"></td><td class="Rrule" colspan="3" valign="top"><p class="First">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.</p><p>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.</p></td></tr><tr><td class="Lrule Rrule" colspan="4" valign="top"><dl><dt>•</dt><dd>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.</dd></dl></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Day 1 to Day 3</p></td><td class="Botrule Rrule Toprule" valign="top"><dl><dt>o</dt><dd><span class="Underline">White </span>tablet (0.5 mg)</dd><dt>o</dt><dd>Take 1 tablet each day</dd></dl></td><td class="Rrule" valign="top"></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Day 4 to Day 7</p></td><td class="Botrule Rrule Toprule" valign="top"><dl><dt>o</dt><dd><span class="Underline">White</span> tablet (0.5 mg)</dd><dt>o</dt><dd>Take 1 in the morning and 1 in the evening</dd></dl></td><td class="Rrule" valign="top"></td></tr><tr><td class="Lrule Rrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"><p class="First">Day 8 to end of treatment</p></td><td class="Botrule Rrule Toprule" valign="top"><dl><dt>o</dt><dd><span class="Underline">Blue</span> tablet (1 mg)</dd><dt>o</dt><dd>Take 1 in the morning and 1 in the evening</dd></dl></td><td class="Rrule" valign="top"></td></tr><tr><td class="Botrule Lrule Rrule" colspan="4" valign="top"><dl><dt>•</dt><dd>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.</dd><dt>•</dt><dd>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.</dd><dt>•</dt><dd>Take CHANTIX after eating and with a full glass (8 ounces) of water.</dd><dt>•</dt><dd>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.</dd><dt>•</dt><dd>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.</dd></dl></td></tr><tr><td class="Lrule Rrule" colspan="4" valign="top"><p class="First"><span class="Bold">What should I avoid while taking CHANTIX?</span></p><dl><dt>•</dt><dd>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.</dd><dt>•</dt><dd>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:</dd></dl></td></tr><tr><td class="Botrule Lrule" valign="top"></td><td class="Botrule" valign="top"><dl><dt>o</dt><dd>increased drunkenness (intoxication)</dd></dl></td><td class="Botrule Rrule" colspan="2" valign="top"><dl><dt>o</dt><dd>unusual or sometimes aggressive behavior</dd><dt>o</dt><dd>no memory of things that have happened</dd></dl></td></tr><tr><td class="Botrule Lrule Rrule" colspan="4" valign="top"><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><dl><dt>•</dt><dd><span class="Bold">See "<a href="#refimportantinfo">What is the most important information I should know about CHANTIX?</a>"</span></dd><dt>•</dt><dd><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.</dd><dt>•</dt><dd><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><dl><dt>o</dt><dd>chest discomfort (uncomfortable pressure, squeezing, fullness or pain) that lasts more than a few minutes, or that goes away and comes back</dd><dt>o</dt><dd>pain or discomfort in one or both arms, back, neck, jaw or stomach</dd><dt>o</dt><dd>shortness of breath, sweating, nausea, vomiting, or feeling lightheaded associated with chest discomfort</dd></dl></dd><dt>•</dt><dd><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.</dd><dt>•</dt><dd><span class="Bold">Allergic reactions</span> can happen with CHANTIX. Some of these allergic reactions can be life-threatening.</dd><dt>•</dt><dd><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.</dd></dl><p><span class="Bold">Stop taking CHANTIX and get medical help right away if you have any of the following symptoms:</span></p><dl><dt>o</dt><dd>swelling of the face, mouth (tongue, lips, and gums), throat or neck</dd><dt>o</dt><dd>trouble breathing</dd><dt>o</dt><dd>rash with peeling skin</dd><dt>o</dt><dd>blisters in your mouth</dd></dl><p>The most common side effects of CHANTIX include:</p><dl><dt>•</dt><dd>nausea</dd><dt>•</dt><dd>sleep problems (trouble sleeping or vivid, unusual, or strange dreams)</dd><dt>•</dt><dd>constipation</dd><dt>•</dt><dd>gas</dd><dt>•</dt><dd>vomiting</dd></dl><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><td class="Botrule Lrule Rrule" colspan="4" valign="top"><p class="First"><span class="Bold">How should I store CHANTIX?</span></p><dl><dt>•</dt><dd>Store CHANTIX at room temperature, between 68°F to 77°F (20°C to 25°C).</dd><dt>•</dt><dd><span class="Bold">Keep CHANTIX and all medicines out of the reach of children.</span></dd></dl></td></tr><tr><td class="Botrule Lrule Rrule" colspan="4" valign="top"><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 <a href="http://www.CHANTIX.com">www.CHANTIX.com</a> 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 class="Last"><td class="Lrule Rrule" colspan="4" valign="top"><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><a name="id4104"></a><img src="ImageHandler.ashx?id=22015" alt="Logo"><p>LAB-0328-18.0</p></td></tr></tbody></table></div></div><p><div class="EffectiveDate">Revised: 9/2025<div class="DocumentMetadata"><div id="docId"><a href="javascript:toggleMixin();">Document Id: </a>166a0560-2999-4e1f-a6fd-826a767f0776</div><div style="display:none" id="documentTypeCode">34391-3</div><div id="setId">Set id: f0ff4f27-5185-4881-a749-c6b7a0ca5696</div><div id="versinNo">Version: 47</div><div>Effective Time: 20250922</div></div></div> <div class="DistributorName">Pfizer Laboratories Div Pfizer Inc</div></p></body></html>
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