20 stories
·
0 followers

tutorial [Aircrack-ng]

1 Share
Read the whole story
CrystalEdg
5 hours ago
reply
Share this story
Delete

World’s top personality test doesn’t really work – should we ditch it?

1 Share

Personality tests are used by researchers, employers and even to shape policy, but a new study has found that the most widely-used test of personality doesn’t seem work for people in low- and middle-income countries. Meanwhile, another study has found that even in Western countries, it may only work for specific age groups. So why are we still using it?

The “Big Five” personality traits are openness to experiences, conscientiousness, extroversion, agreeableness and neuroticism. The theory goes that all human personality traits fall into one of these categories. They tend to be measured using questionnaires that ask people how much certain statements describe them, such as “I have lots of ideas”.

Since it was developed in the 1980s, this model has become the standard way of measuring personality. It has been used in multiple studies to link personality to income, job outcomes, education level, wellbeing, and even mortality, and companies use it in recruitment.

“Policy makers seem to care a lot about this, and more and more so,” says Karen Macours at the Paris School of Economics in France. “So we want to make sure that it actually works.”

But when Macours and her colleagues looked at survey results across 23 low- and middle-income countries, they found that it didn’t. A set of questions developed to test for a specific trait, such as conscientiousness, would be expected to give similar scores in any individual. But that didn’t happen across the 23 countries studied.

There are plenty of reasons why this might be the case. A person’s culture could influence the way they describe themselves, and differences in language could play a role. The first Big Five tests were developed from an English dictionary search of adjectives that could be used to describe personality. Perhaps not everything translates.

In another study, David Condon at the University of Oregon and his colleagues have found that the model doesn’t even apply to everyone in Western countries. While it seems to work for young adults, it fails in older populations, perhaps because the Big Five model was originally developed by studying university students.

Given all of this, and the fact that an individual’s personality can change over time, some researchers are starting to ask questions about the viability of the Big Five model.

Read more: Sixth personality trait measures your Machiavellian potential

For a start, can human personality traits really be whittled down to five categories, which ignore goals, values and interests? It depends who you ask. Luke Smillie at the University of Melbourne thinks there are “between 4 and 7”. The HEXACO model, which expands on the Big Five by including an additional “honesty-humility” trait is gaining ground. But Condon’s team have developed a model to cover 27 traits.

Simply measuring more traits won’t help, however, as survey responses are also problematic. No one can be expected to give a brutally honest and unbiased assessment of their own personality. Often, researchers corroborate responses by asking the person’s close friends or family members – but these individuals will have their own biases.

Despite this, many researchers still defend the Big Five model. It works in some groups, and has harmonised personality research, allowing academics to share and compare their work, they say. “The question is: to what extent do we need to modify it or be aware of its limitations?” says Erik Gahner Larsen at the University of Kent.

Journal reference: Science Advances, DOI: 10.1126/sciadv.aaw5226

Read the whole story
CrystalEdg
17 days ago
reply
Share this story
Delete

Anatomy of a Fake News Scandal

1 Share

This story was reported in partnership with The Investigative Fund and Reveal from the Center for Investigative Reporting. Additional reporting: Aaron Sankin, Laura Starecheski, Michael Corey, Jaime Longoria and Jasper Craven.

The revelations overcame Edgar Maddison Welch like a hallucinatory fever. On December 1st, 2016, the father of two from Salisbury, North Carolina, a man whose pastimes included playing Pictionary with his family, tried to persuade two friends to join a rescue mission. Alex Jones, the Info-Wars host, was reporting that Hillary Clinton was sexually abusing children in satanic rituals a few hundred miles north, in the basement of a Washington, D.C., pizza restaurant. Welch told his friends the “raid” on a “pedo ring” might require them to “sacrifice the lives of a few for the lives of many.” A friend texted, “Sounds like we r freeing some oppressed pizza from the hands of an evil pizza joint.” Welch was undeterred. Three days later, armed with an AR-15 semiautomatic rifle, a .38 handgun and a folding knife, he strolled into the restaurant and headed toward the back, where children were playing ping-pong. As waitstaff went table to table, whispering to customers to get out, Welch maneuvered into the restaurant’s kitchen. He shot open a lock and found cooking supplies. He whipped open another door and found an employee bringing in fresh pizza dough. Welch did not find any captive children – Comet Ping Pong does not even have a basement – but he did prove, if there were any lingering doubts after the election, that fake news has real consequences.

Welch’s arrest was the culmination of an election cycle dominated by fake news – and by attacks on the legitimate press. Several media outlets quickly traced the contours of what became known as Pizzagate: The claim that Hillary Clinton was a pedophile started in a Facebook post, spread to Twitter and then went viral with the help of far-right platforms like Breitbart and Info-Wars. But it was unclear whether Pizzagate was mass hysteria or the work of politicos with real resources and agendas. It took the better part of a year (and two teams of researchers) to sift through the digital trail. We found ordinary people, online activists, bots, foreign agents and domestic political operatives. Many of them were associates of the Trump campaign. Others had ties with Russia. Working together – though often unwittingly – they flourished in a new “post-truth” information ecosystem, a space where false claims are defended as absolute facts. What’s different about Pizzagate, says Samuel Woolley, a leading expert in computational propaganda, is it was “retweeted and picked up by some of the most powerful faces of American politics.”

The original Pizzagate Facebook post appeared on the evening of October 29th, 2016, a day after then-FBI Director James Comey announced that the bureau would be reopening its investigation into Clinton’s use of a private e-mail server while secretary of state. Data from the server had been found on electronics belonging to former Rep. Anthony Weiner (the husband of Clinton’s close aide Huma Abedin), who had been caught texting lewd messages to a 15-year-old. On Facebook, a user named Carmen Katz wrote, “My NYPD source said its much more vile and serious than classified material on Weiner’s device. The email DETAIL the trips made by Weiner, Bill and Hillary on their pedophile billionaire friend’s plane, the Lolita Express. Yup, Hillary has a well documented predilection for underage girls. . . . We’re talking an international child enslavement and sex ring.”

Katz’s Facebook profile listed her residence as Joplin, Missouri. With a link to a story headlined “Breaking: Hillary Clinton strategy memo leaked: ‘Steal yard signs,’ ” Katz posted, “You know how we handle yard sign theft or tampering in South Missouri? With a 3 prong garden hoe buried in the middle of the back.” We found no record of anyone with the name Carmen Katz in the entire state. But searching through her online activity, we noticed another clue: Every time she posted petitions on <a href="http://Change.org" rel="nofollow">Change.org</a>, such as “Put Donald Trump’s Face on Mount Rushmore,” the last signer was invariably Cynthia Campbell of Joplin. Campbell used the same profile picture as “Carmen Katz” on Facebook – that is, the same snapshot of the same cat.

For more than 20 years, a 60-year-old attorney named Cynthia Campbell has practiced law out of her bungalow-style home in Joplin. In April, I began trying to contact her, asking if she was behind the initial Pizzagate post. Within days, the Carmen Katz Facebook account disappeared. I went to Campbell’s house to try in person. A large NRA sticker adorned the screen door; on the porch was feline statuary and gardening equipment, including a three-pronged hoe. She didn’t answer but later texted and called me. Campbell said yes, she set up the Facebook account, but it was hacked two or three years ago. She never explicitly denied posting the comment that started Pizzagate. Instead, she told me to disregard the NRA sticker – she just “supports hunting.” She also claimed to be a rare Democrat in southwest Missouri. “You don’t say much,” she said. “You don’t stick signs out.”

Social-media accounts are routinely- hacked, but the next morning, when Campbell texted me 21 times, she sounded every bit like the user behind the original Carmen Katz post. “Stalking and harassing innocent people who have done nothing to you is wrong, evil and illegal,” she wrote. “You should be helping people get their lives and health back going through such nightmares, not piling on, harassing them, making them feel unsafe and preyed upon.” She threatened to report me to both the ACLU and Best Buy’s Geek Squad.

“[P]eople like you don’t give a shit that you destroy innocent humans’ lives,” she said. “Go back to your soul-sucking job. . . . You are fake news!”

In this Friday Dec. 9, 2016 file photo, flowers and notes left by well-wishers are displayed outside Comet Ping Pong, the pizza restaurant in Washington. There's at least a slice of good news for a pizza restaurant in the nation's capital that has been the target of fake news stories linking it to a child sex trafficking ring. In almost a week since an armed man arrived at Comet Ping Pong to investigate the conspiracy, neighbors and patrons have responded by bringing homemade signs, flowers and their pizza-purchasing power to the store.

It strains the imagination to think how Campbell – a cat lady in Missouri – had pieced together not only the story that Clinton was a sex-trafficking pedophile, but its details: NYPD officials, Weiner’s laptop, Jeffrey Epstein’s private jet. According to Clint Watts, a cyber and homeland-security expert at the Foreign Policy Research Institute, Katz fits neatly into a well-worn blueprint for disinformation campaigns. For a story to gain traction, propagandists plant false information on anonymous chat boards, hoping real people will pick it up and add a “human touch” to acts of digital manipulation. “If you want to sow a conspiracy, you seed it someplace – 4chan or Reddit is a perfect vehicle,” he says, and wait for someone like Katz to take the bait. “Someone or some group,” Watts says, “possibly took this unwitting woman and made her the source that they need.”

On a pair of anonymous message boards, we found several possible seeds of Pizzagate. On July 2nd, 2016, someone calling himself FBIAnon, who claimed to be a “high-level analyst and strategist” for the bureau, hosted an Ask Me Anything forum on 4chan. He claimed to be leaking government secrets – á la Edward Snowden – out of a love for country, but it wasn’t always clear which country he meant. At various times, he wrote, “Russia is more a paragon of freedom and nationalism than any other country” and “We are the aggressors against Russia.” FBIAnon’s secrets were about the Department of Justice’s inquiry into the Clinton Foundation, which federal prosecutors never formalized. “Dig deep,” he wrote. “Bill and Hillary love foreign donors so much. They get paid in children as well as money.”

“Does Hillary have sex with kidnapped girls?” a 4channer asked.

“Yes,” FBIAnon answered.

Another possible germ of Pizzagate appeared online about 10 hours before Katz posted her story on Facebook. TheeRANT describes itself as a message board for “New York City cops speaking their minds.” Virtually everyone on the site uses an identity-masking screen name. Favorite topics include police body cameras (bad) and George Soros (worse). On October 29th, 2016, someone calling himself “Fatoldman” posted that he had a “hot rumor” about the FBI investigation.
“[T]he feds were forced to reopen the hillary email case [because] apparently the NYPD sex crimes unit was involved in the weiner case,” Fatoldman wrote. “On his laptop they saw emails. [T]hey notified the FBI. Feds were afraid that NYPD would go public so they had to reopen or be accused of a coverup.”

Someone posted the news to a law enforcement Facebook group. From there, a user called Eagle Wings (@NIVIsa4031) posted it to Twitter. Eagle Wings’ profile picture shows a smiling middle-aged woman above the description “USAF Vet believes Freedom Soars.” Among her more influential followers are former deputy assistant to President Trump Sebastian Gorka and former national security adviser Gen. Michael Flynn, who actually shared a separate Eagle- Wings tweet last year. Eagle Wings’ enthusiastic following likely has something to do with membership in “Trumps WarRoom,” a private group of online activists who share and amplify political messages. Participants told Politico’s Shawn Musgrave that hundreds, perhaps even thousands, of pro-Trump rooms coalesced during the campaign. “The members aren’t stereotypical trolls,” Musgrave tells me. “Most are baby boomers.” A lot are women from the Midwest.

But Eagle Wings is not a typical political enthusiast, says Woolley, who directs research at the Institute for the Future’s Digital Intelligence Lab. She tweets too often (more than 50,000 times since November 2015) to too many followers (120,000 as of November 2017). “Without a shadow of a doubt,” he says, “Eagle Wings is a highly automated account [and] part of a bot network” – a centrally controlled group of social-media accounts. To explain how they work, Ben Nimmo, a fellow at the Atlantic Council’s Digital Forensic Research Lab, uses a shepherding analogy. “A message that someone or some organization wants to ‘trend’ is typically sent out by ‘shepherd’ accounts,” he says, which often have large followings and are controlled by humans. The shepherds’ messages are amplified by ‘sheepdog’ accounts, which are also run by humans but can be default-set “to boost the signal and harass critics.” At times, the shepherds personally steer conversations, but they also deploy automation, using a kind of Twitter cruise control to retweet particular keywords and hashtags. Together, Nimmo says, the shepherds and sheepdogs guide a herd of bots, which “mindlessly repost content in the digital equivalent of sheep rushing in the same direction and bleating loudly.”

Whether Katz repeated something a herd of bots was bleating, or repackaged tidbits found on other parts of the Internet, her Facebook post was the “human touch” that helped the fake news story go viral. The “tell,” says Watts, was what happened next. Most of us post into Internet oblivion. But about 12 hours after Katz shared her story, a Twitter user named @DavidGoldbergNY tweeted a screenshot of her post, twice – adding, “I have been hearing the same thing from my NYPD buddies too. Next couple days will be -interesting!”

On Twitter, @DavidGoldbergNY described himself as a “Jew, Lawyer & New Yorker.” The account went live around the time of the Republican National Convention, in July 2016, posting divisive tweets like “Attacking the 1 percent is attacking 43 percent of the Jewish community.” The account’s profile picture – a man with a nose Photoshopped to look very large and hooked – has been used online for more than a decade. Based on the limited threads that have been archived, Woolley says, @DavidGoldbergNY appears to have been, like Eagle Wings, “highly automated” and part of “an organized effort” – possibly a bot network – to spread disinformation. One of @DavidGoldbergNY’s tweets about the Katz Facebook post was retweeted 6,369 times.

What’s nearly impossible to tell is who ran @DavidGoldbergNY. The handle is not among the 2,752 Twitter accounts linked to the Internet Research Agency, a disinformation shop run by the Kremlin, which the House Intelligence Committee released in November. And Twitter has yet to make public the handles of an additional 36,746 bot accounts its attorney Sean Edgett told Congress have “characteristics we used to associate an account with Russia.” In any case, Russia is not the only one playing this game. “We’ve also had sources tell us that using bot networks has become a common practice among U.S. political campaigns,” says Woolley, a practice that is difficult to trace. “They do it with subcontractors,” he explains. “And the Federal Election Commission doesn’t require reporting for subcontractors.” One thing that does stand out, he adds, is “the more sophisticated bot nets, the ones that are successful at spreading stories, are built by people with a lot of resources. In our experience, across multiple different countries, the people that have deep pockets are the powerful political actors.”

According to a sample of tweets with Pizzagate or related hashtags provided by Filippo Menczer, a professor of informatics at Indiana University, Pizzagate was shared roughly 1.4 million times by more than a quarter of a million accounts in its first five weeks of life – from @DavidGoldbergNY’s tweet to the day Welch showed up at Comet Ping Pong. The vast majority of tweeters in our sample, just 10 percent of all possible hits, posted about the story only a few times. But more than 3,000 accounts in our set tweeted about Pizzagate five times or more. Among these were dozens of users who tweet so frequently – up to 900 times a day – that experts believe they were likely highly automated. Even more striking: 22 percent of the tweets in our sample were later deleted by the user. This could be a sign, Woolley says, of “someone sweeping away everything so that we can’t follow the trail.”

Next, we decided to cross-reference the most frequent Pizzagate tweeters with a list of 139 handles associated with Trump campaign staffers, advisers and surrogates. We also ran our entire sample against the list of accounts linked to Russia’s Internet Research Agency. We found that at least 14 Russia-linked accounts had tweeted about Pizzagate, including @Pamela_Moore13, whose avatar is, aptly, an anonymous figure wrapped in an American flag; that account has been retweeted by such prominent Trump supporters as Donald Trump Jr., Ann Coulter and Roger Stone, the political operative who recommended Paul Manafort as Trump’s campaign manager. (Special Counsel Robert Mueller recently indicted Manafort for money laundering as part of his investigation into possible collusion with Russian efforts to influence the presidential race.) “Well! Well! Well!” “Pamela Moore” tweeted on November 19th, 2016, above the fake news headline “FBI: Rumors About Clinton Pedophile Ring Are True.”

The campaign’s engagement went far deeper. We found at least 66 Trump campaign figures who followed one or more of the most prolific Pizzagate tweeters. Michael Caputo, a Trump adviser who tweeted frequently about Clinton’s e-mails, followed 146 of these accounts; Corey Stewart, Trump’s campaign chair in Virginia, who lost a tight primary race for governor in June, followed 115; Paula White-Cain, Trump’s spiritual adviser, followed 71; Pastor Darrell Scott, a prominent member of Trump’s National Diversity Coalition, followed 33. Flynn’s son, Michael Flynn Jr., who followed 58 of these accounts, famously took the bait and was ousted from the Trump transition team in early December after tweeting, “Until #Pizzagate proven to be false, it’ll remain a story.”

Many of the Pizzagate tweeters had the characteristics of political bots – Twitter handles made up of random or semi-random letters and numbers and twin passions for conservative politics and pets (puppies and kitties win audience, Watts says). Others were all too human. Crystal Kemp, a 50-year-old grandmother who lives in Confluence, Pennsylvania, tweeted about the story more than 4,000 times in five weeks. I reached out to her via Facebook to ask why. “Didn’t want Hillary to win at any cost,” Kemp tells me, “but liked Trump from day one. I don’t really know that much about the Pizzagate thing. Everything I tweeted or retweeted was stuff that I found through my own research or from another follower.”

Kemp tweeted links to articles from well-known right-wing sites like Fox News and Breitbart. But she also shared stories from obscure outlets like <a href="http://ConservativeDailyPost.com" rel="nofollow">ConservativeDailyPost.com</a>, which appears to be among the fake-news sites that operated from Macedonia during the election. Buzzfeed had found that teenagers in the deindustrialized town of Veles published pro-Trump stories because they were profitable as click-bait. When I traveled to Macedonia last summer, Borce Pejcev, a computer programmer who has set up dozens of fake-news sites – for around 100 euros each – said it wasn’t quite that simple. Macedonians don’t invent fake news stories, he told me. “No one here knows anything about American politics. They copy and paste from American sites, maybe try to come up with more dramatic headline.” Fox News, <a href="http://TruePundit.com" rel="nofollow">TruePundit.com</a>, <a href="http://DailyCaller.com" rel="nofollow">DailyCaller.com</a>, InfoWars and Breitbart, he said, were among the Macedonians’ most common source material (“Breit-bart was best”). Macedonians would’ve happily copied anti-Trump fake news too, he said. “Unfortunately, there weren’t any good U.S. pro-Clinton fake-news sites to copy and paste.”

That was exactly how the right-wing-media ecosystem worked during the 2016 campaign, explains Yochai Benkler, who directs the Berkman-Klein Center for the Internet and Society at Harvard. After the election, he and his colleagues mapped about 2 million campaign-news stories. He found that far-right-media outlets were organized extremely tightly around Breitbart and, to a lesser degree, <a href="http://FoxNews.com" rel="nofollow">FoxNews.com</a>. “The right paid attention to right-wing sites, and the more right-wing they were, the more attention they got,” Benkler says. More extreme sites would distort and exaggerate the claims, but they would use a “relatively- credible source” such as Breitbart as a validator. “Because they were repeated not only on the very far-fringe sites but also by sites that are at the center of this cluster, the right-wing disinformation circulated and amplified very quickly.”

Douglas Hagmann is a self-employed private investigator and host of <a href="http://HagmannReport.com" rel="nofollow">HagmannReport.com</a>, a webcast that exposes the “New World Order agenda.” It was Hagmann who – four days after Carmen Katz first posted the story and six days before Election Day – brought Pizzagate from social media to fake news’ largest stage. On the November 2nd broadcast of InfoWars, arguably the most influential conspiracy-theory outlet in the country, with 7.7 million unique visitors to its website a month, Alex Jones asked Hagmann to tell his audience what sources had revealed about the e-mails recovered on Weiner’s computer. “[T]he most disgusting aspect of this is the sexual angle,” Hagmann said. “I don’t want to be graphic or gross here. . . . Based on my source, Hillary did in fact participate on some of the junkets on the Lolita Express.”

The story took off. Google Trends measures interest in topics among the 1.17 billion users of its search engine on a 0-100 scale. On October 29th, the day Katz posted the story on Facebook, searches for “Hillary” and “pedophile” ranked zero. Ninety-six hours later, when Hagmann “broke” the story on InfoWars, they scored 100.

In April, Hagmann agreed to meet with me for a look at his “courtroom-ready” documents on Pizzagate. His split-level home in Erie, Pennsylvania, is on a quiet leafy street. In the front yard, there’s a small waterfall, a rock garden and a large sign warning that the place is under surveillance. He greeted me in the foyer wearing a suit and tie, his hair slicked back with Brylcreem, and led the way downstairs to his basement broadcast center.

In October 2016, Hagmann claimed, he “communicated” with a friend who knows someone affiliated with the NYPD. The friend of the friend had been on the “task force” that secured Weiner’s computer and had copied documents onto a thumb drive “proving” Clinton and her associates were involved in pedophilia. “Now, I can’t get him to give me the thumb drive,” he said. “Or even admit to the fact that he had it.” When I asked how he knew the files existed, he said, “I trust my source.”

Hagmann then launched into a synopsis of three decades of rumors that Clinton and her associates are lesbians and perverts. He started with the claims of Cathy O’Brien, a conspiracy theorist from Muskegon, Michigan, who alleged that while held as a CIA sex slave, she was forced to service Hillary Clinton. Hagmann moved on to Clinton’s “close” relationship with Weiner’s estranged wife, and the allegation that her campaign manager, John Podesta, and his brother Tony resemble sketches of the suspects in the 2007 disappearance of four-year-old Madeleine McCann in Portugal. “Sorry,” Hagmann stopped himself. “I know this case is difficult. Circumstantial.”

When I asked if he had verified anything, Hagmann shuffled some papers, lifting one sheet by a corner, like a poker player. With apparent reluctance, he turned over a color copy of an image showing a clean, uninjured boy wearing a green T-shirt in a dog cage. The child could have been playing or held hostage. “That might be a disturbing image,” I said. “But I don’t see what it has to do with Hillary Clinton.” He shrugged. “You could say I have dog crap for answers and dog crap for sources,” he said, adding later, “I hope you don’t think this was a waste.”

The following month, at Awaken to the Shakin’, a Bible conference in Gurnee, Illinois, Hagmann presented his evidence to an audience of about 40 middle-aged churchgoers. His courtroom-ready exhibits included the Wikipedia entry for “fake news,” the New Oxford Dictionary definition of “post-truth,” a quote by John Wayne, a photo of people sitting on a couch wearing horse masks, a photo of scars on the fingers of John Podesta. And the kicker – a photo of a decapitated body that Hagmann said was a victim of serial killer Jeffrey Dahmer and another of a sculpture by Louise Bourgeois in Tony Podesta’s home, ironically titled “The Arch of Hysteria.” The two images, he said, are shockingly similar.

All the same, two days after Hagmann’s appearance on InfoWars, Erik Prince, the brother of Trump’s secretary of education, Betsy DeVos, “confirmed” that the terrible rumor was true in an interview on Breitbart. Prince is best known as the founder of the private military company Blackwater USA, whose mercenaries shot and killed 17 unarmed Iraqi civilians in Baghdad’s Nisour Square in 2007. He donated $250,000 to the Trump campaign and became an informal adviser on intelligence and security issues, traveling to the Seychelles during the transition to meet with a Kremlin associate in an attempt to create back-channel communications between Moscow and the president-elect. On Breitbart radio, Prince painted a picture sure to stir the far right. “Because of Weinergate and the sexting scandal, the NYPD started investigating,” he said. “They found a lot of other really damning criminal information, including money-laundering, including the fact that Hillary went to this sex island with convicted pedophile Jeffrey Epstein. Bill Clinton went there more than 20 times. Hillary Clinton went there at least six times.”

The right-wing-media system went into overdrive. Prince’s story was picked up and embellished by other right-wing outlets, and made its way back to InfoWars that afternoon. Citing Prince’s interview, Jones fumed, “When I think about all the children Hillary Clinton has personally murdered and chopped up and raped . . . yeah, you heard me right. Hillary Clinton has personally murdered children.” Jones’ video was viewed on YouTube more than 427,000 times. Prince’s interview was shared another 81,000 times. On Twitter, the numbers were increasing exponentially- – 300 percent in just six days.

Long before October 28th, 2016, when Comey wrote to Congress that the FBI would be reexamining Clinton’s use of a private e-mail server, her campaign knew they had a huge e-mail problem. In focus groups, voters conflated the case with the e-mails Russian operatives had hacked from the Democratic National Committee and Podesta, her campaign manager. Though U.S. intelligence agencies now agree that a Kremlin–associated group, Fancy Bear, hacked the e-mails – which WikiLeaks began posting less than an hour after The Washington Post published Trump’s “grab them by the pussy” video – a senior Clinton campaign staffer tells me, “There was just more voyeuristic interest in the content of the e-mails than in how they were obtained.”

The confusion was encouraged online by the likes of @DavidGoldbergNY. The e-mails on Weiner’s laptop had nothing to do with Podesta’s Gmail account, but one of his tweets of the Katz post included #podestaemails23. “That hashtag is a flag,” Woolley says. “It suggests that @DavidGoldbergNY is attempting to get people to look at something.” On message boards, amateur sleuths searched for encoded evidence in the Podesta e-mails. A particular source of fascination was an invitation from the performance artist Marina Abramovic for Podesta to attend a “Spirit Cooking dinner.” Allegations started circulating that Clinton consumed semen, breast milk and menstrual blood.

The story still hadn’t penetrated Clinton’s campaign headquarters. They’d become inured to the avalanche of fake news – the rumors that she was on her deathbed, funding ISIS, even dissed by the pope. But when a Clinton campaign staffer noticed “Podesta Spirit Cooking Emails Reveal Clinton’s Inner Circle as Sex Cult with Connections to Human Trafficking” on <a href="http://DangerandPlay.com" rel="nofollow">DangerandPlay.com</a> become “Podesta Practices Occult Magic” on the Drudge Report, and then saw Alex Jones shouting that Clinton “is an abject, psychopathic demon from hell,” who “smell[s] like sulfur,” he went straight into Podesta’s office at the campaign’s Brooklyn headquarters. “You’re not going to believe it,” the aide told him. “Now you’re a fucking witch.”

It got even weirder after users on 8chan read a Podesta e-mail that revealed that Democratic activist David Brock had dated the owner of Comet Ping Pong pizzeria, James Alefantis. The citizen investigators considered Brock their archenemy – he’d founded Correct the Record, a Super PAC that defended Clinton against defamation by online trolls. Suddenly, they saw sinister meaning in any mention of pizza; for instance, the first letters in the words “cheese pizza” are the same as in “child porn.”

Until November 2016, the Pizzagate hashtag had mostly referred to Trump’s use of a fork and knife to eat pizza. But on November 4th, two days after Hagmann’s appearance on InfoWars, Cassandra Fairbanks, then a reporter for Sputnik News (which U.S. intelligence says spreads Kremlin-directed- disinformation), tweeted, “I’ve literally spent the last hour wondering if podesta ingested sperm mixed with breast milk with his brother.” In response, another user, @GodlessNZ, appears to have launched the hashtag: “Tweets assembling under #JohnMolesta and maybe #PizzaGate.”

That day, Alefantis got a phone call from a reporter at The Washington City Paper seeking a comment about a rumor going viral on Reddit. “What’s Reddit?” Alefantis asked.

It was just beginning. Even as the election came and went, several Twitter accounts tweeted exclusively about Pizzagate to a number of alt-right “influencers” – among them InfoWars and Brittany Pettibone, one of a handful of alt-right “girls” who regularly appear at the movement’s events. At least one single-minded account, @Pizza_Gate, likely caught the attention of Mehmet Ali Önel, a Turkish TV anchor. The network Önel works for is linked to the government of President Recep Tayyip Erdoan, which was facing international condemnation (including from the Obama State Department) for proposing a law that would risk decriminalizing pedophilia for offenders who married their victims. Önel, who has 196,000 Twitter followers, was one of dozens of Turkish commentators who claimed Americans had no right calling out Turkey for sex crimes with Pizzagate erupting in their own capital. One of the most shared Pizzagate tweets was posted by the anchor on November 16th. Roughly translated, it reads, “USA #PizzaGate shaken by the pedophilia scandals.”

Among the users who picked up the thread was Jack Posobiec, a well-known alt-right troll whom Trump himself has retweeted. During the campaign, Posobiec was special-projects director for Citizens for Trump, a never-officially-organized voter-fraud prevention group. Several hours after Önel sent his November 16th tweet, Posobiec went to investigate Comet Ping Pong and another nearby pizzeria. Live-streaming the visit on Periscope, he described evidence of “what’s really going on” – a double pane of glass near an oven, security cameras, a texting cashier. Posobiec paused, worrying his viewers might not understand the situation. “It’s like in the movie Jurassic Park,” he said. “Nedry had the shaving cream bottle. And you could press the top and a little bit of shaving cream came out. . . . The bottom part is where they had the dinosaur embryos.”

The Twittersphere went wild. The previous day, our sample indicates there were roughly 6,000 tweets about Pizzagate. Now, it was closer to 55,000. Alefantis tried and failed to get Facebook and Twitter to remove the posts. (Both companies declined to comment for this story.) When the restaurant started getting death threats, Alefantis called the police, then the FBI, and got nowhere. “It turns out you can say anything about anyone online,” he says. “It’s your First Amendment right to terrorize.”

Alefantis thought he’d finally scored a victory when The New York Times published an article debunking Pizzagate. He learned what the Clinton campaign found out too late. As Harvard’s Benkler puts it, “The right-wing-media ecosystem had become so hyperpartisan, so self-referential and so superinsular it often simply ignored information that’s disconfirming.” Instead, right-wing social media referenced mainstream coverage as a way to “legitimate” their claims. On November 21st, the day the Times published its story, our sample shows Twitter traffic about Pizzagate hit unprecedented levels: some 120,000 tweets.

Trolls on message boards began posting whole “dossiers” of private information about Comet Ping Pong employees and top Democrats, down to the movies that Podesta ordered on Netflix. On November 22nd, when Reddit banned a Pizzagate subreddit for posting obviously stolen private information, a moderator responded, “We have all made life insurance videos. We have all vowed to continue this fight. You have only increased our number. This morning we were numerous, tonight we are legion.” About 145,000 tweets flew that day.

The next day, InfoWars posted a video called “Pizzagate Is Real.” On November 27th, Jones spent a half-hour explaining the story. “Something’s being covered up,” he told his audience. “All I know is, God help us, we’re in the hands of pure evil.” Hours later, he released another video, “Down the #Pizzagate Rabbit Hole.” On December 1st, the show posted “Pizzagate: The Bigger Picture.” In North Carolina, Edgar Maddison Welch was obsessively watching much of this coverage. By the evening of December 4th, he was in solitary confinement in a Washington, D.C., jail.

Nearly a year after the election, in three separate hearings with members of Congress, executives from Twitter, Facebook and Google took turns expressing contrition for hosting Russia’s attempts to manipulate U.S. public opinion. A Facebook vice president said it “pains us as a company” that foreign actors “abused our platform.” Twitter’s general counsel said he too was “troubled” that the power of Twitter was misused.

“There was this concept of ‘Social media is going to save democracy,’ ” Woolley tells me. “Twitter didn’t envision that powerful political actors were going to use social media in attempts to spread propaganda.” Among the many strange aspects of Pizzagate was the fact that the story went viral after the election. All of the Russia-linked tweets we found were sent after November 8th. Bot networks appear to be tweeting out the hashtag to this day. Woolley suggests it could be an attempt to “bolster” Trump’s position, to “win over people’s hearts and minds.” Clinton had lost the presidency, he says, but “she was not done in terms of her ability to be a representative of democratic ideals, or of the ideals that were oppositional to Donald Trump.”

Watts, the cyber-security expert, doesn’t know if Russia and the Trump campaign colluded on Pizzagate, or anything else. But both camps were clearly opportunistic. “You can’t say that there was no indigenous support,” he says. “The Russians don’t create this whole [alt-right] movement. They just harness it.” Of course, so did Trump. But Watts believes the Russians, at least, are playing for much higher stakes than one presidential election. “The goal is to create division between communities,” he says. “It is making you not trust the state. It’s eroding the mandate of elected officials so that they can’t govern properly. It’s making people want to not participate in democracy because they think it’s corrupt. It’s getting you to either believe that it’s all stacked against you or you just opt out altogether because you don’t know what to believe. When you don’t know what to believe, you’ll believe anything.”

To learn more about how #Pizzagate spread, tune in to Reveal, distributed by PRX. Download the episode at revealnews.org/podcast starting Nov. 18. 

Read the whole story
CrystalEdg
18 days ago
reply
Share this story
Delete

DailyMed - ZOLOFT- sertraline hydrochloride tablet, film coated

1 Share

Updated May 27, 2020

If you are a consumer or patient please visit this version.

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use ZOLOFT safely and effectively. See full prescribing information for ZOLOFT. ZOLOFT (sertraline hydrochloride) tablets, for oral use ZOLOFT (sertraline hydrochloride) oral solution

    Initial U.S. Approval: 1991

    • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients ( 5.1)
    • Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1)

    ZOLOFT is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of ( 1):

    • Major depressive disorder (MDD)
    • Obsessive-compulsive disorder (OCD)
    • Panic disorder (PD)
    • Post-traumatic stress disorder (PTSD)
    • Social anxiety disorder (SAD)
    • Premenstrual dysphoric disorder (PMDD)
    IndicationStarting DosageMaximum Dosage
    MDD ( 2.1) 50 mg per day200 mg per day
    OCD ( 2.1) 25 mg per day (ages 6–12)
    50 mg per day (ages 13)
    200 mg per day
    PD, PTSD, SAD ( 2.1) 25 mg per day200 mg per day
    PMDD ( 2.2) continuous dosing 50 mg per day150 mg per day
    PMDD ( 2.2) intermittent dosing 50 mg per day during luteal phase only100 mg per day during luteal phase only
    • If inadequate response to starting dosage, titrate in 25–50 mg per day increments once weekly in MDD, OCD, PD, PTSD, and SAD ( 2.1)
    • See Full Prescribing Information for titration in PMDD ( 2.2)
    • Hepatic impairment:
      • Mild: Recommended starting and maximum dosage is half recommended dosage ( 2.4)
      • Moderate or severe: Not recommended ( 2.4)
    • When discontinuing ZOLOFT, reduce dose gradually ( 2.6, 5.4)
    • Oral solution: Must be diluted before administration ( 2.7)
    • Tablets: 25 mg, 50 mg and 100 mg ( 3)
    • Oral solution: 20 mg/mL ( 3)
    • Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4, 7.1)
    • Concomitant use of pimozide ( 4, 7.1)
    • Known hypersensitivity to sertraline or excipients ( 4, 5.4)
    • ZOLOFT oral solution only: Concomitant use of disulfiram ( 4)
    • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue ZOLOFT and initiate supportive treatment. ( 5.2)
    • Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk. ( 5.3)
    • Activation of Mania/Hypomania: Screen patients for bipolar disorder. ( 5.4)
    • Seizures: Use with caution in patients with seizure disorders. ( 5.6)
    • Angle Closure Glaucoma: Avoid use of antidepressants, including ZOLOFT, in patients with untreated anatomically narrow angles. ( 5.7)
    • QTc Prolongation: ZOLOFT should be used with caution in patients with risk factors for QTc prolongation. ( 5.10)

    Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled MDD, OCD, PD, PTSD, SAD and PMDD clinical trials were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1)


    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" rel="nofollow">www.fda.gov/medwatch</a> .

    • Protein-bound drugs: Monitor for adverse reactions and reduce dosage of ZOLOFT or other protein-bound drugs (e.g., warfarin) as warranted. ( 7.1, 12.3)
    • CYP2D6 substrates: Reduce dosage of drugs metabolized by CYP2D6 ( 7.1, 12.3)
    • Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the neonate ( 8.1)
    • Pediatric use : Safety and effectiveness of ZOLOFT in pediatric patients other than those with OCD have not been established ( 8.4)

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 4/2019

  • Table of Contents
  • BOXED WARNING (What is this?)

    WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

    Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [See Warnings and Precautions (5.1)].

  • 1 INDICATIONS AND USAGE

    ZOLOFT is indicated for the treatment of the following [See Clinical Studies (14)] :

    • Major depressive disorder (MDD)
    • Obsessive-compulsive disorder (OCD)
    • Panic disorder (PD)
    • Posttraumatic stress disorder (PTSD)
    • Social anxiety disorder (SAD)
    • Premenstrual dysphoric disorder (PMDD)
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD

    The recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage.

    For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week.

    2.2 Dosage in Patients with PMDD

    The recommended starting ZOLOFT dosage in adult women with PMDD is 50 mg per day. ZOLOFT may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle.

    • When dosing continuously, patients not responding to a 50 mg dosage may benefit from dosage increases at 50 mg increments per menstrual cycle up to 150 mg per day.
    • When dosing intermittently, patients not responding to a 50 mg dosage may benefit from increasing the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle.

    2.3 Screen for Bipolar Disorder Prior to Starting ZOLOFT

    Prior to initiating treatment with ZOLOFT or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [See Warnings and Precautions (5.4)].

    2.4 Dosage Modifications in Patients with Hepatic Impairment

    Both the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage [See Dosage and Administration (2.1, 2.2)] . The use of ZOLOFT in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10–15) is not recommended [See Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

    2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant

    At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of ZOLOFT. In addition, at least 14 days must elapse after stopping ZOLOFT before starting an MAOI antidepressant [See Contraindications (4), Warnings and Precautions (5.2)] .

    2.6 Discontinuation of Treatment with ZOLOFT

    Adverse reactions may occur upon discontinuation of ZOLOFT [See Warnings and Precautions (5.5)]. Gradually reduce the dosage rather than stopping ZOLOFT abruptly whenever possible.

    2.7 Preparation of ZOLOFT Oral Solution

    ZOLOFT oral solution must be diluted before use.

    • Use the supplied calibrated dropper to measure the amount of ZOLOFT oral solution needed
    • Note: The supplied calibrated dropper has 25 mg and 50 mg graduation marks only
    • Mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. After mixing, a slight haze may appear, which is normal.

    Instruct patients or caregivers to immediately take the dose after mixing.

  • 3 DOSAGE FORMS AND STRENGTHS

    25 mg tablets: light green film-coated, engraved on one side with "ZOLOFT" and on the other side scored and engraved with "25 mg"

    50 mg tablets: light blue film-coated, engraved on one side with "ZOLOFT" and on the other side scored and engraved with "50 mg"

    100 mg tablets: light yellow film-coated, engraved on one side with "ZOLOFT" and on the other side scored and engraved with "100 mg"

    Oral solution: a clear, colorless solution with a menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper that has 25 mg and 50 mg graduation marks.

  • 4 CONTRAINDICATIONS

    ZOLOFT is contraindicated in patients:

    In addition to the contraindications for all ZOLOFT formulations listed above, ZOLOFT oral solution is contraindicated in patients:

    • Taking disulfiram. ZOLOFT oral solution contains alcohol, and concomitant use of ZOLOFT and disulfiram may result in a disulfiram-alcohol reaction.
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

    In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

    No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

    It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.

    Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing ZOLOFT, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

    5.2 Serotonin Syndrome

    Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including ZOLOFT, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [See Contraindications (4), Drug Interactions (7.1)] . Serotonin syndrome can also occur when these drugs are used alone.

    Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

    The concomitant use of ZOLOFT with MAOIs is contraindicated. In addition, do not initiate ZOLOFT in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking ZOLOFT, discontinue ZOLOFT before initiating treatment with the MAOI [See Contraindications (4), Drug Interactions (7.1)] .

    Monitor all patients taking ZOLOFT for the emergence of serotonin syndrome. Discontinue treatment with ZOLOFT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ZOLOFT with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

    5.3 Increased Risk of Bleeding

    Drugs that interfere with serotonin reuptake inhibition, including ZOLOFT, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

    Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

    5.4 Activation of Mania or Hypomania

    In patients with bipolar disorder, treating a depressive episode with ZOLOFT or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with ZOLOFT. Prior to initiating treatment with ZOLOFT, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

    5.5 Discontinuation Syndrome

    Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.6)] .

    5.6 Seizures

    ZOLOFT has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. ZOLOFT should be prescribed with caution in patients with a seizure disorder.

    5.7 Angle-Closure Glaucoma

    The pupillary dilation that occurs following use of many antidepressant drugs including ZOLOFT may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including ZOLOFT, in patients with untreated anatomically narrow angles.

    5.8 Hyponatremia

    Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including ZOLOFT. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

    In patients with symptomatic hyponatremia, discontinue ZOLOFT and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [See Use in Specific Populations (8.5)] .

    5.9 False-Positive Effects on Screening Tests for Benzodiazepines

    False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking ZOLOFT. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of ZOLOFT. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish ZOLOFT from benzodiazepines [See Drug Interactions (7.3)] .

    5.10 QTc Prolongation

    During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP) have been reported. Most reports were confounded by other risk factors. In a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and serum sertraline concentration. Therefore, ZOLOFT should be used with caution in patients with risk factors for QTc prolongation [See Drug Interactions (7.1), Clinical Pharmacology (12.2)] .

  • 6 ADVERSE REACTIONS

    The following adverse reactions are described in more detail in other sections of the prescribing information:

    6.1 Clinical Trials Experience

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

    The data described below are from randomized, double-blind, placebo-controlled trials of ZOLOFT (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to ZOLOFT for 8 to12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males.

    The most common adverse reactions (≥5% and twice placebo) in all pooled placebo-controlled clinical trials of all ZOLOFT-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of ZOLOFT (≥5% and twice placebo) by indication that were not mentioned previously.

    • MDD: somnolence;
    • OCD: insomnia, agitation;
    • PD: constipation, agitation;
    • PTSD: fatigue;
    • PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain;
    • SAD: insomnia, dizziness, fatigue, dry mouth, malaise.

    Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials

    In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received ZOLOFT discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in ZOLOFT-treated patients:

    • MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%).
    • MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.
    • OCD: somnolence.
    • PD: nervousness and somnolence.

    Male and Female Sexual Dysfunction

    Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

    Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of ZOLOFT-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido.

    Adverse Reactions in Pediatric Patients

    In 281 pediatric patients treated with ZOLOFT in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety.

    Other Adverse Reactions Observed During the Premarketing Evaluation of ZOLOFT

    Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with ZOLOFT were:

    • Cardiac disorders – tachycardia
    • Ear and labyrinth disorders – tinnitus
    • Endocrine disorders - hypothyroidism
    • Eye disorders - mydriasis, blurred vision
    • Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage
    • General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia
    • Hepatobiliary disorders - elevated liver enzymes
    • Immune system disorders - anaphylaxis
    • Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite
    • Musculoskeletal and connective tissue disorders - arthralgia, muscle spasms, tightness, or twitching
    • Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope
    • Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination
    • Renal and urinary disorders - hematuria
    • Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage
    • Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning
    • Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura; erythematous, follicular, or maculopapular rash; urticaria
    • Vascular disorders - hemorrhage, hypertension, vasodilation

    6.2 Post-marketing Experience

    The following adverse reactions have been identified during postapproval use of ZOLOFT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    • Bleeding or clotting disorders - increased coagulation times (altered platelet function)
    • Cardiac disorders - AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes) [See Clinical Pharmacology (12.2)]
    • Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH
    • Eye disorders - blindness, optic neuritis, cataract
    • Hepatobiliary disorders - severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis
    • Hemic and lymphatic disorders - agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness
    • Immune system disorders - angioedema
    • Metabolism and nutrition disorders - hyponatremia, hyperglycemia
    • Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus
    • Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis
    • Psychiatric disorders - psychosis, enuresis, paroniria
    • Renal and urinary disorders - acute renal failure
    • Respiratory, thoracic and mediastinal disorders - pulmonary hypertension
    • Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)
    • Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis
  • 7 DRUG INTERACTIONS

    7.1 Clinically Significant Drug Interactions

    Table 5 includes clinically significant drug interactions with ZOLOFT [See Clinical Pharmacology (12.3)] .

    7.2 Drugs Having No Clinically Important Interactions with ZOLOFT

    Based on pharmacokinetic studies, no dosage adjustment of ZOLOFT is necessary when used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam, lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when ZOLOFT is administered concomitantly [See Clinical Pharmacology (12.3)] .

    7.3 False-Positive Screening Tests for Benzodiazepines

    False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking ZOLOFT. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of ZOLOFT. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive [See Data] . There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including ZOLOFT, during the third trimester of pregnancy [See Clinical Considerations].

    Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m 2 basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD [See Data] .

    The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing ZOLOFT.

    ZOLOFT oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.

    Clinical Considerations

    Disease-associated maternal and/or embryo/fetal risk

    A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

    Fetal/Neonatal adverse reactions

    Exposure to SSRIs and SNRIs, including ZOLOFT in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).

    When treating a pregnant woman with ZOLOFT during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to ZOLOFT in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data].

    Data

    Human Data

    Third Trimester Exposure

    Neonates exposed to ZOLOFT and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [See Warnings and Precautions (5.2)] .

    Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1–2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997–2005 found a PPHN risk ratio of 2.4 (95% CI 1.2–4.3) associated with patient-reported maternal use of SSRIs "in early pregnancy" and a PPHN risk ratio of 3.6 (95% CI 1.2–8.3) associated with a combination of patient-reported maternal use of SSRIs "in early pregnancy" and an antenatal SSRI prescription "in later pregnancy".

    First Trimester Exposure

    The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88–1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70–1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations.

    Animal Data

    Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m 2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m 2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (0.8 times the MRHD on a mg/m 2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m 2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.

    8.2 Lactation

    Risk Summary

    Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [See Data] . There are no data on the effects of sertraline on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZOLOFT and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

    Data

    In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants.

    8.4 Pediatric Use

    The safety and efficacy of ZOLOFT have been established in the treatment of OCD in pediatric patients aged 6 to 17 [See Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] . Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients.

    Monitoring Pediatric Patients Treated with ZOLOFT

    Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [See Boxed Warning, Warnings and Precautions (5.1)] . Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as ZOLOFT.

    Weight Loss in Studies in Pediatric Patients with MDD

    In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50–200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between ZOLOFT and placebo of roughly 1 kg, for both children (ages 6–11) and adolescents (ages 12–17), in both age groups representing a slight weight loss for the ZOLOFT group compared to a slight gain for the placebo group. For children, about 7% of the ZOLOFT-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of ZOLOFT-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.

    A subset of patients who completed the randomized controlled trials in patients with MDD (ZOLOFT n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of ZOLOFT treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of ZOLOFT on the growth, development, and maturation in pediatric patients.

    Alcohol Content in ZOLOFT Oral Solution

    ZOLOFT oral solution contains 12% alcohol.

    Juvenile Animal Data

    A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.

    In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 – 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).

    8.5 Geriatric Use

    Of the total number of patients in clinical studies of ZOLOFT in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old.

    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. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    In 354 geriatric subjects treated with ZOLOFT in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3 [See Adverse Reactions (6.1)], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.

    SNRIs and SSRIs, including ZOLOFT, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [See Warnings and Precautions (5.8)] .

    8.6 Hepatic Impairment

    The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6 ) is half the recommended dosage due to increased exposure in this patient population. The use of ZOLOFT in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10–15) is not recommended, because ZOLOFT is extensively metabolized, and the effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied [See Dosage and Administration (2.4), Clinical Pharmacology (12.3)] .

    8.7 Renal Impairment

    No dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does not appear to be affected by renal impairment [See Clinical Pharmacology (12.3)] .

  • 9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    ZOLOFT contains sertraline, which is not a controlled substance.

    9.2 Abuse

    In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans, ZOLOFT did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs.

  • 10 OVERDOSAGE

    Human Experience

    The most common signs and symptoms associated with non-fatal ZOLOFT overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. No cases of fatal overdosage with only sertraline have been reported.

    Other important adverse events reported with ZOLOFT overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QTc-interval prolongation, Torsade de Pointes, serotonin syndrome, stupor, and syncope [See Clinical Pharmacology (12.2)] .

    Overdose Management

    No specific antidotes for ZOLOFT are known. Contact Poison Control (1-800-222-1222) for latest recommendations.

  • 11 DESCRIPTION

    ZOLOFT contains sertraline hydrochloride, an SSRI. Sertraline hydrochloride has a molecular weight of 342.7 and has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C 17H 17NCl 2∙HCl is represented by the following structural formula:

    Chemical Structure

    Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

    ZOLOFT tablets for oral administration contain 28.0 mg, 56.0 mg and 111.9 mg sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

    ZOLOFT oral solution is available in a multidose 60 mL bottle. Each mL of solution contains 22.4 mg sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral solution must be diluted prior to administration [See Dosage and Administration (2.7)] . The dispenser contains dry natural rubber.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

    12.2 Pharmacodynamics

    Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase.

    Alcohol

    In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by ZOLOFT.

    Cardiac Electrophysiology

    The effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N- desmethylsertraline concentrations. These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis [See Warnings and Precautions (5), Adverse Reactions (6), Drug Interactions (7), Overdosage (10)] .

    12.3 Pharmacokinetics

    Absorption

    Following oral once-daily ZOLOFT dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C max) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the C max and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. The single dose bioavailability of ZOLOFT tablets is approximately equal to an equivalent dose of ZOLOFT oral solution. Administration with food causes a small increase in C max and AUC.

    Metabolism

    Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40–45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40–45% of the administered radioactivity was accounted for in feces, including 12–14% unchanged sertraline.

    Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0–24-hour), C max and C min, with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.

    Protein Binding

    In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol.

    Studies in Specific Populations

    Pediatric Patients

    Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6–12 years, 32 aged 13–17 years) including both males (N=28) and females (N=33). Relative to the adults, pediatric patients aged 6–12 years and 13–17 years showed about 22% lower AUC (0–24 hr) and C max values when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed [See Dosage and Administration (2.1), Use in Specific Populations (8.4)] .

    Geriatric Patients

    Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of ZOLOFT for 14 days was approximately 40% lower than in a similarly studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females [See Use in Specific Populations (8.5)] .

    Hepatic Impairment

    In patients with chronic mild liver impairment (N=10: 8 patients with Child-Pugh scores of 5–6; and 2 patients with Child-Pugh scores of 7–8) who received 50 mg of ZOLOFT per day for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with normal hepatic function (N=10). The exposure to desmethylsertraline was approximately 2-fold greater in patients with mild hepatic impairment compared to age-matched volunteers with normal hepatic function. There were no significant differences in plasma protein binding observed between the two groups. The effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied [See Dosage and Administration (2.4), Use in Specific Populations (8.6)] .

    Renal Impairment

    Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30–60 mL/min), moderate to severe (CLcr=10–29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment [See Use in Specific Populations (8.7)] .

    Drug Interaction Studies

    Pimozide

    In a controlled study of a single dose (2 mg) of pimozide, 200 mg ZOLOFT (once daily) co-administration to steady state was associated with a mean increase in pimozide AUC and C max of about 40%, but was not associated with any changes in ECG. The highest recommended pimozide dose (10 mg) has not been evaluated in combination with ZOLOFT. The effect on QTc interval and PK parameters at doses higher than 2 mg of pimozide are not known [See Drug Interactions (7.1)] .

    Drugs Metabolized by CYP2D6

    Many antidepressant drugs (e.g., SSRIs, including ZOLOFT, and most tricyclic antidepressant drugs) inhibit the biochemical activity of the drug metabolizing isozyme CYP2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by CYP2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by CYP2D6 and that have a narrow therapeutic index (e.g., tricyclic antidepressant drugs and the Type 1C antiarrhythmics propafenone and flecainide). The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of CYP2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of MDD in the extent of clinically important 2D6 inhibition, and in fact ZOLOFT at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even ZOLOFT has the potential for clinically important 2D6 inhibition [See Drug Interactions (7.1)] .

    Phenytoin

    Clinical trial data suggested that ZOLOFT may increase phenytoin concentrations [See Drug Interactions (7.1)] .

    Cimetidine

    In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were increases in ZOLOFT mean AUC (50%), C max (24%) and half-life (26%) compared to the placebo group [See Drug Interactions (7.2)] .

    Diazepam

    In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in T max for desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03) [See Drug Interactions (7.2)] .

    Lithium

    In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-state lithium levels or the renal clearance of lithium [See Drug Interactions (7.2)] .

    Tolbutamide

    In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug [See Drug Interactions (7.2)] .

    Atenolol

    ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol [See Drug Interactions (7.2)] .

    Digoxin

    In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance [See Drug Interactions (7.2)] .

    Drugs Metabolized by CYP3A4

    In three separate in vivo interaction studies, ZOLOFT was co-administered with CYP3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that ZOLOFT did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that ZOLOFT's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that ZOLOFT 200 mg (once daily) induces the metabolism of cisapride (cisapride AUC and C max were reduced by about 35%) [See Drug Interactions (7.2)] .

    Microsomal Enzyme Induction

    Preclinical studies have shown ZOLOFT to induce hepatic microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg of ZOLOFT per day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

  • 13 NONCLINICALTOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10–40 mg/kg (0.25–1.0 times the MRHD on a mg/m 2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m 2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10–40 mg/kg (0.5–2.0 times the MRHD on a mg/m 2 basis) compared to placebo controls, this effect was not clearly drug related.

    Mutagenesis

    Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

    Impairment of Fertility

    A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m 2 basis in adolescents).

  • 14 CLINICAL STUDIES

    Efficacy of ZOLOFT was established in the following trials:

    14.1 Major Depressive Disorder

    The efficacy of ZOLOFT as a treatment for MDD was established in two randomized, double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

    • Study MDD-1 was an 8-week, 3-arm study with flexible dosing of ZOLOFT, amitriptyline, and placebo. Adult patients received ZOLOFT (N=126, in a daily dose titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N=123, in a daily dose titrated weekly to 50 mg, 100 mg, or 150 mg), or placebo (N= 130).
    • Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of ZOLOFT administered once daily at 50 mg (N=82), 100 mg (N=75), and 200 mg (N=56) doses and placebo (N=76) in the treatment of adult outpatients with MDD.

    Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose response relationship for effectiveness.

    A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50–200 mg/day. These patients (n=295) were randomized to continuation on double-blind ZOLOFT 50–200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo: ZOLOFT [n=11 (8%)] and placebo [n=31 (39%)]. The mean ZOLOFT dose for completers was 70 mg/day.

    Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

    14.2 Obsessive-Compulsive Disorder

    Adults with OCD

    The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult (age 18–65) non-depressed outpatients (Studies OCD-1, OCD-2, and OCD-3). Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score ranging from 23 to 25.

    • Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day, titrated in 50 mg increments every 4 days to a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT (N=43) experienced a mean reduction of approximately 4 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of 2 points in placebo-treated patients (N=44). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -3.79 (ZOLOFT) and -1.48 (placebo).
    • Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. ZOLOFT (N=240) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the Y-BOCS total score, which were statistically significantly greater than the approximately 3 point reduction in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -5.7 (pooled results from ZOLOFT 50 mg, 100 mg, and 150 mg) and -2.85 (placebo).
    • Study OCD-3 was a 12-week randomized, placebo controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. ZOLOFT (N=241) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was - 6.5 (ZOLOFT) and -3.6 (placebo).

    Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

    The effectiveness of ZOLOFT was studied in the risk reduction of OCD relapse. In Study OCD-4, patients ranging in age from 18–79 meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50–200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for analysis of discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the Y-BOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Insufficient clinical response during the double-blind phase indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and condition 3 being met at visit 3):

    • Condition 1: Y-BOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline;
    • Condition 2: CGI-I increased by ≥ one point; and
    • Condition 3: Worsening of the patient's condition in the investigator's judgment, to justify alternative treatment.

    Patients receiving continued ZOLOFT treatment experienced a statistically significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

    Pediatric Patients with OCD

    The effectiveness of ZOLOFT for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (ages 6–17) (Study OCD-5). ZOLOFT (N=92) was initiated at doses of either 25 mg/day (pediatric patients ages 6–12) or 50 mg/day (adolescents, ages 13–17), and then titrated at 3 and 4 day intervals (25 mg incremental dose for pediatric patients ages 6–12) or 1 week intervals (50 mg incremental dose adolescents ages 13–17) over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score of 22. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 units on the CY-BOCS total score which was statistically significantly greater than the 3 unit reduction for placebo patients (n=95). Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

    14.3 Panic Disorder

    The effectiveness of ZOLOFT in the treatment of PD was demonstrated in three double-blind, placebo-controlled studies (Studies PD-1, PD-2, and PD-3) of adult outpatients who had a primary diagnosis of PD (DSM-III-R), with or without agoraphobia.

    • Studies PD-1 and PD-2 were 10-week flexible dose studies of ZOLOFT (N=80 study PD-1 and N=88 study PD-2) compared to placebo (N=176 study PD-1 and PD-2). In both studies, ZOLOFT was initiated at 25 mg/day for the first week, then titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies PD-1 and PD-2. In these studies, ZOLOFT was shown to be statistically significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
    • Study PD-3 was a 12-week randomized, double-blind fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Patients receiving ZOLOFT (50 mg N=43, 100 mg N=44, 200 mg N=45) experienced a statistically significantly greater reduction in panic attack frequency than patients receiving placebo (N=45). Study PD-3 was not readily interpretable regarding a dose response relationship for effectiveness.

    Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.

    In Study PD-4, patients meeting DSM-III-R criteria for PD who had responded during a 52-week open trial on ZOLOFT 50–200 mg/day (n=183) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Insufficient clinical response in the double-blind phase indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits:

    • CGI-I ≥ 3;
    • meets DSM-III-R criteria for PD;
    • number of panic attacks greater than at baseline.

    Patients receiving continued ZOLOFT treatment experienced a statistically significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

    14.4 Posttraumatic Stress Disorder

    The effectiveness of ZOLOFT in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies PSTD-1 and PSTD-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies PSTD-1 and PSTD-2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.

    Studies PSTD-1 and PSTD-2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first week, and titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and tolerability. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively, for Studies PSTD-1 and PSTD-2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS), which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES), which measures intrusion and avoidance symptoms. Patients receiving ZOLOFT (N=99 and N=94, respectively) showed statistically significant improvement compared to placebo (N=83 and N=92) on change from baseline to endpoint on the CAPS, IES, and on the Clinical Global Impressions (CGI-S) Severity of Illness and Global Improvement (CGI-I) scores.

    In two additional placebo-controlled PTSD trials (Studies PSTD-3 and PSTD-4), the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies PSTD-1 and PSTD-2, while the second additional study was conducted in predominantly male veterans.

    As PTSD is a more common disorder in women than men, the majority (76%) of patients in Studies PSTD-1 and PSTD-2 described above were women. Post hoc exploratory analyses revealed a statistically significant difference between ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender effect is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.

    In Study PSTD-5, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50–200 mg/day (n=96) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits:

    • CGI-I ≥ 3;
    • CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and
    • worsening of the patient's condition in the investigator's judgment.

    Patients receiving continued ZOLOFT treatment experienced statistically significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

    14.5 Social Anxiety Disorder

    The effectiveness of ZOLOFT in the treatment of SAD (also known as social phobia) was established in two multicenter, randomized, placebo-controlled studies (Study SAD-1 and SAD-2) of adult outpatients who met DSM-IV criteria for SAD.

    Study SAD-1 was a 12-week, flexible dose study comparing ZOLOFT (50–200 mg/day), n=211, to placebo, n=204, in which ZOLOFT was initiated at 25 mg/day for the first week, then titrated to the maximum tolerated dose in 50 mg increments biweekly. Study outcomes were assessed by the:

    • Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety, and avoidance of social and performance situations, and
    • Proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved).

    ZOLOFT was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.

    Study SAD-2 was a 20-week, flexible dose study that compared ZOLOFT (50–200 mg/day), n=135, to placebo, n=69. ZOLOFT was titrated to the maximum tolerated dose in 50 mg increments every 3 weeks. Study outcome was assessed by the:

    • Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations,
    • Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and
    • CGI-I responder criterion of ≤ 2.

    ZOLOFT was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have statistically significantly more responders than placebo as defined by the CGI-I. Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome.

    In Study SAD-3, patients meeting DSM-IV criteria for SAD who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on ZOLOFT 50–200 mg/day were randomized to continuation of ZOLOFT or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase in the Clinical Global Impression Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving ZOLOFT continuation treatment experienced a statistically significantly lower relapse rate during this 24-week period than patients randomized to placebo substitution.

    14.6 Premenstrual Dysphoric Disorder

    The effectiveness of ZOLOFT for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies PMDD-1 and PMDD-2) conducted over 3 menstrual cycles in adult female patients. The effectiveness of ZOLOFT for PMDD for more than 3 menstrual cycles has not been systematically evaluated in controlled trials.

    Patients in Study PMDD-1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity referred to as PMDD in DSM-IV. Patients in Study PMDD-2 met DSM-IV criteria for PMDD. Study PMDD-1 utilized continuous daily dosing throughout the study, while Study PMDD-2 utilized luteal phase dosing (intermittent dosing) for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms was approximately 10.5 years in both studies. Patients taking oral contraceptives were excluded from these trials; therefore, the efficacy of ZOLOFT in combination with oral contraceptives for the treatment of PMDD is unknown.

    Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Rating Scale for Depression (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.

    • In Study PMDD-1, involving 251 randomized patients, (n=125 on ZOLOFT and n=126 on placebo), ZOLOFT treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, ZOLOFT was titrated in 50 mg increments at the beginning of each menstrual cycle up to a maximum of 150 mg/day on the basis of clinical response and tolerability. The mean dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual cycle was statistically significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
    • In Study PMDD-2, involving 281 randomized patients, (n=142 on ZOLOFT and n=139 on placebo), ZOLOFT treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses (intermittent dosing). In subsequent cycles, patients were dosed in the range of 50–100 mg/day in the luteal phase of each cycle, on the basis of clinical response and tolerability. Patients who received 100 mg/day started with 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT administered in the late luteal phase of the menstrual cycle was statistically significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint (Week 12).

    There was insufficient information to determine the effect of race or age on outcome in these studies.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING


    ZOLOFT 50 mg tablets: light blue, film-coated, capsular-shaped tablets engraved on one side with "ZOLOFT" and on the other side scored and engraved with "50 mg"

    Store ZOLOFT at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Suicidal Thoughts and Behaviors

    Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [See Boxed Warning and Warnings and Precautions (5.1)] .

    Important Administration Instructions for Oral Solution

    For patients prescribed ZOLOFT oral solution, inform them that:

    • ZOLOFT oral solution must be diluted before use. Do not mix in advance.
    • Use the dropper provided to remove the required amount of ZOLOFT oral solution and mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix ZOLOFT oral solution with anything other than the liquids listed.
    • Take the dose immediately after mixing. At times, a slight haze may appear after mixing; this is normal.
    • The dropper dispenser contains dry natural rubber, a consideration for patients with latex sensitivity.

    Disulfiram Contraindication for ZOLOFT Oral Solution

    Inform patients not to take disulfiram when taking ZOLOFT oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution [See Contraindication (4)] .

    Serotonin Syndrome

    Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [See Warnings and Precautions (5.2), Drug Interactions (7.1)] .

    Increased Risk of Bleeding

    Inform patients about the concomitant use of ZOLOFT with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [See Warnings and Precautions (5.3)].

    Activation of Mania/Hypomania

    Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them

    to report such symptoms to the healthcare provider [See Warnings and Precautions (5.4)] .

    Discontinuation Syndrome

    Advise patients not to abruptly discontinue ZOLOFT and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when ZOLOFT is discontinued [See Warnings and Precautions (5.5)].

    Allergic Reactions

    Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [See Adverse Reactions (6.2)] .

    Pregnancy

    Inform pregnant women that ZOLOFT may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [See Use in Specific Populations (8.1)] .

  • SPL UNCLASSIFIED SECTION

    This product's label may have been updated. For current full prescribing information, please visit <a href="http://www.pfizer.com" rel="nofollow">www.pfizer.com</a>.

    LAB-0218-41.0

  • MEDICATION GUIDE

    LAB-0540-9.0
    Revised January 2018

  • PRINCIPAL DISPLAY PANEL - 50 mg Tablet Bottle Label

    ALWAYS DISPENSE WITH MEDICATION GUIDE

    Zoloft ® (sertraline hydrochloride)

    tablets

50 mg*

Rx only

image

Read the whole story
CrystalEdg
32 days ago
reply
Share this story
Delete

RSS Feeds

1 Share

What is an RSS feed?
An RSS feed is a stream of information that can be delivered conveniently and automatically through a simple application. RSS (Really Simple Syndication) information is transferred as XML code. Subscribing to an RSS feed is an easy way to keep up with news and information that's important to you, without having to browse or search for information on websites.

What is an RSS reader?
An RSS reader is a piece of software that collects and displays an RSS feed's XML information in a form that people can read. RSS readers allow users to manage and organize their feed subscriptions in a central location.

Where can I get an RSS reader?
Some browsers have built-in RSS readers. If you are using a browser that doesn't currently support RSS, an online search will quickly produce a range of options. Most RSS Readers are free to download and use.

How do I use RSS Feeds?
The process of adding an RSS feed differs slightly from one RSS reader to the next. Follow the steps below to add a new feed (also referred to as a "channel") to your RSS reader:

  1. Choose an RSS reader.
  2. Click on the link or small RSS button near the feed you want to add -- for example, " New/Modified Opportunities by Agency." (You will see a page displaying XML code.)
  3. From your web browser's address bar, copy the URL (web address). For example, the URL you would copy for "New/Modified Opportunities by Agency" is: https://www.grants.gov/rss/GG_OppModByCategory.xml.
  4. Paste that URL into the "Add New Channel" section of the RSS reader. The RSS feed will start to display and regularly update the headlines for you.

Using RSS Feeds:
Grants.gov introduced the Opportunity Modification RSS feeds as an alternative to receiving multiple emails for updates to grant opportunities. Now, applicants can view – at their convenience and in one place – all new grant opportunities and updates to existing grant opportunities.

Available RSS Feeds:
New Opportunities by Agency- Receive a listing of new opportunities by agency name.

New Opportunities by Category- Receive a listing of new opportunities by category.

Modified Opportunities by Agency- Receive a listing of recently modified opportunities by agency name.

Modified Opportunities by Category- Receive a listing of recently modified opportunities by category.

Read the whole story
CrystalEdg
61 days ago
reply
Share this story
Delete

Caller ID Spoofing | Federal Communications Commission

1 Share

Read the whole story
CrystalEdg
66 days ago
reply
Share this story
Delete
Next Page of Stories