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March 13, 2015 Day 53 of the Seventh Year - History

March 13, 2015 Day 53 of the Seventh Year - History


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President Barack Obama visits with Sgt. 1st Class Cory Remsburg and family members at his newly finished home in Gilbert, Arizona, March 13, 2015. Remsburg suffered a severe brain injury in Afghanistan several years ago and has made remarkable progress.


10:05AM THE PRESIDENT departs Los Angeles, California en route Phoenix, Arizona
Los Angeles International Airport

MST

11:15AM THE PRESIDENT arrives in Phoenix, Arizona
Phoenix Sky Harbor International Airport, Phoenix, Arizona

12:10PM THE PRESIDENT receives a briefing on veterans issues
Phoenix VA Medical Center, Phoenix, Arizona

3:25PM THE PRESIDENT departs Phoenix, Arizona
Phoenix Sky Harbor International Airport, Phoenix, Arizona

EDT

8:00PM In-Town Travel Pool Call Time

10:00PM THE PRESIDENT arrives Joint Base Andrews

10:15PM THE PRESIDENT arrives the White House
South Lawn


Pi Day Hits a Milestone That Comes Only Once a Century: 3/14/15

Pi Day was dreamed up 27 years ago to celebrate 3.14 on 3/14, but this year the geek dial is being turned up to 15 — as in 3/14/15. And this'll be the only year until 2115 that you can turn the dial up to the max, at 3/14/15, 9:26:53, an exact match for pi's first 10 digits.

As a matter of fact, there are two opportunities to celebrate the mysteries of 3.141592653 on Saturday.

"One of my former students sent me an email stating that he is going to celebrate the once-in-a-century Pi Day by eating pie both at 9:26:53 a.m. and 9:26:53 p.m.," Aziz Inan, an electrical engineering professor at the University of Portland, told NBC News in an email.


2015: The Year in Mass Shootings

So far this year there have been 353 mass shootings in the United States. Here they are.

Tessa Stuart

Tessa Stuart's Most Recent Stories

Mass shootings have happened almost every day in America this year &mdash often more than once a day. They happen in backyards and at block parties, in mansions and housing projects, in quiet neighborhoods and at rowdy bars, at schools, restaurants, churches, gas stations and grocery stores. They are random, and they are premeditated. They happen during dice games, family dinners, funerals and sweet sixteens.

So far this year there have been 353 mass shootings in the United States, according the Mass Shooting Tracker, a crowd-sourced database. (The tracker defines a mass shooting as one in which at least four people are killed or wounded the FBI uses three dead or wounded as its criteria.)

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Here they all are, including Wednesday’s attack in San Bernardino &mdash the deadliest shooting in the U.S. since Sandy Hook.

January 1, 2015: Five wounded when a shooter opened fire on a party bus in Memphis, Tennessee.

January 2, 2015: One dead, four injured in a domestic dispute in Savannah, Georgia.

January 4, 2015: Three dead, one wounded in the early morning, in southeast Dallas, Texas.

January 6, 2015: One killed, three wounded in a drive-by shooting in Miami, Florida.

January 7, 2015: One dead, three wounded, including a one-year-old, in Chattanooga, Tennessee.

January 8, 2015: One dead, three wounded when a gunman opened fire on a car in Boston, Massachusetts.

January 9, 2015: Four dead in a San Francisco California’s Hayes Valley neighborhood.

January 10, 2015: Three dead, one wounded after a shooting spree in Moscow, Idaho.

January 11, 2015: Five wounded during a party hosted by R&B singer Chris Brown in San Jose, California.

Two dead, five wounded at a party in Hope Mills, North Carolina.

One dead, three wounded during a botched home invasion in Lakeland, Florida.

Five wounded at an off-campus party near Tuskegee University in Tuskegee, Alabama.

January 12, 2015: Two dead, two wounded in a fight outside a bar in Wichita, Kansas.

January 13, 2015: Five wounded in a shooting inside a bar in Portsmouth, Virginia.

January 14, 2015: Two dead, three wounded at a house party in Rockford, Illinois.

January 19, 2015: Two dead, five wounded in a 100-person brawl at a car wash in San Antonio, Texas.

January 20, 2015: One dead, three wounded at an apartment complex in Clarksville, Tennessee.

January 23, 2015: Six wounded at a party in Boston, Massachusetts’s Jamaica Plain neighborhood.

January 24, 2015: Three dead, five wounded at a party in Omaha, Nebraska.

Four dead, one wounded &mdash three generations of women in one family &mdash in Queens, New York.

January 26, 2015: One dead, three wounded, including a pair of cousins, in Stockton, California.

January 28, 2015: One dead, three wounded inside a home in DeKalb, Georgia.

January 29, 2015: Five dead inside a home in LaGrange, Georgia.

February 1, 2015: Six wounded at a family birthday party in a pub in Syracuse, New York.

One killed, four wounded at an intersection in New York City’s Hamilton Heights neighborhood.

February 4, 2015: Four dead in a murder-suicide in King, North Carolina

February 5, 2015: Three dead, three wounded at a barbershop in Warrensville Heights, Ohio.

February 6, 2015: One dead, three wounded at barbershop in in Tulsa, Oklahoma.

February 7, 2015: Five dead, two wounded in family home outside at Atlanta.

February 8, 2015: Six wounded in the parking lot outside a bar and grill in Maury City, Tennessee.

February 9, 2015: Three dead, one wounded inside a mobile home in Moon Lake, Florida.

February 15, 2015: Five wounded in a drive-by shooting in Long Beach, California.

February 17, 2015: One dead, three wounded at an America’s Best Value Inn and Suites in Little Rock, Arkansas.

February 22, 2015: Three dead, two injured, including a sheriff and a deputy, in a shoot-out in Clarkesville, Georgia.

Four wounded inside a nightclub in Charleston, South Carolina.

Four dead, one wounded at a home in Killeen, Texas.

February 25, 2015: Three dead, two wounded during a robbery at a duplex in Houston, Texas.

February 27, 2015: Nine dead, one wounded in shooting spree that spanned six locations across Tyrone, Missouri.

February 28, 2015: One dead, three wounded in the middle of the afternoon in Baltimore, Maryland’s Hillen neighborhood.

Four dead in a shooting spree that first struck a barbershop, then a mobile home park in Tarboro, North Carolina.

Three dead, one wounded outside a home in Columbia, Missouri.

March 1, 2015: Four wounded in a drive-by shooting in Tangelo Park, Florida.

One dead, five wounded at a community center in Detroit, Michigan.

March 2, 2015: One dead, four wounded at a Mexican restaurant in Santa Ana, California.

March 3, 2015: Three dead, one wounded outside an apartment complex in Las Vegas, Nevada.

March 4, 2015: Two dead, five wounded in a pair of shootings at a nightclub and a gas station in San Bernardino, California.

March 9, 2015: One dead, three wounded, including a mother who was placing her two-year-old son in a carseat outside a friend’s home, in Chicago, Illinois.

March 10, 2015: Five wounded in a pair of shootings at two strip clubs in Columbus, Georgia.

March 11, 2015: Four wounded at a party in Aurora, Illinois.

March 13, 2015: Two dead, three wounded after a man in Brookhaven, Mississippi, shot his landlord and his landlord’s wife and children.

March 14, 2015: Five wounded at three different crime scenes in Atlanta, Georgia.

March 15, 2015: Four wounded at a party in Lillington, North Carolina.

Three dead, one wounded by a fugitive in Houston County, Alabama.

March 16, 2015: Four wounded at a birthday party in Compton, California.

March 17, 2015: Three dead, four wounded outside a grocery store in Stockton, California.

March 18, 2015: One dead, five wounded in string of shootings across Mesa, Arizona.

One dead, three wounded in the middle of the afternoon, near a school in Newark, New Jersey.

March 19, 2015: Two dead, two wounded after a domestic dispute in Navajo Nation, in Arizona.

March 20, 2015: Four wounded at park in Columbus, Mississippi.

Four wounded inside an apartment complex in Oklahoma City, Oklahoma.

Four wounded after a dice game in Joliet, Illinois.

One dead, five wounded after a drive-by shooting in Lancaster, Texas.

March 21, 2015: Four wounded on the patio of a restaurant in Ybor City, Florida.

Five wounded at 16-year-old’s birthday party in Lehigh Acres, Florida.

March 22, 2015: One dead, six injured at a skate park in Albuquerque, New Mexico.

March 23, 2015: One dead, four wounded in a drive-by shooting in Clarksville, Tennessee.

March 24, 2015: Four dead inside a home Indianapolis, Indiana.

March 26, 2015: Four wounded near an elementary school in Amarillo, Texas.

March 28, 2015: Seven wounded during a spring break party in Panama City Beach, Florida.

March 29, 2015: Four wounded, including a ten-year-old girl, after a biker brawl in Stockton, California.

March 30, 2015: Four dead in a murder-suicide at a home in Tulsa, Oklahoma.

April 2, 2015: Five wounded in an afternoon drive-by shooting in Baltimore, Maryland.

April 3, 2015: Four wounded, all college students, during a house party in Daytona Beach, Florida.

April 5, 2015: One dead, four wounded after a fight early on Easter Sunday in Louisville, Kentucky.

Five wounded, including a toddler and two preschoolers, inside a town house in Indianapolis, Indiana.

April 7, 2015: One dead, three wounded outside a home in Rome, Georgia.

April 16, 2015: Five dead after an argument about a family business turned violent in Phoenix, Arizona.

One dead, four wounded when gunfire broke out near an elementary and middle school in Los Angeles, California.

April 18, 2015: One dead, three wounded, including a high school basketball star, in Paterson, New Jersey.

Four wounded at a birthday party in Charlotte, North Carolina.

One dead, three wounded in a mobile home park in Lumberton, North Carolina.

Five wounded outside a club in Williamsport, Pennsylvania.

Five wounded in a residential neighborhood of Montgomery, Alabama.

April 19, 2015: Four wounded in a housing project in Richmond, Virginia.

April 21, 2015: Two dead, three wounded at two apartment complexes in Killeen, Texas.

April 25, 2015: Four wounded in an early evening shooting in Trenton, New Jersey.

One dead, six wounded inside a pub in Gates, New York

April 27, 2015: Two dead, four wounded outside a funeral in Brooklyn, New York.

Two dead, two wounded near “bales of marijuana” in the desert outside Gila Bend, Arizona.

May 1, 2015: Two dead, three wounded during a family fight in Milwaukee, Wisconsin.

May 3, 2015: Four dead, one wounded on a walking bridge in Menasha, Wisconsin.

Four wounded in South Bend, Indiana, after a watch party for the Mayweather-Pacquiao fight.

Six wounded after a fight at nightclub in Houston, Texas.

One dead, six wounded at a house in Dayton, Ohio.

May 4, 2015: Four wounded at a house party in the Bronx.

One dead, three wounded inside a house in Buffalo, New York.

May 7, 2015: Four wounded in a drive-by shooting in Cincinnati, Ohio.

May 10, 2015: Four wounded in a drive-by shooting in Jersey City, New Jersey.

One dead, four wounded, including a pregnant woman, in Cleveland, Ohio, on Mother’s Day.

One dead, three wounded after a motorcycle blessing in Newark, New Jersey.

May 12, 2015: One dead, four wounded in Capitol Heights, Maryland.

Five dead &mdash all members of the same family &mdash in Tucson, Arizona.

May 13, 2015: Four dead, including a four-year-old and a 17-month-old, in Anchorage, Alaska.

May 16, 2015: Five wounded at a vigil for a victim of gun violence in Milwaukee, Wisconsin.

Five wounded a couple hours before the Preakness, and a few miles from Pimlico Race Course in Baltimore, Maryland.

Four wounded on a residential street in Rochester, New York.

May 17, 2015: Nine dead, 18 wounded after a fight broke out inside a Twin Peaks restaurant in Waco, Texas.

May 18, 2015: One dead, four wounded after a game of craps in Miami, Florida.

Four wounded after a graduation ceremony in Kinloch, Missouri.

May 19, 2015: One dead, three wounded, including two police officers, in Arlington, Virginia.

May 20, 2015: One dead, four wounded at five crime scenes within a one-mile radius in Baltimore, Maryland.

May 23, 2015: Two dead, two wounded at a house party in Fresno, California.

May 24, 2015: Four wounded on a Sunday night in St. Louis, Missouri.

One dead, three wounded after gunfire broke out in a crowd in Montgomery, Alabama.

Seven wounded in a parking lot in Flint, Michigan.

Five wounded outside a bar in Brockton, Massachusetts.

May 25, 2015: One dead, four wounded at a concert in Decatur, Illinois.

May 26, 2015: Two dead, two wounded in the parking lot of a New Orleans apartment complex.

May 28, 2015: Four wounded inside a car in Omaha, Nebraska.

One dead, three wounded on a sidewalk in Chester, Pennsylvania.

Five wounded, including a two-year-old girl, in Chicago, Illinois.

May 29, 2015: One dead, three wounded in front of a grocery store in Miami, Florida.

May 30, 2015: Four wounded at a motorcycle club in San Diego, California.

One dead, three wounded at a Freemason Hall in North Amityville, New York.

May 31, 2015: Three dead, one wounded, including a Vietnam veteran, in Cleveland, Ohio.

One dead, three wounded inside a liquor store, then a house, in Conyers, Georgia.

One dead, three wounded in the middle of the afternoon at a park in Springdale, Maryland.


Recipes (1)

Old Calendar: Third Sunday of Lent

He found in the temple area those who sold oxen, sheep, and doves, as well as the money-changers seated there. He made a whip out of cords and drove them all out of the temple area, with the sheep and oxen, and spilled the coins of the money-changers and overturned their tables, and to those who sold doves he said, "Take these out of here, and stop making my Father's house a marketplace." His disciples recalled the words of scripture, "Zeal for your house will consume me (John 2:12-14)."

Today is the Feast of St. John of God which is superseded by the Sunday Liturgy.

Sunday Readings
The first reading is taken from the Book of Exodus 20:1-17. When God had freed the Chosen People from the slavery of Egypt, He led them to Mount Sinai. There he made a Covenant with the Israelites through which He promised to make them His own people, to lead them into the Promised Land, and to protect them from their enemies there. The Israelites were to reverence Him and Him only as their Lord, and they were to obey the moral and cultic laws which He laid down for them.

The second reading is from the letter of St. Paul to the Corinthians 1:22-25. In these few sentences St. Paul gives us the basic reasons which motivated opposition to the gospel message on the part of Jews and Gentiles. The Jews because Christ did not fit the preconceived ideas they had formed of the Messiah and the Gentiles because they looked to philosophy or human "wisdom" for the solution of man's problems.

The Gospel is from St. John 2:13-25. If we had only the Synoptic gospels (Mt., Mk., Lk.) we could easily conclude that Jesus spent almost all his public life and did all his preaching in Galilee and its neighborhood. St. John who wrote his gospel several years later corrects this false impression by mentioning visits made by our Lord to Jerusalem, He gave the "leaders of the people" in Jerusalem plenty of opportunity of hearing his message and his claims. He also worked some astounding miracles in or near the city. For instance, the man crippled for thirty-eight years (Jn. 5) the man born blind (Jn. 9), the raising of Lazarus who had been four days buried (Jn. 11). St. John makes it very clear that the leaders (the priests and Pharisees) in Jerusalem were given every opportunity to learn who Jesus was, and every help to believe in him, but they would not. The fault was theirs, therefore, and the loss.

On this particular visit he made it clear to them that he was someone special, someone close to God whose house they were desecrating, and whom he even called his Father. In hidden language he told them that they would put him to death but that that would not be the end, for he would rise again. Some of them seem to have remembered this saying of his after they had put him to death, for they asked Pilate to place a guard on his tomb lest his disciples should remove the body and pretend he had risen for: "we recall," they said, "that this impostor said while he was still living, 'after three days I shall rise again"' (Mt. 27 : 63). But even the miracle of his resurrection did not affect the majority of them. They had made up their minds and "there are none so blind as those who will not see."

The reasons for their blindness were the same as those that keep millions of the neo-pagans of today from accepting and living the Christian faith. These, like the priests and Pharisees of Jerusalem in the year 28, are so immersed in the affairs of this world that they can give no thought to their own future. Their eyes are so fixed on the earthly objectives that they have set themselves, that they can see nothing else. The priests and Pharisees wanted more than political freedom from Rome. They had hopes that their Messiah would give them a great world empire, and with it wealth and power without limit. Our contemporaries' aims may not go so far, but worldly aims are important enough in their eyes to make them exclude from their minds the thought of anything higher. Yet, they have more than enough reminders whichever way they turn to recall their minds to the historical facts of Christianity. This is 2006 A.D., that is 2006 years since the birth of Christ. Who was he, why was he born, why does the world divide its history into before he came, B.C., and after he came, A.D.? In every town and village of our once Christian western world there is a church or two with steeples pointing to the sky. Why? What do churches mean to men? Near every town there are cemeteries or "sleeping places," according to the meaning of that Greek word. Are those buried there only sleeping and waiting to be called, if not already called, or are they finished forever just like the ox or the unthinking cow that may be buried in the next field.

The agnostics and free-thinkers of our day should start to think about the real facts of life—the central ones of which are that Christ, who was the Son of God, took our human nature and lived for some time on this earth, so that he would raise us up to sonship with God. He suffered crucifixion, because the world was full of sin when he came. But his death made atonement to the heavenly Father for all the sins of the world. His resurrection from the dead was the prelude and the guarantee that we shall all rise to a life of glory in heaven, if only we have followed him faithfully during our years on earth.

Excerpted from The Sunday Readings by Fr. Kevin O'Sullivan, O.F.M.

The Station is in the basilica of St. Lawrence outside the walls. The name of this, the most celebrated of the martyrs of Rome, would remind the catechumens that the faith they were about to profess would require them to be ready for many sacrifices. In the primitive Church, the third Sunday in Lent was called Scrutiny Sunday, because it was on this day that they began to examine the catechumens, who were to be admitted to Baptism on Easter night.

Commentary for the Readings in the Extraordinary Form:
Third Sunday of Lent

"When (Jesus) cast out the devil, the dumb man spoke." But as indicated by the little whining group to the right, some complained: "By Beelzebub, the prince of devils, He casts out devils" (Gospel).

Formerly, on this day, candidates were examined in preparation for Baptism on Holy Saturday. The first effect of Baptism is to free the souls from the power of the devil. The house of which Jesus speaks, is the human soul before His coming, degraded by idolatry, by sensuality, under the tyranny of the evil spirit.

Mary holding the Infant (pictured in the upper left corner) is a symbol of our Baptism. Mary gives birth to us as members of the Mystical Body of her Christ. Moreover, like her, "blessed are they who hear the word of God and keep it" (Gospel).

These baptismal duties of death to sin and life in God (Epistle are meant to gladden, not to oppress the human heart (Offertory), intended by God for Divine possession (Communion Verse), safe from diabolical obsession.

Excerpted from My Sunday Missal, Confraternity of the Precious Blood


Turn March 5 Into A 'Hug Day' For This 8-Year-Old Boy

There are lots of ways to give back in the world, but this little boy is simply asking for a hug.

As explained in the video above, 8-year-old Sebastian from Toronto will be undergoing surgery on March 5 to remove the last parts of a brain tumour he was first treated for at the age of four.

But now this little boy has discovered the Internet, and has made a request of his mother: to gather together as many people to hug each other on that date in order to not only give him strength, but her as well.

He may not realize exactly how much his request could help. After all, hugs can do anything from alleviating fears to helping our hearts, and they definitely, definitely remind us how much others care.

Watch the video to hear how Sebastian believes this will help him heal, and don't forget — hug everyone you see on March 5.

UPDATE: Since this story was written, Sebastian's tale has been spread around the world, and March 5 has been designated Give-a-Hug Day by the Brain Tumour Foundation of Canada. Make sure to spread the love today!


Programming routines

Microsoft Excel / LibreOffice Calc

Where the return type '21' is ISO-8601 (week starting on Monday).

In Excel 2007 your best choice is WEEKNUM(TODAY(),2) (2=week starting Monday).
WEEKNUM(TODAY()) will show the week number with weeks starting on Sunday (return type = 1).

Google Docs Spreadsheet

Type (here '21') is compatible with Excel/LibreOffice, 21 is ISO-8601

or date("W", epoch) for other week numbers. Remember to use capital 'W' not 'w'.

Python

Replace time with other epoch/UNIX timestamps for other week numbers.

JavaScript

Extend the Date class using the above code.

MySQL

Replace now() with other dates eg. SELECT WEEKOFYEAR('2021-02-20')
(You can also use the WEEK function with mode=3 select week(now(),3) )

PostgreSQL

MS SQL

Oracle

IW: Week of year (1-52 or 1-53) based on the ISO-8601 standard.
WW: Week of year (1-53) where week 1 starts on the first day of the year and continues to the seventh day of the year (Mostly NOT used)

ISeries SQL

IPhone/Mac

IPhone/iOS/Swift

Replace Time.now with Time.local(year,month,day) for other dates.
Formats:
%U - Week number of the year, starting with the first Sunday as the first day of the first week (00..53)
%V - Week number of year according to ISO-8601 (01..53)
%W - Week number of the year, starting with the first Monday as the first day of the first week (00..53)

Linux/Unix shell (bash)

Returns the ISO-8601 week number.
Other formats under 'Ruby'. More details in the Linux Programmer's Manual


Analyst Price Targets (38)

1515 3rd Street
San Francisco, CA 94158
United States
415 612 8582
http://www.uber.com

Sector(s) : Technology
Industry : Software—Application
Full Time Employees : 22,200

Uber Technologies, Inc. develops and operates proprietary technology applications in the United States, Canada, Latin America, Europe, the Middle East, Africa, and the Asia Pacific. It connects consumers with independent providers of ride services for ridesharing services and other forms of transportation services, including public transit, as well as connect riders and other consumers with restaurants, grocers, other stores, and delivery service providers for meal preparation, grocery, and other delivery services. The company operates through four segments: Mobility, Delivery, Freight, and Advanced Technologies Group (ATG) and Other Technology Programs. The Mobility segment provides products that connect consumers with mobility drivers who provide rides in a range of vehicles, such as cars, auto rickshaws, motorbikes, minibuses, or taxis. It also offers Uber for Business, financial partnerships, transit, and vehicle solutions offerings. The Delivery segment allows consumers to search for and discover local restaurants, order a meal, and either pick-up at the restaurant or have the meal delivered, as well as offers grocery and convenience store delivery, and select other goods. The Freight segment connects carriers with shippers on the company's platform and enable carriers upfront, transparent pricing, and the ability to book a shipment. The ATG and Other Technology Programs segment engages in the development and commercialization of autonomous vehicle and ridesharing technologies, as well as Uber Elevate. The company was formerly known as Ubercab, Inc. and changed its name to Uber Technologies, Inc. in February 2011. Uber Technologies, Inc. was founded in 2009 and is headquartered in San Francisco, California.


Timeline of Selected FDA Activities and Significant Events Addressing Opioid Misuse and Abuse

This timeline provides chronological information about FDA activities and significant events related to opioids, including abuse and misuse.

1911-1999

1911 to 1990s

Opioid pain medications were used primarily for acute pain and cancer pain. Studies showing inadequate treatment of chronic non-cancer pain by physicians lead to an increased use of opioids.

May: MS Contin, (morphine sulfate) approved first formulation of an opioid pain medicine that allowed dosing every 12 hours instead of every 4 to 6 hours.

August: Duragesic (fentanyl transdermal system) approved first formulation of an opioid pain medicine in a patch (sometimes referred to as a “skin patch”) that is changed every 3 days.

December: OxyContin (oxycodone controlled-release) approved first formulation of oxycodone that allowed dosing every 12 hours instead of every 4 to 6 hours. OxyContin would soon become a focal point of opioid abuse issues that would continue to escalate into the late 2000s and beyond.

  • At the time of approval, FDA believed the controlled-release formulation of OxyContin would result in less abuse potential, since the drug would be absorbed slowly and there would not be an immediate “rush” or high that would promote abuse. In part, FDA based its judgment on the prior marketing history of a similar product, MS Contin, a controlled-release formulation of morphine approved by FDA and used in the medical community since 1987 without significant reports of abuse and misuse.
  • Also at the time of OxyContin’s approval, FDA product labeling warned of the danger of abuse of the drug and that crushing a controlled-release tablet followed by intravenous injection could result in a lethal overdose. There was no evidence to suggest at the time that crushing the controlled-release capsule followed by oral ingestion or snorting would become widespread and lead to a high level of abuse.

November: Actiq (fentanyl) approved first pain medicine approved to treat cancer breakthrough pain but with additional safety concerns. Actiq was approved with a restricted distribution program to try to prevent 1) accidental exposure in children because the product looked like a lollipop, and 2) potential abuse. This drug would later become part of a category of opioids now known as transmucosal immediate-release fentanyl (TIRF) products. Transmucosal means that the dose of the drug is delivered across mucous membranes, such as inside the cheek, under the tongue, or in the nose.

2000-2004

Early 2000s

Reports of overdose and death from prescription drug products, especially opioids, began to rise sharply, with OxyContin at the center of the problem. For instance, the number of people who admitted to using OxyContin for non-medical purposes increased dramatically from approximately 400,000 in 1999 to 1.9 million in 2002 and to 2.8 million in 2003.

By 2009, about 1.2 million emergency department (ED) visits were related to misuse or abuse of pharmaceuticals, an increase of more than 98% since 2004 and more than the number of ED visits related to use of illicit drugs such as heroin and cocaine. Most prominent among these prescription drug-related deaths and ED visits were opioid pain relievers (OPR), especially OxyContin.

FDA had worked with sponsors for more than a decade to implement risk management programs for a number of opioid products. However, data demonstrated that these programs did not adequately manage the risks of misuse, abuse, addiction, and overdose. More was needed.

January: Beginning in 2001 and ongoing, inter-agency collaboration occurred to develop public education regarding prescription drug abuse. The involved agencies included FDA, SAMHSA, the Center for Substance Abuse Treatment (CSAT), and the National Institute on Drug Abuse (NIDA).

March: CSAT hosted a meeting with FDA and other federal agencies, including DEA, NIDA, and the Centers for Disease Control and Prevention (CDC).

July: Additional stronger warnings about the potential for misuse and abuse were added to the OxyContin label.

  • To help prescribers choose patients who would benefit from using OxyContin, the indication for using the drug was changed from “moderate to severe pain where use of an opioid analgesic is needed for more than a few days” to “management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.”
  • The label was also changed to say that OxyContin is not appropriate for “as needed” pain or in the immediate-post operative period if the pain is mild or not expected to persist for an extended period of time.
  • A Boxed Warning was added to reinforce the most important warnings, and information in the DRUG ABUSE AND DEPENDENCE section was updated. OxyContin’s manufacturer, Purdue Pharma, agreed to implement a Risk Management Program (RMP) to try to reduce misuse and abuse of OxyContin and issued a Dear Healthcare Professional Letter about changes to the label.

January: Patient Package Insert (PPI) approved for OxyContin. This is a document written for patients that provides information about how to safely use the drug.

March: Inter-Agency Working Group Meeting held to discuss OxyContin and other extended-release opioids and their abuse and diversion. FDA, DEA, NIDA, and SAMHSA involved.

January: FDA issued a Warning Letter (PDF - 149KB) to OxyContin’s manufacturer, Purdue Pharma, for misleading advertisements. Among many other details, the warning specified that the ads left out and minimized the serious safety risks associated with OxyContin and promoted it for uses beyond those which had been proven safe and effective. Specifically, the letter pointed out that the advertisements failed to clearly present information from the product label’s Boxed Warning regarding the potentially fatal risks and the danger of abuse.

2005-2008

September: PPI for Actiq converted to a Medication Guide (MG) due to heightened safety considerations. The conversion was to better ensure that each patient prescribed the drug was fully informed of its serious risks. In contrast to PPIs, MGs are required to be given to each patient when they fill a prescription.

September: Fentora (fentanyl buccal tablets), the second TIRF product, approved with an MG and RMP but not restricted distribution.

September: FDA issued a Public Health Advisory for Fentora due to reports of medication errors resulting in adverse events and deaths.

September: The Food and Drug Administration Amendments Act (FDAAA) became law, providing the Agency with a wide array of new authority designed to enhance drug safety. One of these is the authority to require Risk Evaluation and Mitigation Strategies (REMS) in order to ensure the benefits of the drugs continue to outweigh their risks. REMS are intended to require manufacturers to implement various safety measures for certain drugs. This new law helped provide the basis for a future comprehensive REMS program for all FDA-approved Extended-Release (ER)/Long Acting (LA) opioid products (see 2009 through 2012 below).

September: FDA announced it would require companies to stop marketing any unapproved drug containing the opioid pain medication hydrocodone bitartrate (the active ingredient in the opioid sold under the familiar trade name Vicodin).

Fentora’s manufacturer, Cephalon, requested an expansion of the drug’s indication to include patients with non-cancer breakthrough pain. An FDA Advisory Committee concluded that the existing RMP for the drug was not effective, and Cephalon was told that a REMS program would be required before the drug could be considered for a broader indication.

February: Fentora’s label and MG were revised to strengthen warnings.

February: FDA informed Cephalon that the RMP was not sufficient to ensure the safe use of Fentora for the already approved indication for treatment of breakthrough cancer pain and needed to be replaced by a REMS.

March: FDA met with manufacturers of ER/LA opioid pain medications to discuss the requirement for a class-wide, shared-system REMS, which is a single uniform program for all products in a drug class.

April: FDA partnered with SAMHSA to launch an initiative to help ensure the safe use of the opioid methadone, as this drug appeared to be responsible for a highly disproportionate number of overdoses and deaths in pain patients compared with all other opioids. (Methadone is best known as a treatment for addiction to and dependence on heroin and other narcotic pain medicines, but it is also prescribed to treat moderate-to-severe chronic pain.)

May: Among a variety of public and stakeholder meetings that occurred in 2009, FDA held a large public meeting on May 27-28 where more than 100 people provided comments on their experiences with opioid drugs along with suggestions for a REMS targeting ER/LA opioid products. Groups that participated included patient advocacy organizations, prescriber organizations, pharmacy organizations, insurance providers, and other government agencies. In addition, FDA solicited written comments through a public docket. (See summary of comments (PDF - 6MB).)

July: FDA approved Onsolis (fentanyl), the third TIRF for breakthrough cancer pain. It was approved with a REMS in place. At this point, FDA decided that a separate REMS for each TIRF product would create a great burden to patients, pharmacies, and prescribers and so began discussion of a single-shared REMs for all TIRF products.

FDA informed Cephalon in 2009 of the requirement to convert the RMP for Fentora and Actiq to a REMS.

August: Embeda (morphine sulfate and naltrexone extended-release tablets) approved. Naltrexone helps block the effects of opioids. Embeda was the first product approved combining an opioid pain medicine and opioid blocker since Talwin NX (pentazocine and naloxone) was approved in 1982. [Suboxone (buprenorphine and naloxone) sublingual tablets, approved in 2002, has an opioid blocker but is specifically for the treatment of opioid dependence, not for pain.]

October: Similar to actions in 2007 against makers of unapproved hydrocodone products, FDA warned companies they must stop marketing unapproved codeine sulfate tablets, a widely used opioid to treat pain.

November: FDA launched the Safe Use Initiative to create and facilitate public and private collaborations within the health care community, with a goal to reduce preventable harm from medication. Safe use of opioids is a primary focus of this ongoing effort.

November: The November 26, 2009, issue of The New England Journal of Medicine featured an article titled A Difficult Balance – Pain Management, Drug Safety, and the FDA by Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research (CDER). In the article, Dr. Woodcock discussed FDA’s efforts to strike a balance between legitimate patient access to pain medications and managing the risks posed by various analgesics. She cited recent FDA actions on the over-the-counter pain reliever acetaminophen, the low-potency opioid propoxyphene, and high-potency opioids such as OxyContin.

December: FDA held a stakeholder meeting on December 4 with the Industry Working Group (IWG), consisting of representatives from 22 pharmaceutical companies asked to help develop an effective opioid REMS program for a proposed class-wide opioid REMS. [IWG would be re-named REMS Program Companies (RPC) in August, 2011].

A significant percentage of deaths and overdose from opioids, especially from ER/LA opioids, results from theft of pain medicine from medicine cabinets and accidental exposure to the drugs. Since 2009, FDA has worked with DEA and other organizations to help educate the public on safe disposal of opioids when they are no longer needed for pain.

July: FDA held a joint meeting of its Anesthetic and Life Support Drugs Advisory Committee (ALSDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee to discuss the Agency’s proposal for a class-wide REMS for ER/LA opioid analgesics (for complete background information discussed at this meeting, see the July 22-23, 2010, AC meeting entry).

September: To improve clinical studies of pain medicines with the goal of advancing the development of novel, less abusable, safer, and more effective pain medicines, FDA announced a plan to establish a public-private partnership to conduct multiple scientific projects under the umbrella of the Analgesic Clinical Trial Translation, Innovations, Opportunities, and Networks (ACTTION) Initiative. The University of Rochester (UR) was chosen for the contract to establish the infrastructure of the ACTTION PPP initiative and to establish relationships with the key experts and organizations in the field.

October: FDA held a joint Advisory Committee Meeting (PDF - 149KB) (ALSDAC and DSaRM) on studies for demonstrating effectiveness of abuse-deterrent formulations on addiction, overdose, and death, with OxyContin and Embeda featured.

October: FDA held a meeting with TIRF sponsors and informed them that in order to decrease the burden on the healthcare system, they must form a single-shared REMS for these products. The Agency committed to working with the firms to assist in the regulatory aspects of developing this program. Regular meetings followed, after which the firms formed a working group, the Transmucosal Immediate-release Fentanyl REMS Industry Group (TRIG).

November: Separate from the developing REMS program but connected to FDA’s overall effort toward safe use of opioids, FDA recommended voluntary market withdrawal of propoxyphene, sold under the familiar trade name Darvon. New data showed the drug could cause serious toxicity to the heart, even in therapeutic doses.

January: Abstral (fentanyl) approved the fourth TIRF product. This product was approved with a MG and REMS in place.

April: FDA supported the White House Office of National Drug Control Policy (ONDCP) report Epidemic: Responding to America’s Prescription Drug Abuse Crisis(PDF - 306KB), a comprehensive action plan to address the national prescription drug abuse epidemic.

June: Oxecta (oxycodone hydrochloride) approved.

June: Lazanda (fentanyl) approved the fifth TIRF product. This product was approved with a MG and REMS in place.

September: FDA provided funds through a one-year cooperative agreement grant to the University of South Carolina to develop a statewide collaboration to decrease rates of misuse, overuse, and abuse of opioids. This was to be accomplished through the detailing of information regarding prescription opioids and the use of state prescription drug monitoring programs (PDMPs) geared to individual physicians who are high volume prescribers of opioids.

October: As part of a three-year inter-agency agreement with the Department of Justice’s Bureau of Justice Administration and in collaboration with the CDC, FDA provided funding to support efforts by the Prescription Drug Monitoring Program Center of Excellence at Brandeis University. The effort was to develop a national database of state PDMP data to be used for surveillance of emerging problems or concerns with scheduled drugs and to examine the impact of national, state and community initiatives implemented to curb misuse, overuse, and abuse of opioids.

December: FDA announced the approval of a new formulation of the ER/LA opioid OPANA ER (oxymorphone hydrochloride).

December: FDA approved a single-shared REMS system for all TIRF products (the “go-live” date would be March 2012). The industry working group (TRIG, see above) was encouraged to continue working to complete its single-shared TIRF REMS system. The Agency continued to provide regulatory input and review of TRIG’s proposals throughout the year.

December: FDA began working to streamline the process for managing the TIRF single-shared REMS.

January: Subsys (fentanyl sublingual spray) approved the sixth TIRF product. It was approved directly into the single-shared TIRF REMS in anticipation of its upcoming “go live” date.

January: FDA awarded a Center of Excellence in Research Science and Innovation grant to the University of Maryland to examine the use and utility of Patient Prescriber Agreements in reducing prescription opioid abuse.

March: The single-shared TIRF REMS went “live,” and FDA began work with TRIG to address patient access issues.

April: FDA hosted a scientific workshop to initiate a public discussion about the potential value of making naloxone available in the community to reduce the number of opioid overdose fatalities. In simple terms, naloxone, marketed under the trade name Narcan and others, reverses the effects of opioids.

May: FDA and the National Institutes of Health (NIH) Pain Consortium held a meeting on May 30-31, called Assessment of Analgesic Treatment of Chronic Pain: A Scientific Workshop, to review available data on the effectiveness of pain medications in the treatment of chronic non-cancer pain.

September: FDA awarded funding for up to three years for three cooperative agreement grants to examine strategies and interventions and their potential to impact opioid analgesic misuse and abuse. The following research topics were funded:

Examine the prescribing habits of physicians who prescribe doses of opioids above 100 mg morphine equivalents per day and/or prescribe opioids in combination with benzodiazepines. Those prescribers will be targeted for educational and informational mailings, and the PDMP data will be examined for changes in prescribing habits post-education and over time.

Examine the clinical use of different tools that can guide a clinician in prescribing opioids and reduce patient misuse, overuse, and abuse of opioids. All of the risk reduction strategies described are currently in use. They include 1) screening, brief intervention, and referral to treatment (SBIRT), 2) PDMPs, 3) REMS, 4) health insurer initiatives, and 5) treatment contracts. The study will survey approximately 1,300 prescribers (1,000 internists, 200 pain specialists and 100 addiction specialists) to gain an understanding of the knowledge, use, and perceptions of utility of these strategies.

Estimate the incidence of urine drug testing (UDT) during the year following initiation of chronic opioid therapy (COT) and identify demographic, clinical, provider, and facility variables associated with the use of UDT within the national Veterans Affairs (VA) healthcare system. Use qualitative interviews with primary care providers to explore perceptions of barriers to UDT, appropriate care for patients who misuse opioids, and opportunities to coordinate treatment with substance abuse specialty care. Describe current clinical practice following an aberrant UDT result, including rates of follow-up assessments and treatment changes among patients who initiate COT for chronic pain.

June: The Randomized Enrollment Study of Opioid Long-term use to eValuate Efficacy (RESOLVE) working group, under the auspices of ACTTION (see September 2010 above), was established. Formation of this group was initiated based on the FDA-sponsored meeting held at NIH in May (see directly above) and on plans to develop protocols for clinical trials to assess the effectiveness of long-term use of opioid pain medicines.

July: FDA approved the ER/LA opioids class REMS program. This program included new product labeling for ER/LA opioids and a requirement for manufacturers to develop and offer opioid training programs that prescribers can take on a voluntary basis.

August: ACTTION established the Consortium for Addiction Research on Efficacy and Safety (CARES) to address challenges in addiction drug trials. The Abuse Liability Evaluation for Research, Treatment, and Training (ALERTT) project was also initiated under ACTTION. This project was initiated with the intent to create a classification scheme and a risk assessment tool for use in clinical trials and for post-marketing adverse event reports to help identify incidents of drug abuse or emergence of drug addiction.

October: FDA and ACTTION hosted a scientific workshop October 24-26 to discuss preclinical models and clinical study issues to find ways to improve analgesic drug discovery and development.

October: FDA scheduled a meeting of the Drug Safety and Risk Management Advisory Committee for October 29-30 to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone, either combined with other analgesics or as a cough suppressant. This meeting was postponed due to Hurricane Sandy.

November: FDA scheduled a meeting November 28-29 for ACTTION’s ALERTT project working group for stakeholders to discuss consensus recommendations and research studies on definitions, measures, and prediction tools for abuse liability.

December: FDA held a December 7 meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the risks and benefits of new drug application, for hydrocodone bitartrate extended-release capsules, which would be the first single-entity hydrocodone-containing drug product. The committee voted against approval.

January: FDA issued a draft guidance document, January 9, to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties. The document, entitled Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling (PDF - 463KB), explains FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties, how those studies will be evaluated by the agency, and what labeling claims may be approved based on the results of those studies.

January: FDA held a January 24-25 meeting of its Drug Safety and Risk Management Advisory Committee (PDF - 69KB) to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone either combined with other analgesics or as an antitussive. The Department of Health and Human Services (HHS) received a request from the Drug Enforcement Administration (DEA) for a scientific and medical evaluation and scheduling recommendation for drugs containing hydrocodone either combined with other analgesics or as an antitussive, in response to a citizen petition citing increasing reports of abuse related to these products. Currently, these products are Schedule III drugs under the Controlled Substances Act (CSA), and DEA is considering whether to reschedule the products to Schedule II, which would subject the products to more stringent requirements regarding storage, record keeping, and prescribing, such as limitations on oral prescriptions and refills. The committee voted in favor of rescheduling hydrocodone products from Schedule III controlled substances to Schedule II controlled substances.

February: FDA held public hearing on February 7 & 8 to obtain information -- particularly scientific evidence, such as study data or peer-reviewed analyses -- on issues pertaining to the use of opioid drugs in the treatment of chronic pain. Impact of Approved Drug Labeling on Chronic Opioid Therapy: Part 15 Hearing.

March: March 1, in an open letter to prescribers, FDA and health professional organizations asked all prescribers of opioids to ensure they have thorough knowledge of the FDA-approved product labeling for the opioids they prescribe, and to ensure they have adequate training in opioid therapy. FDA also encouraged all prescribers to help curb our nation's opioid epidemic.

April: April 16, FDA took multiple actions related to OxyContin.

May: May 10, FDA responded to a petition and decided that the original formulation of Opana ER (oxymorphone hydrochloride) Extended-Release Tablets was not withdrawn from the market for reasons of safety or effectiveness. As a result, generic versions of the original formulation can continue to be approved and marketed.

July: On July 29, FDA held the Clinical Development Programs for Opioid Conversion Public Workshop Request for Comments. The scientific workshop was held to address public health concerns associated with the inclusion of equianalgesic opioid conversion tables in opioid product labeling.

September: On September 10, FDA announced a set of significant measures to enhance the safe and appropriate use of extended-release and long-acting (ER/LA) opioids. These actions include class-wide safety labeling changes and new post-marketing requirements for all ER/LA opioid analgesics. FDA also responded to two citizen petitions regarding labeling of opioids.

April: On April 3, FDA approved Evzio (naloxone hydrochloride injection) for the emergency treatment of known or suspected opioid overdose. Naloxone is a medication that rapidly reverses the effects of opioid overdose. Evzio is the first auto-injector designed to deliver a dose of naloxone outside of a healthcare setting.

April: On April 14, FDA finalized the proposed class-wide safety labeling changes for all extended-release and long-acting (ER/LA) opioid analgesics, and responded to two citizen petitions regarding labeling for neonatal opioid withdrawal syndrome (NOWS).

July: On July 23, FDA approved Targiniq ER, an extended-release pain reliever that contains a combination of oxycodone and naloxone. Targiniq ER is the second extended-release/long-acting (ER/LA) opioid analgesic with FDA-approved labeling describing the product’s abuse-deterrent properties.

August: On August 19, FDA approved revisions to the ER/LA Opioid Analgesics REMS to incorporate information from the ER/LA opioid analgesic safety labeling changes (SLCs) announced on September 10, 2013, and approved on April 16, 2014. The most significant changes were to clarify the approved indications for use and limitations of use, and to revise warnings, including boxed warnings.

October: On October 17, FDA approved new labeling for Embeda (morphine sulfate and naltrexone hydrochloride), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Embeda is the third ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance, Abuse- Deterrent Opioids – Evaluation and Labeling. The new labeling includes a claim indicating that Embeda has properties that are expected to reduce oral and intranasal abuse when the product is crushed.

November: On November 20, FDA approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Hysingla ER is the fourth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Hysingla ER has properties that are expected to reduce, but not totally prevent, abuse of the drug when chewed and then taken orally, or crushed and snorted or injected.

January: On January 30, FDA approved a modified formulation of Zohydro ER (hydrocodone bitartrate extended-release capsules). The FDA has not approved an abuse-deterrent labeling claim for Zohydro ER.

April: On April 1, FDA issued a final guidance to assist industry in developing opioid drug products with potentially abuse-deterrent properties.

June: On June 8-9, the FDA’s Risk Communication Advisory Committee discussed approaches to communicating information about fetal effects in product labeling for methadone or buprenorphine maintenance therapy for opioid addiction, and about the maternal benefits and risks of treatment, to best enable patients and healthcare providers to make informed decisions about the use of these drugs during pregnancy.

July: On July 1-2, FDA, in collaboration with the National Institutes of Drug Abuse, the Centers for Disease Control and Prevention, the Substance Abuse and Mental Health Services Administration, and the Health Resources and Services Administration, held a scientific workshop to initiate a public discussion about issues surrounding the uptake of naloxone in certain medical settings – such as on ambulances and in association with prescriptions for opioids – as well as outside of conventional medical settings to reduce the incidence of opioid overdose fatalities. Discussions focused on which populations are at risk for opioid overdose how public health groups can work together to use naloxone to reduce the risk of overdose and legal, regulatory, logistical and clinical aspects related to making naloxone more widely available.

August: On August 13, FDA approved OxyContin for certain pediatric patients for pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. This approval is limited to opioid-tolerant pediatric patients 11 and up who are already taking and tolerating a minimum daily dose of at least 20 mg oxycodone orally or its equivalent. These patients can be expected to remain on treatment with an opioid for several weeks or more.

October: On October 2, FDA approved MorphaBond (morphine sulfate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. MorphaBond is the fifth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. MorphaBond has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and snorted or injected.

November: On November 18, FDA approved Narcan nasal spray, the first FDA-approved nasal spray version of naloxone hydrochloride, a life-saving medication that can temporarily stop or reverse the effects of an opioid overdose, including an overdose from heroin.

February: On February 4, FDA leaders, in response to the opioid abuse epidemic, called for a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.

On February 4, FDA released five postmarketing (PMR) requirements announced on September 13, 2013, and replaced them with 11 PMRs (10 postmarketing studies and one clinical trial) because the 10 postmarketing observational studies and one clinical trial include refined measures for assessing the known serious risks of misuse, abuse, addiction, overdose, and death.

On February 19 the FDA announced that during the April 12th meeting of the Pediatric Advisory Committee (PAC) they will present a framework of current plans for a 2-day joint meeting of the PAC, the Anesthetic and Analgesic Drug Products Advisory Committee, and the Drug Safety and Risk Management Advisory Committees. This joint meeting is scheduled for September 15 and 16, 2016 and during this meeting the FDA will be calling on a broad range of independent experts with real-world experience to provide recommendations on how to address the unique needs of children in pain.

March: On March 1, the FDA convened the Science Board to hear about and discuss a range of pressing issues related to the current opioid epidemic, including: (1) the role of opioids in pain management (2) scientific challenges facing FDA in supporting the development of pain medications (3) scientific challenges facing FDA in seeking to understand the real-world use of opioids to treat pain (4) the role that FDA plays as a part of a larger Federal, State and local response to the challenges of providing appropriate pain treatment while reducing opioid abuse and (5) postmarket surveillance activities related to opioids.

On March 22, FDA announced required class-wide safety labeling changes for immediate-release (IR) opioid pain medications. Among the changes, the FDA is requiring a new boxed warning about the serious risks of misuse and abuse, which can lead to addiction, overdose and death. The FDA is also requiring several additional safety labeling changes across all prescription opioid products to include additional information on the risk of these medications.

On March 24, FDA issued a draft guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.” This guidance recommends studies a generic applicant should conduct so FDA can evaluate the abuse deterrence of certain generic opioid drug products and help ensure that generic versions of approved opioids with abuse-deterrent formulations (ADFs) are no less abuse-deterrent than the brand named drug.

April: On April 26, FDA approved Xtampza ER (oxycodone), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Xtampza ER is the sixth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Xtampza ER has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and snorted or injected.

May: On May 3-4, FDA convened a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss results from assessments of the extended-release and long-acting (ER/LA) Opioid Analgesics Risk Evaluation and Mitigation Strategies (REMS). The committees provided comments as to whether this REMS with Elements to Assure Safe Use (ETASU) assures safe use, is not unduly burdensome to patient access to the drugs, and to the extent practicable, minimizes the burden to the healthcare delivery system.

On May 26, FDA announced required safety labeling changes for methadone and buprenorphine products when used by pregnant women for medication-assisted treatment (MAT) of opioid use disorder to ensure providers have complete information about the benefits and risks of these products.

On May 26, FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine, an implant designed to provide a constant, low level of buprenorphine for six months, should be used in patients who are already stable on low-to-moderate doses of other forms of buprenorphine and as part of a complete treatment program that includes counseling and psychosocial support.

August: On August 19, FDA approved Troxyca ER (oxycodone hydrochloride and naltrexone hydrochloride extended-release capsules), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Troxyca ER is the seventh ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Troxyca ER has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and then taken orally, snorted, or injected.

On August 31, FDA announced required class-wide changes to drug labeling to help inform health care providers and patients of the serious risks associated with the combined use of certain opioid medications and a class of central nervous system depressant drugs called benzodiazepines. Among the changes, the FDA is requiring boxed warnings and Medication Guides for prescription opioid analgesics, opioid-containing cough products, and benzodiazepines with information about the serious risks, including extreme sleepiness, respiratory depression, coma and death, associated with using these medications at the same time.

September: On September 15-16, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee to discuss the appropriate development plans for establishing the safety and efficacy of prescription opioid analgesics for pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation.

October: On October 5, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management to discuss naloxone products intended for use in the community, specifically the most appropriate dose or doses of naloxone to reverse the effects of life-threatening opioid overdose in all ages, and the role of having multiple doses available in this setting. The committees also discussed the criteria prescribers will use to select the most appropriate dose in advance of an opioid overdose event and the labeling to inform this decision, if multiple doses are available.

On October 31 – November 1, the FDA held a public meeting, Pre-Market Evaluation of Abuse-Deterrent Properties of Opioid Drug Products, to discuss scientific and technical issues relating to formulation development and pre-market evaluation of opioid drug products with abuse-deterrent properties. The meeting was intended to give FDA the opportunity to discuss, and seek public input from stakeholders on, the approach to testing FDA recommended in its draft guidance General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products. The meeting also provided an opportunity to discuss FDA’s efforts to develop standardized in vitro testing methodologies for evaluating the abuse deterrence of opioid drug products.

December: On December 16, the FDA approved several safety labeling changes (SLCs) about the serious risks of prescription opioid analgesics and opioids approved for medication assisted treatment (MAT) of opioid addiction including class-wide SLCs for immediate-release (IR) opioid pain medications, SLCs for methadone and buprenorphine products, and class-wide SLCs about the serious risks associated with the combined use of certain opioid medications with benzodiazepines or other central nervous system (CNS) depressants.

January: On January 9, FDA approved Arymo ER (morphine sulfate extended-release tablets), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Arymo ER is the eighth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Arymo ER is formulated to give it physicochemical properties expected to make abuse by injection difficult.

On January 17, FDA approved Vantrela ER (hydrocodone bitartrate extended-release tablets), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Vantrela ER is the ninth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. The physical and chemical properties of Vantrela ER are expected to make intravenous (injection) abuse difficult and are expected to reduce, but not eliminate, abuse by nasal and oral routes. However, abuse of Vantrela ER by these routes is still possible.

April: On April 20, FDA announced the restricted the use of codeine and tramadol medicines in children because these medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. These medicines should also be limited in some older children. The FDA also recommended against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants.

On April 20, the FDA approved RoxyBond (oxycodone hydrochloride), an opioid analgesic indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. RoxyBond is the first immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s 2015 Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling. Based on laboratory studies, RoxyBond tablets are resistant to certain forms of manipulation such as crushing, grinding, or otherwise extracting oxycodone from the tablet that are typically used to make opioids easier to abuse by the nasal and intravenous routes.

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May: On May 9-10, FDA held a public meeting, Training Health Care Providers on Pain Management and Safe Use of Opioid Analgesics – Exploring the Path Forward, to obtain input on issues and challenges associated with Federal efforts to support training on pain management and the safe prescribing, dispensing, and patient use of opioids (safe use of opioids) for health care providers.

On May 10, FDA released the "FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain" (draft revisions to the Blueprint), which broadens the current Blueprint to include information on pain management, including the principles of acute and chronic pain management non-pharmacologic treatments for pain and pharmacologic treatments for pain (both non-opioid analgesic and opioid analgesic).

June: On June 8, FDA requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market based on its concern that the benefits of the drug may no longer outweigh its risks.

July: On July 6, the JAMA Viewpoint article by Dr. Scott Gottlieb and Dr. Janet Woodcock entitled, “Marshaling FDA Benefit-Risk Expertise to Address the Current Opioid Abuse Epidemic," was published.

On July 6, following the FDA’s request, Endo announced that it would voluntarily remove reformulated Opana ER from the market.

On July 10-11, FDA held a public meeting, Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities, to discuss ways to improve the analysis and interpretation of existing data, as well as to discuss opportunities and challenges for collecting and/or linking additional data to improve national surveillance and research capabilities in this area.

On July 13, the National Academies of Science, Engineering, and Medicine release the consensus report, commissioned by the FDA, which outline the state of the science regarding prescription opioid abuse and misuse, as well as the evolving role that opioids play in pain management.

September: On September 11, FDA held a Pediatric Advisory Committee meeting to discuss the use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients. The discussion included current practice for the treatment of cough in children and benefit-risk considerations regarding the use of prescription opioid products in pediatric patients.

On September 20, FDA advised that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS). The combined use of these drugs increases the risk of serious side effects however, the harm caused by untreated opioid addiction can outweigh these risks. Careful medication management by health care professionals can reduce these risks.

On September 28, after determining that a REMS is necessary for IR opioid analgesics to ensure that the benefits of these drugs continue to outweigh the risks, FDA sent letters to IR opioid analgesic manufacturers informing them that their products that are intended to be used in the outpatient setting will be subject to the same REMS requirements as the ER/LA opioid analgesics.

November: On November 21, FDA issued a final guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.” This guidance recommends studies, including comparative in vitro and pharmacokinetic studies, that the potential abbreviated new drug application (ANDA) applicant should conduct and submit to FDA in an ANDA to demonstrate that a generic solid oral opioid drug product is no less abuse-deterrent than its reference listed drug with respect to all potential routes of abuse.

On November 30, FDA approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe opioid use disorder in adult patients who have initiated treatment with a transmucosal (absorbed through mucus membrane) buprenorphine-containing product. It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days.

December: On December 11-12, FDA hosted a public workshop regarding the role of packaging, storage, and disposal options within the larger landscape of activities aimed at addressing abuse, misuse, or inappropriate access of prescription opioid drug products guiding principles and considerations for the design of packaging, storage, and disposal options for opioids integrating packaging, storage, and disposal options into existing health care and pharmacy systems, including both open and closed health care systems data needs and how to address challenges in assessing the impact of packaging, storage, and disposal options in both the premarket and postmarket settings and ways in which FDA could encourage the development and assessment of packaging, storage, and disposal options for opioids that have the potential to enhance opioid safety.

January: On January 11, FDA Commissioner, Scott Gottlieb, M.D., announced the 2018 Strategic Policy Roadmap, which provides an overview of some of the key priorities the agency will pursue advance FDA’s public health mission. Part of the Roadmap is reducing misuse and abuse of opioid drugs.

On January 11, FDA announced that it is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older because the risks of these medicines outweigh their benefits in children younger than 18. The agency is also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the Boxed Warning of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone.

On January 24, FDA and the Federal Trade Commission posted joint warning letters to the marketers and distributors of 12 opioid cessation products, for illegally marketing unapproved products with claims about their ability to help in the treatment of opioid addiction and withdrawal.

On January 30, FDA held a public hearing, “Opioid Policy Steering Committee: Prescribing Intervention—Exploring a Strategy for Implementation,” to receive stakeholder input on how FDA might, under its REMS authority, improve the safe use of opioid analgesics by curbing overprescribing to decrease the occurrence of new addictions and limit misuse and abuse of opioid analgesics.

On January 30, FDA announced limits to packaging for anti-diarrhea medicine Loperamide (Imodium) to encourage safe use.

On January 30, FDA posted the revised Blueprint, “Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain,” which broadens the current Blueprint to include information on pain management, including the principles of acute and chronic pain management non-pharmacologic treatments for pain and pharmacologic treatments for pain. (It is important to note that the revised Blueprint will not be considered final until the Opioid Analgesic Risk Evaluation and Mitigation Strategy is approved.)

February: On February 14, FDA held a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for Hydexor (proposed tradename), a fixed-dose combination oral tablet, submitted by Charleston Laboratories, Inc., that contains hydrocodone, acetaminophen, and promethazine, for the short-term management of acute pain severe enough to require an opioid analgesic while preventing and reducing opioid-induced nausea and vomiting. The committees also discussed the abuse potential of this non-abuse-deterrent product and whether it should be approved.

On February 15, through a cooperative agreement with the FDA, the Duke-Margolis Center hosted a public workshop, “Strategies for Promoting the Safe Use and Appropriate Prescribing of Prescription Opioids,” to examine the landscape of health system and payer interventions to promote safe and appropriate prescribing of opioids discuss how health systems and payers are using data and health IT tools to support interventions discuss how health system approaches were implemented, barriers to their adoption, and potential unintended consequences of adoption and discuss how to build an evidence base to support existing health system and payer interventions as well as how success may be defined and measured.

March: On March 27, FDA held a meeting of the Psychopharmacologic Drugs Advisory Committee to discuss the new drug application for lofexidine hydrochloride, submitted by US WorldMeds, LLC, for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment.

April: On April 17, FDA is hosting a public meeting on Patient-Focused Drug Development for Opioid Use Disorder (OUD), in collaboration with National Institute of Drug Abuse (NIDA). In addition to NIDA, FDA is also working closely with patient advocacy and community organizations to encourage participation from individuals with OUD. This meeting aligns with FDA’s ongoing work aimed at reducing the impact of opioid abuse and addiction.

On April 20, FDA issued the draft guidance, “Opioid Dependence: Developing Buprenorphine Depot Products for Treatment,” which reflects the agency’s current thinking regarding drug development and trial design issues relevant to the study of depot buprenorphine products (i.e. modified-release products for injection or implantation).

May: On May 16, FDA approved Lucemyra (lofexidine hydrochloride), the first non-opioid treatment for the mitigation of withdrawal symptoms associated with abrupt discontinuation of opioids.

On May 22, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for buprenorphine sublingual spray, submitted by INSYS Development Company, Inc., for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate. The committees will also be asked to discuss whether this product should be approved.

May: On May 30, FDA launched an innovation challenge to spur development of medical devices ‒ including digital health and diagnostics ‒ that target pain, addiction and diversion.

June: On June 1, FDA sent safety labeling change notification letters to drug companies with approved opioid analgesic products intended for use in an outpatient setting, which require the companies to include new safety information regarding the Opioid Analgesic REMS in the Boxed Warning and Warnings and Precautions sections of prescribing information due to a general lack of awareness of the REMS among all opioid analgesic prescribers.

June: On June 5, FDA took action against 53 websites marketing unapproved opioids as part of a comprehensive effort to target illegal online sales.

June: On June 26, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for oxycodone extended-release capsules, submitted by Pain Therapeutics, with the proposed indication of the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The product is intended to have abuse-deterrent properties based on its physicochemical properties. The committees will be asked to discuss whether the data submitted by the Applicant are sufficient to support labeling of the product with the properties expected to deter abuse.

June: On June 27, FDA convened internet stakeholders, government entities, academic researchers, and advocacy groups at a one-day Online Opioid Summit to discuss ways to collaboratively take stronger action in combatting the opioid crisis by reducing the availability of illicit opioids online.

July: On July 9, FDA hosted a public meeting on Patient-Focused Drug Development for chronic pain to hearing patients’ perspectives on chronic pain, views on treatment approaches, and challenges or barriers to accessing treatments for chronic pain.

August: On August 3, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss results from assessments of the transmucosal immediate-release fentanyl (TIRF) medicines’ risk evaluation and mitigation strategy (REMS), approved in December 2011. The TIRF REMS requires that healthcare providers who prescribe TIRF medicines for outpatient use are specially certified, that pharmacies that dispense TIRF medicines for inpatient and outpatient use are specially certified, and that completion of the prescriber-patient agreement form occurs prior to dispensing TIRF medicines for outpatient use. The Agency will seek the committees’ assessment as to whether this REMS with elements to assure safe use (ETASU) assures safe use, is not unduly burdensome to patient access to the drugs, and to the extent practicable, minimizes the burden to the healthcare delivery system. The Agency will also seek the committees’ input on any possible modifications to the TIRF REMS goals and requirements, as well as input on the adequacy of the evaluations conducted in the REMS assessments to determine whether the TIRF REMS goals are being met.

On August 6, FDA issued the draft guidance for industry, “Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Medication-Assisted Treatment,” which is intended to assist sponsors in developing drugs for medication-assisted treatment of opioid use disorder (OUD) and addresses the clinical endpoints acceptable to demonstrate effectiveness of such drugs.

On August 22, FDA awarded a contract to the National Academies of Sciences, Engineering, and Medicine (NASEM) to help advance the development of evidence-based guidelines for appropriate opioid analgesic prescribing for acute pain resulting from specific conditions or procedures.

On August 28, FDA took action against 21 websites marketing unapproved opioids as part of agency’s effort to target illegal online sales.

September: On September 7, FDA approved a new dosage strength of buprenorphine and naloxone sublingual film as maintenance treatment for opioid dependence.

On September 18, FDA approved the Opioid Analgesic REMS.

On September 20, through a cooperative agreement with the FDA, the Duke Margolis Center for Health Policy convened a public workshop, “Expanding Access to Effective Treatment for Opioid Use Disorder: Provider Perspectives on Reducing Barriers to Evidence-Based Care.”

On September 27-28, FDA’s Office of Women’s Health, in collaboration with CDER and CTP, hosted a 2-day public meeting, “Opioid and Nicotine Use, Dependence, and Recovery: Influences of Sex and Gender.”

On October 11, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss new drug application 210730, for oliceridine 1 milligram/milliliter injection, submitted by Trevena, Inc., for the management of moderate-to-severe acute pain in adult patients for whom an intravenous opioid is warranted. The committee also discussed the efficacy and safety data and benefit-risk considerations.

On October 12, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss new drug application 209128, sufentanil sublingual tablets, submitted by AcelRx Pharmaceuticals, Inc., for the management of moderate-to-severe acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, in adult patients in a medically supervised setting. The committee also discussed risk-benefit considerations and whether this product should be approved.

On November 1, FDA convened a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss efficacy, safety and risk-benefit profile of new drug application 210417 for buprenorphine and samidorphan sublingual tablets, submitted by Alkermes, Inc., for adjunctive treatment of major depressive disorder.

On November 2, FDA approved first oral sufentanil pain medication for use in a medically supervised setting.

On November 14, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss new drug application 209774, for an immediate-release oral tablet formulation of oxycodone, which is intended to resist common methods of physical or chemical manipulation and to deter intravenous and intranasal abuse, submitted by SpecGx Inc., for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The committees also determined whether the Applicant adequately demonstrated that the abuse-deterrent properties of the proposed product are sufficient to include this information in the product label, and whether the product should be approved.

November 15, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the assessment of opioid analgesic sparing outcomes in clinical trials of acute pain. The committee also commented on the trial design and endpoints of these studies and how to determine the clinical relevance of the results.

January: On January 17, FDA announced the results of unprecedented work to design, test, and validate the key labeling requirements necessary to approve an over-the-counter (OTC) version of naloxone, including posting two model Drug Facts labels (DFLs) and the supporting FDA review. Overall, the study demonstrated that the model DFL was well-understood by consumers and is acceptable for use by manufacturers in support of their OTC naloxone development programs.

February: On February 6, FDA issued the final guidance, “Opioid Use Disorder: Developing Depot Buprenorphine Products for Treatment,” which reflects the agency’s current thinking regarding drug development and trial design issues relevant to the study of depot buprenorphine products (i.e. modified-release products for injection or implantation).

On February 12, FDA announced ongoing efforts to stop the spread of illicit opioids, further secure the U.S. drug supply chain and forcefully confront opioid epidemic.

March: On March 19, FDA took action against marketer of unapproved products claiming to treat addiction, chronic pain and other serious conditions.

On March 27, FDA announced new steps to strengthen agency’s safety requirements aimed at mitigating risks associated with transmucosal immediate-release fentanyl products.

April: On April 2, FDA took new enforcement actions as part of the agency’s ongoing effort to combat the illegal online sales of opioids.

On April 2, FDA hosted internet stakeholders, thought leaders, government entities, academic researchers, and advocacy groups at its second Online Opioid Summit.

On April 9, FDA announced harm reported from sudden discontinuation of opioid pain medicines and required label changes to guide prescribers on gradual, individualized tapering.

On April 19, FDA approved first generic naloxone nasal spray to treat opioid overdose.

On April 25, FDA launched a public education campaign to encourage safe removal of unused opioid pain medicines from homes.

May: On May 30, FDA opened a public docket to request information on requiring fixed-quantity blister packaging for certain opioid pain medicines to help decrease unnecessary exposure to opioids.

On September 30, 2019 FDA and DEA warned website operators illegally selling opioids

October: On October 24, FDA outlined the agency’s first year accomplishments implementing SUPPORT Act authorities to address the opioids crisis

November: On November 26, FDA issues warning letter for products illegally marketed for the treatment of health conditions, including opioid withdrawal symptoms

December: On December 11, FDA issued warning letter for not including the most serious risks in advertisement for medication-assisted treatment drug

On December 19, the National Academies of Sciences, Engineering, and Medicine released a consensus report, commissioned by the FDA, on framing opioid prescribing guidelines for acute pain.

January: On January 14, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application (NDA) for oxycodegol, a new molecular entity full mu-opioid receptor agonist, submitted by Nektar Therapeutics, for the management of chronic low back pain in adult patients with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The committees were asked to discuss the safety and efficacy data as well as the overall risk-benefit profile of the product.

January: On January 15, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee. During the morning session, the committees discussed the NDA for tramadol 44 milligrams (mg) and celecoxib 56 mg tablet, which contains a fixed-dose combination of an opioid and a non-steroid anti-inflammatory drug, submitted by Esteve Pharmaceuticals, S.A., for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The committees were asked to discuss the safety and efficacy data as well as the overall risk-benefit profile of the product.

During the afternoon session, the committees discussed the NDA for an extended-release oral tablet formulation of oxycodone, submitted by Intellipharmaceutics Corp., for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. The product has been formulated with properties intended to deter abuse, and the applicant has submitted data to support these abuse-deterrent properties for this product. The committees were asked to discuss whether the applicant has demonstrated abuse-deterrent properties for their product that would support labeling, as well as the overall risk-benefit profile of the product.

June: On June 8, FDA and the National Telecommunications and Information Administration (NTIA) are launching a 120-day pilot to help reduce the availability of unapproved opioids illegally offered for sale online.

July: On July 23, the FDA issued a Drug Safety Communication announcing that the agency is requiring the drug manufacturers for all opioid pain relievers and medicines to treat OUD to add new recommendations about naloxone to the prescribing information to help ensure that health care professionals discuss the availability of naloxone and assess each patient’s need for a naloxone prescription when opioid pain relievers or medicines to treat OUD are being prescribed or renewed. In addition, the agency recommended that health care professionals consider prescribing naloxone to patients at increased risk of opioid overdose, regardless of whether they are receiving a prescription for an opioid pain reliever or medicine to treat OUD. These may include people with a current or past diagnosis of OUD or who have experienced a previous opioid overdose.

August: On August 7, the FDA approved Olinvyk (oliceridine), an opioid agonist for the management of moderate to severe acute pain in adults, where the pain is severe enough to require an intravenous opioid and for whom alternative treatments are inadequate.

September:On September 10-11, the FDA convened a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the results of required postmarketing studies (Postmarketing Requirements 3051-1, 3051-2, 3051-3, and 3051-4) that evaluated the effect of the reformulation of OxyContin (oxycodone hydrochloride extended-release tablets, manufactured by Purdue Pharma L.P., NDA 022272) on abuse, misuse, and fatal and non-fatal overdose, associated with OxyContin. The committees discussed whether these studies, in concert with other information from the published literature, have demonstrated that the reformulated OxyContin product has resulted in a meaningful reduction in these outcomes. The committees also discussed the broader public health impact of OxyContin’s reformulation.

October: On October 2, the FDA published the final guidance for industry, Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment, which is intended to help sponsors develop drugs for treatment of opioid use disorder (OUD). This guidance addresses clinical endpoints acceptable for demonstrating effectiveness of such drugs.

November: On November 2, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for Hydexor, a fixed-dose combination oral tablet, submitted by Õlas Pharma, Inc., that contains hydrocodone, acetaminophen, and promethazine, for the short-term (not to exceed 3 days) management of acute post-operative pain severe enough to require an opioid analgesic and the prevention of opioid-induced nausea and vomiting in patients who are at risk for or have a history of nausea and vomiting.

December: On December 23, the FDA finalized modifications to the transmucosal immediate-release fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) to address the persistence of concerning prescribing practices and improve the agency’s ability to monitor for adverse events and ensure safe use of these medicines.

February: On February 1, the FDA provided an update on the pilot program with the National Telecommunications and Information Administration (NTIA) and three domain name registries to help reduce the availability of unapproved opioids illegally offered for sale online.

February: On February 16, the FDA issued a warning letter to AcelRx Pharmaceuticals, Inc. for the false and misleading promotion of Dsuvia (sufentanil sublingual tablet), a potent opioid analgesic.

March: On March 1, the FDA approved Hydrocodone bitartrate (reference listed drug: Hysingla ER), the first FDA-approved generic opioid with an abuse-deterrent formulation (ADF)—meaning the product has properties that are expected to reduce, though not totally prevent, abuse of the drug when chewed and then taken orally or crushed and snorted or injected.

March: On March 24, the FDA issued a white paper, Introduction to FDA’s Opioid Systems Model, which introduces FDA’s opioid systems modeling effort, discusses potential uses of the model, provides an overview of the model’s scope and structure, highlights preliminary areas for potential policy analysis and outlines on-going work.​

Summary Timeline

1995. OxyContin (oxycodone controlled-release) approved first formulation of oxycodone that allowed dosing every 12 hours instead of every 4 to 6 hours.

1998. Actiq (fentanyl) approved first pain medicine approved to treat cancer breakthrough pain, but with additional safety measures.

Early 2000s. Reports of overdose and death from prescription pain drugs, especially OxyContin, began to rise sharply.

2001. OxyContin label was changed to add and strengthen warnings about the drug’s potential for misuse and abuse.

2003. FDA issued a Warning Letter (PDF - 149KB) to OxyContin’s manufacturer for misleading advertisements.

2007. FDA Amendments Act granted FDA authority to require for certain drugs specified safety measures known as Risk Evaluation and Mitigation Strategies (REMS).

2009. FDA held several public and stakeholder meetings, including May 27-28 public meeting and December 4 stakeholder meeting, to discuss opioid risks, misuse, and abuse.

FDA partnered with U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) to launch an initiative to help ensure the safe use of the opioid methadone.

FDA launched the Safe Use Initiative to reduce preventable harm by medications, including opioids.

FDA began working with U.S. Drug Enforcement Administration (DEA) and others to help educate the public on safe disposal of opioids.

2010. FDA approved a new formulation of OxyContin.

FDA held joint advisory committee meeting to discuss its proposal for a class-wide REMS for Extended-Release (ER)/Long acting (LA) opioids, such as OxyContin.

2011. FDA approved REMS for transmucosal immediate-release fentanyl (TIRF) products, such as Actiq.

2012. FDA implemented the ER/LA opioids REMS program, which includes voluntary training for prescribers.

2013. January: On January 9, FDA issued a draft guidance to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties: Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling (PDF - 463KB).

FDA held a January 24-25 meeting of its Drug Safety and Risk Management Advisory Committee (PDF - 69KB) to discuss the public health benefits and risks, including the potential for abuse, of drugs containing hydrocodone either combined with other analgesics or as an antitussive.

February: FDA held a public hearing on February 7-8 to obtain information on issues pertaining to the use of opioid drugs in the treatment of chronic pain. Impact of Approved Drug Labeling on Chronic Opioid Therapy: Part 15 Hearing.

In an open letter to prescribers on March 1, FDA and health professional organizations asked all prescribers of opioids to ensure they have thorough knowledge of the FDA-approved product labeling for the opioids they prescribe, and to ensure they have adequate training in opioid therapy. FDA also encouraged all prescribers to help curb our nation's opioid epidemic.

April: On April 16, FDA took multiple actions related to OxyContin.

May: On May 10, FDA responded to a petition and decided that the original formulation of Opana ER (oxymorphone hydrochloride) Extended-Release Tablets was not withdrawn from the market for reasons of safety or effectiveness. As a result, generic versions of the original formulation can continue to be approved and marketed.

FDA held the Clinical Development Programs for Opioid Conversion Public Workshop Request for Comments on July 29. The scientific workshop was held to address public health concerns associated with the inclusion of equianalgesic opioid conversion tables in opioid product labeling.

September: On September 10, FDA announced a set of significant measures to enhance the safe and appropriate use of extended-release and long-acting (ER/LA) opioids, including class-wide safety labeling changes and new post-marketing requirements for all ER/LA opioid analgesics. FDA also responded to two citizen petitions regarding labeling of opioids.

2014. April: On April 3, FDA approved Evzio (naloxone hydrochloride injection) for the emergency treatment of known or suspected opioid overdose. Naloxone is a medication that rapidly reverses the effects of opioid overdose. Evzio is the first auto-injector designed to deliver a dose of naloxone outside of a healthcare setting.

On April 14, FDA finalized the proposed class-wide safety labeling changes for all extended-release and long-acting (ER/LA) opioid analgesics, and responded to two citizen petitions regarding labeling for neonatal opioid withdrawal syndrome (NOWS).

July: On July 23, FDA approved Targiniq ER, an extended-release pain reliever that contains a combination of oxycodone and naloxone. Targiniq ER is the second extended-release/long-acting (ER/LA) opioid analgesic with FDA-approved labeling describing the product’s abuse-deterrent properties.

August: On August 19, FDA approved revisions to the ER/LA Opioid Analgesics REMS to incorporate information from the ER/LA opioid analgesic safety labeling changes (SLCs) announced on September 10, 2013, and approved on April 16, 2014. The most significant changes were to clarify the approved indications for use and limitations of use, and to revise warnings, including boxed warnings.

October: On October 17, FDA approved new labeling for Embeda (morphine sulfate and naltrexone hydrochloride), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Embeda is the third ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance, Abuse- Deterrent Opioids – Evaluation and Labeling. The new labeling includes a claim indicating that Embeda has properties that are expected to reduce oral and intranasal abuse when the product is crushed.

November: On November 20, FDA approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Hysingla ER is the fourth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Hysingla ER has properties that are expected to reduce, but not totally prevent, abuse of the drug when chewed and then taken orally, or crushed and snorted or injected.

2015. January: January: On January 30, FDA approved a modified formulation of Zohydro ER (hydrocodone bitartrate extended-release capsules). The FDA has not approved an abuse-deterrent labeling claim for Zohydro ER.

April: On April 1, FDA issued a final guidance to assist industry in developing opioid drug products with potentially abuse-deterrent properties. Guidance for Industry: Abuse-Deterrent Opioids” (PDF - 227KB) explains the FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties, makes recommendations about how those studies should be performed and evaluated, and discusses what labeling claims may be approved based on the results of those studies.

August: On August 13, FDA approved OxyContin for certain pediatric patients for pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. This approval is limited to opioid-tolerant pediatric patients 11 and up who are already taking and tolerating a minimum daily dose of at least 20 mg oxycodone orally or its equivalent. These patients can be expected to remain on treatment with an opioid for several weeks or more.

October: On October 2, FDA approved MorphaBond (morphine sulfate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. MorphaBond is the fifth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. MorphaBond has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and snorted or injected.

November On November 18, FDA approved Narcan nasal spray, the first FDA-approved nasal spray version of naloxone hydrochloride, a life-saving medication that can temporarily stop or reverse the effects of an opioid overdose, including an overdose from heroin.

2016. February: On February 4, FDA leaders, in response to the opioid abuse epidemic, called for a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.

On February 4, FDA released five postmarketing (PMR) requirements announced on September 13, 2013, and replaced them with 11 PMRs (10 postmarketing studies and one clinical trial) because the 10 postmarketing observational studies and one clinical trial include refined measures for assessing the known serious risks of misuse, abuse, addiction, overdose, and death.

On February 19 the FDA announced that during the April 12th meeting of the Pediatric Advisory Committee (PAC) they will present a framework of current plans for a 2-day joint meeting of the PAC, the Anesthetic and Analgesic Drug Products Advisory Committee, and the Drug Safety and Risk Management Advisory Committees. This joint meeting is scheduled for September 15 and 16, 2016 and during this meeting the FDA will be calling on a broad range of independent experts with real-world experience to provide recommendations on how to address the unique needs of children in pain.

March: On March 1, the FDA convened the Science Board to hear about and discuss a range of pressing issues related to the current opioid epidemic, including: (1) the role of opioids in pain management (2) scientific challenges facing FDA in supporting the development of pain medications (3) scientific challenges facing FDA in seeking to understand the real-world use of opioids to treat pain (4) the role that FDA plays as a part of a larger Federal, State and local response to the challenges of providing appropriate pain treatment while reducing opioid abuse and (5) postmarket surveillance activities related to opioids.

On March 22, FDA announced required class-wide safety labeling changes for immediate-release (IR) opioid pain medications. Among the changes, the FDA is requiring a new boxed warning about the serious risks of misuse and abuse, which can lead to addiction, overdose and death. The FDA is also requiring several additional safety labeling changes across all prescription opioid products to include additional information on the risk of these medications.

On March 24, FDA issued a draft guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.” This guidance recommends studies a generic applicant should conduct so FDA can evaluate the abuse deterrence of certain generic opioid drug products and help ensure that generic versions of approved opioids with abuse-deterrent formulations (ADFs) are no less abuse-deterrent than the brand named drug.

April: On April 26, FDA approved Xtampza ER (oxycodone), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Xtampza ER is the sixth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Xtampza ER has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and snorted or injected.

May: On May 3-4, FDA convened a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss results from assessments of the extended-release and long-acting (ER/LA) Opioid Analgesics Risk Evaluation and Mitigation Strategies (REMS). The committees provided comments as to whether this REMS with Elements to Assure Safe Use (ETASU) assures safe use, is not unduly burdensome to patient access to the drugs, and to the extent practicable, minimizes the burden to the healthcare delivery system.

On May 26, FDA announced required safety labeling changes for methadone and buprenorphine products when used by pregnant women for medication-assisted treatment (MAT) of opioid use disorder to ensure providers have complete information about the benefits and risks of these products.

On May 26, FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine, an implant designed to provide a constant, low level of buprenorphine for six months, should be used in patients who are already stable on low-to-moderate doses of other forms of buprenorphine and as part of a complete treatment program that includes counseling and psychosocial support.

August: On August 19, FDA approved Troxyca ER (oxycodone hydrochloride and naltrexone hydrochloride extended-release capsules), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Troxyca ER is the seventh ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Troxyca ER has properties that are expected to reduce, but not eliminate, abuse of the drug when crushed and then taken orally, snorted, or injected.

On August 31, FDA announced required class-wide changes to drug labeling to help inform health care providers and patients of the serious risks associated with the combined use of certain opioid medications and a class of central nervous system depressant drugs called benzodiazepines. Among the changes, the FDA is requiring boxed warnings and Medication Guides for prescription opioid analgesics, opioid-containing cough products, and benzodiazepines with information about the serious risks, including extreme sleepiness, respiratory depression, coma and death, associated with using these medications at the same time.

September: On September 15-16, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee to discuss the appropriate development plans for establishing the safety and efficacy of prescription opioid analgesics for pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation.

October: On October 5, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management to discuss naloxone products intended for use in the community, specifically the most appropriate dose or doses of naloxone to reverse the effects of life-threatening opioid overdose in all ages, and the role of having multiple doses available in this setting. The committees also discussed the criteria prescribers will use to select the most appropriate dose in advance of an opioid overdose event and the labeling to inform this decision, if multiple doses are available.

On October 31 – November 1, the FDA held a public meeting, Pre-Market Evaluation of Abuse-Deterrent Properties of Opioid Drug Products, to discuss scientific and technical issues relating to formulation development and pre-market evaluation of opioid drug products with abuse-deterrent properties. The meeting was intended to give FDA the opportunity to discuss, and seek public input from stakeholders on, the approach to testing FDA recommended in its draft guidance General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products. The meeting also provided an opportunity to discuss FDA’s efforts to develop standardized in vitro testing methodologies for evaluating the abuse deterrence of opioid drug products.

December: On December 16, the FDA approved several safety labeling changes (SLCs) about the serious risks of prescription opioid analgesics and opioids approved for medication assisted treatment (MAT) of opioid addiction including class-wide SLCs for immediate-release (IR) opioid pain medications, SLCs for methadone and buprenorphine products, and class-wide SLCs about the serious risks associated with the combined use of certain opioid medications with benzodiazepines or other central nervous system (CNS) depressants.

2017. January: On January 9, FDA approved Arymo ER (morphine sulfate extended-release tablets), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Arymo ER is the eighth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. Arymo ER is formulated to give it physicochemical properties expected to make abuse by injection difficult.

On January 17, FDA approved Vantrela ER (hydrocodone bitartrate extended-release tablets), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Vantrela ER is the ninth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. The physical and chemical properties of Vantrela ER are expected to make intravenous (injection) abuse difficult and are expected to reduce, but not eliminate, abuse by nasal and oral routes. However, abuse of Vantrela ER by these routes is still possible.

April: On April 20, FDA announced the restricted the use of codeine and tramadol medicines in children because these medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. These medicines should also be limited in some older children. The FDA also recommended against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants.

On April 20, the FDA approved RoxyBond (oxycodone hydrochloride), an opioid analgesic indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. RoxyBond is the first immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s 2015 Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling. Based on laboratory studies, RoxyBond tablets are resistant to certain forms of manipulation such as crushing, grinding, or otherwise extracting oxycodone from the tablet that are typically used to make opioids easier to abuse by the nasal and intravenous routes.

On April 27, FDA held an expert roundtable for healthcare professionals to discuss their experiences with the use of cough suppressants in children (<18 years of age), particularly opioid containing antitussive products, as well as the data available to support recommendations made by various professional societies regarding the treatment of cough in children.

May: On May 9-10, FDA held a public meeting, Training Health Care Providers on Pain Management and Safe Use of Opioid Analgesics – Exploring the Path Forward, to obtain input on issues and challenges associated with Federal efforts to support training on pain management and the safe prescribing, dispensing, and patient use of opioids (safe use of opioids) for health care providers.

On May 10, FDA released the "FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain" (draft revisions to the Blueprint), which broadens the current Blueprint to include information on pain management, including the principles of acute and chronic pain management non-pharmacologic treatments for pain and pharmacologic treatments for pain (both non-opioid analgesic and opioid analgesic).

June: On June 8, FDA requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market based on its concern that the benefits of the drug may no longer outweigh its risks.

July: On July 6, the JAMA Viewpoint article by Dr. Scott Gottlieb and Dr. Janet Woodcock entitled, “Marshaling FDA Benefit-Risk Expertise to Address the Current Opioid Abuse Epidemic," was published.

On July 6, following the FDA’s request, Endo announced that it would voluntarily remove reformulated Opana ER from the market.

On July 10-11, FDA held a public meeting, Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities, to discuss ways to improve the analysis and interpretation of existing data, as well as to discuss opportunities and challenges for collecting and/or linking additional data to improve national surveillance and research capabilities in this area.

On July 13, the National Academies of Science, Engineering, and Medicine release the consensus report, commissioned by the FDA, which outline the state of the science regarding prescription opioid abuse and misuse, as well as the evolving role that opioids play in pain management.

September: On September 11, FDA held a Pediatric Advisory Committee meeting to discuss the use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients. The discussion included current practice for the treatment of cough in children and benefit-risk considerations regarding the use of prescription opioid products in pediatric patients.

On September 20, FDA advised that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS). The combined use of these drugs increases the risk of serious side effects however, the harm caused by untreated opioid addiction can outweigh these risks. Careful medication management by health care professionals can reduce these risks.

On September 28, after determining that a REMS is necessary for IR opioid analgesics to ensure that the benefits of these drugs continue to outweigh the risks, FDA sent letters to IR opioid analgesic manufacturers informing them that their products that are intended to be used in the outpatient setting will be subject to the same REMS requirements as the ER/LA opioid analgesics.

November: On November 21, FDA issued a final guidance titled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.” This guidance recommends studies, including comparative in vitro and pharmacokinetic studies, that the potential abbreviated new drug application (ANDA) applicant should conduct and submit to FDA in an ANDA to demonstrate that a generic solid oral opioid drug product is no less abuse-deterrent than its reference listed drug with respect to all potential routes of abuse.

On November 30, FDA approved Sublocade, the first once-monthly injectable buprenorphine product for the treatment of moderate-to-severe opioid use disorder in adult patients who have initiated treatment with a transmucosal (absorbed through mucus membrane) buprenorphine-containing product. It is indicated for patients that have been on a stable dose of buprenorphine treatment for a minimum of seven days.

December: On December 11-12, FDA hosted a public workshop regarding the role of packaging, storage, and disposal options within the larger landscape of activities aimed at addressing abuse, misuse, or inappropriate access of prescription opioid drug products guiding principles and considerations for the design of packaging, storage, and disposal options for opioids integrating packaging, storage, and disposal options into existing health care and pharmacy systems, including both open and closed health care systems data needs and how to address challenges in assessing the impact of packaging, storage, and disposal options in both the premarket and postmarket settings and ways in which FDA could encourage the development and assessment of packaging, storage, and disposal options for opioids that have the potential to enhance opioid safety.

2018. January: On January 11, FDA Commissioner, Scott Gottlieb, M.D., announced the 2018 Strategic Policy Roadmap, which provides an overview of some of the key priorities the agency will pursue advance FDA’s public health mission. Part of the Roadmap is reducing misuse and abuse of opioid drugs.

On January 11, FDA announced that it is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older because the risks of these medicines outweigh their benefits in children younger than 18. The agency is also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the Boxed Warning of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone.

On January 24, FDA and the Federal Trade Commission posted joint warning letters to the marketers and distributors of 12 opioid cessation products, for illegally marketing unapproved products with claims about their ability to help in the treatment of opioid addiction and withdrawal.

On January 30, FDA held a public hearing, “Opioid Policy Steering Committee: Prescribing Intervention—Exploring a Strategy for Implementation,” to receive stakeholder input on how FDA might, under its REMS authority, improve the safe use of opioid analgesics by curbing overprescribing to decrease the occurrence of new addictions and limit misuse and abuse of opioid analgesics.

On January 30, FDA announced limits to packaging for anti-diarrhea medicine Loperamide (Imodium) to encourage safe use.

On January 30, FDA posted the revised Blueprint, “Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain,” which broadens the current Blueprint to include information on pain management, including the principles of acute and chronic pain management non-pharmacologic treatments for pain and pharmacologic treatments for pain. (It is important to note that the revised Blueprint will not be considered final until the Opioid Analgesic Risk Evaluation and Mitigation Strategy is approved.)

On February 14, FDA held a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for Hydexor (proposed tradename), a fixed-dose combination oral tablet, submitted by Charleston Laboratories, Inc., that contains hydrocodone, acetaminophen, and promethazine, for the short-term management of acute pain severe enough to require an opioid analgesic while preventing and reducing opioid-induced nausea and vomiting. The committees also discussed the abuse potential of this non-abuse-deterrent product and whether it should be approved.

February: On February 15, through a cooperative agreement with the FDA, the Duke-Margolis Center hosted a public workshop, “Strategies for Promoting the Safe Use and Appropriate Prescribing of Prescription Opioids,” to examine the landscape of health system and payer interventions to promote safe and appropriate prescribing of opioids discuss how health systems and payers are using data and health IT tools to support interventions discuss how health system approaches were implemented, barriers to their adoption, and potential unintended consequences of adoption and discuss how to build an evidence base to support existing health system and payer interventions as well as how success may be defined and measured.

March: On March 27, FDA held a meeting of the Psychopharmacologic Drugs Advisory Committee to discuss the new drug application for lofexidine hydrochloride, submitted by US WorldMeds, LLC, for mitigation of symptoms associated with opioid withdrawal and facilitation of completion of opioid discontinuation treatment.

April: On April 17, FDA is hosting a public meeting on Patient-Focused Drug Development for Opioid Use Disorder (OUD), in collaboration with National Institute of Drug Abuse (NIDA). In addition to NIDA, FDA is also working closely with patient advocacy and community organizations to encourage participation from individuals with OUD. This meeting aligns with FDA’s ongoing work aimed at reducing the impact of opioid abuse and addiction.

On April 20, FDA issued the draft guidance, “Opioid Dependence: Developing Buprenorphine Depot Products for Treatment,” which reflects the agency’s current thinking regarding drug development and trial design issues relevant to the study of depot buprenorphine products (i.e. modified-release products for injection or implantation).

May: On May 16, FDA approved Lucemyra (lofexidine hydrochloride), the first non-opioid treatment for the mitigation of withdrawal symptoms associated with abrupt discontinuation of opioids.

On May 22, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for buprenorphine sublingual spray, submitted by INSYS Development Company, Inc., for the treatment of moderate-to-severe acute pain where the use of an opioid analgesic is appropriate. The committees will also be asked to discuss whether this product should be approved.

May: On May 30, FDA launched an innovation challenge to spur development of medical devices ‒ including digital health and diagnostics ‒ that target pain, addiction and diversion.

June: On June 1, FDA sent safety labeling change notification letters to drug companies with approved opioid analgesic products intended for use in an outpatient setting, which require the companies to include new safety information regarding the Opioid Analgesic REMS in the Boxed Warning and Warnings and Precautions sections of prescribing information due to a general lack of awareness of the REMS among all opioid analgesic prescribers.

June: On June 5, FDA took action against 53 websites marketing unapproved opioids as part of a comprehensive effort to target illegal online sales.

June: On June 26, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for oxycodone extended-release capsules, submitted by Pain Therapeutics, with the proposed indication of the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The product is intended to have abuse-deterrent properties based on its physicochemical properties. The committees will be asked to discuss whether the data submitted by the Applicant are sufficient to support labeling of the product with the properties expected to deter abuse.

June: On June 27, FDA convened internet stakeholders, government entities, academic researchers, and advocacy groups at a one-day Online Opioid Summit to discuss ways to collaboratively take stronger action in combatting the opioid crisis by reducing the availability of illicit opioids online.

July: On July 9, FDA hosted a public meeting on Patient-Focused Drug Development for chronic pain to hearing patients’ perspectives on chronic pain, views on treatment approaches, and challenges or barriers to accessing treatments for chronic pain.

August: On August 3, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss results from assessments of the transmucosal immediate-release fentanyl (TIRF) medicines’ risk evaluation and mitigation strategy (REMS), approved in December 2011. The TIRF REMS requires that healthcare providers who prescribe TIRF medicines for outpatient use are specially certified, that pharmacies that dispense TIRF medicines for inpatient and outpatient use are specially certified, and that completion of the prescriber-patient agreement form occurs prior to dispensing TIRF medicines for outpatient use. The Agency will seek the committees’ assessment as to whether this REMS with elements to assure safe use (ETASU) assures safe use, is not unduly burdensome to patient access to the drugs, and to the extent practicable, minimizes the burden to the healthcare delivery system. The Agency will also seek the committees’ input on any possible modifications to the TIRF REMS goals and requirements, as well as input on the adequacy of the evaluations conducted in the REMS assessments to determine whether the TIRF REMS goals are being met.

On August 6, FDA issued the draft guidance for industry, “Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Medication-Assisted Treatment,” which is intended to assist sponsors in developing drugs for medication-assisted treatment of opioid use disorder (OUD) and addresses the clinical endpoints acceptable to demonstrate effectiveness of such drugs.

On August 22, FDA awarded a contract to the National Academies of Sciences, Engineering, and Medicine (NASEM) to help advance the development of evidence-based guidelines for appropriate opioid analgesic prescribing for acute pain resulting from specific conditions or procedures.

On August 28, FDA took action against 21 websites marketing unapproved opioids as part of agency’s effort to target illegal online sales.

September: On September 7, FDA approved a new dosage strength of buprenorphine and naloxone sublingual film as maintenance treatment for opioid dependence.

On September 18, FDA approved the Opioid Analgesic REMS.

On September 20, through a cooperative agreement with the FDA, the Duke Margolis Center for Health Policy convened a public workshop, “Expanding Access to Effective Treatment for Opioid Use Disorder: Provider Perspectives on Reducing Barriers to Evidence-Based Care.”

On September 27-28, FDA’s Office of Women’s Health, in collaboration with CDER and CTP, hosted a 2-day public meeting, “Opioid and Nicotine Use, Dependence, and Recovery: Influences of Sex and Gender.”

On October 11, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss new drug application 210730, for oliceridine 1 milligram/milliliter injection, submitted by Trevena, Inc., for the management of moderate-to-severe acute pain in adult patients for whom an intravenous opioid is warranted. The committee also discussed the efficacy and safety data and benefit-risk considerations.

On October 12, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss new drug application 209128, sufentanil sublingual tablets, submitted by AcelRx Pharmaceuticals, Inc., for the management of moderate-to-severe acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, in adult patients in a medically supervised setting. The committee also discussed risk-benefit considerations and whether this product should be approved.

On November 1, FDA convened a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss efficacy, safety and risk-benefit profile of new drug application 210417 for buprenorphine and samidorphan sublingual tablets, submitted by Alkermes, Inc., for adjunctive treatment of major depressive disorder.

On November 2, FDA approved first oral sufentanil pain medication for use in a medically supervised setting.

On November 14, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss new drug application 209774, for an immediate-release oral tablet formulation of oxycodone, which is intended to resist common methods of physical or chemical manipulation and to deter intravenous and intranasal abuse, submitted by SpecGx Inc., for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The committees also determined whether the Applicant adequately demonstrated that the abuse-deterrent properties of the proposed product are sufficient to include this information in the product label, and whether the product should be approved.

November 15, FDA convened a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the assessment of opioid analgesic sparing outcomes in clinical trials of acute pain. The committee also commented on the trial design and endpoints of these studies and how to determine the clinical relevance of the results.

January: On January 17, FDA announced the results of unprecedented work to design, test, and validate the key labeling requirements necessary to approve an over-the-counter (OTC) version of naloxone, including posting two model Drug Facts labels (DFLs) and the supporting FDA review. Overall, the study demonstrated that the model DFL was well-understood by consumers and is acceptable for use by manufacturers in support of their OTC naloxone development programs.

February: On February 6, FDA issued the final guidance, “Opioid Use Disorder: Developing Depot Buprenorphine Products for Treatment,” which reflects the agency’s current thinking regarding drug development and trial design issues relevant to the study of depot buprenorphine products (i.e. modified-release products for injection or implantation).

On February 12, FDA announced ongoing efforts to stop the spread of illicit opioids, further secure the U.S. drug supply chain and forcefully confront opioid epidemic.

March: On March 19, FDA took action against marketer of unapproved products claiming to treat addiction, chronic pain and other serious conditions.

On March 27, FDA announced new steps to strengthen agency’s safety requirements aimed at mitigating risks associated with transmucosal immediate-release fentanyl products.

April: On April 2, FDA took new enforcement actions as part of the agency’s ongoing effort to combat the illegal online sales of opioids.

On April 2, FDA hosted internet stakeholders, thought leaders, government entities, academic researchers, and advocacy groups at its second Online Opioid Summit.

On April 9, FDA announced harm reported from sudden discontinuation of opioid pain medicines and required label changes to guide prescribers on gradual, individualized tapering.

On April 19, FDA approved first generic naloxone nasal spray to treat opioid overdose.

On April 25, FDA launched a public education campaign to encourage safe removal of unused opioid pain medicines from homes.

May: On May 30, FDA opened a public docket to request information on requiring fixed-quantity blister packaging for certain opioid pain medicines to help decrease unnecessary exposure to opioids.

On September 30, 2019 FDA and DEA warned website operators illegally selling opioids

October: On October 24, FDA outlined the agency’s first year accomplishments implementing SUPPORT Act authorities to address the opioids crisis

November: On November 26, FDA issues warning letter for products illegally marketed for the treatment of health conditions, including opioid withdrawal symptoms

December: On December 11, FDA issued warning letter for not including the most serious risks in advertisement for medication-assisted treatment drug

On December 19, the National Academies of Sciences, Engineering, and Medicine released a consensus report, commissioned by the FDA, on framing opioid prescribing guidelines for acute pain.

January: On January 14, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application (NDA) for oxycodegol, a new molecular entity full mu-opioid receptor agonist, submitted by Nektar Therapeutics, for the management of chronic low back pain in adult patients with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The committees were asked to discuss the safety and efficacy data as well as the overall risk-benefit profile of the product.

On January 15, FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee. During the morning session, the committees discussed the NDA for tramadol 44 milligrams (mg) and celecoxib 56 mg tablet, which contains a fixed-dose combination of an opioid and a non-steroid anti-inflammatory drug, submitted by Esteve Pharmaceuticals, S.A., for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The committees were asked to discuss the safety and efficacy data as well as the overall risk-benefit profile of the product.

During the afternoon session, the committees discussed the NDA for an extended-release oral tablet formulation of oxycodone, submitted by Intellipharmaceutics Corp., for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. The product has been formulated with properties intended to deter abuse, and the applicant has submitted data to support these abuse-deterrent properties for this product. The committees were asked to discuss whether the applicant has demonstrated abuse-deterrent properties for their product that would support labeling, as well as the overall risk-benefit profile of the product.

June: On June 8, FDA and the National Telecommunications and Information Administration (NTIA) are launching a 120-day pilot to help reduce the availability of unapproved opioids illegally offered for sale online.

July: On July 23, the FDA issued a Drug Safety Communication announcing that the agency is requiring the drug manufacturers for all opioid pain relievers and medicines to treat OUD to add new recommendations about naloxone to the prescribing information to help ensure that health care professionals discuss the availability of naloxone and assess each patient’s need for a naloxone prescription when opioid pain relievers or medicines to treat OUD are being prescribed or renewed. In addition, the agency recommended that health care professionals consider prescribing naloxone to patients at increased risk of opioid overdose, regardless of whether they are receiving a prescription for an opioid pain reliever or medicine to treat OUD. These may include people with a current or past diagnosis of OUD or who have experienced a previous opioid overdose.

August: On August 7, the FDA approved Olinvyk (oliceridine), an opioid agonist for the management of moderate to severe acute pain in adults, where the pain is severe enough to require an intravenous opioid and for whom alternative treatments are inadequate.

September: On September 10-11, the FDA convened a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the results of required postmarketing studies (Postmarketing Requirements 3051-1, 3051-2, 3051-3, and 3051-4) that evaluated the effect of the reformulation of OxyContin (oxycodone hydrochloride extended-release tablets, manufactured by Purdue Pharma L.P., NDA 022272) on abuse, misuse, and fatal and non-fatal overdose, associated with OxyContin. The committees discussed whether these studies, in concert with other information from the published literature, have demonstrated that the reformulated OxyContin product has resulted in a meaningful reduction in these outcomes. The committees also discussed the broader public health impact of OxyContin’s reformulation.

October: On October 2, the FDA published the final guidance for industry, Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment, which is intended to help sponsors develop drugs for treatment of opioid use disorder (OUD). This guidance addresses clinical endpoints acceptable for demonstrating effectiveness of such drugs.

November: On November 2, the FDA convened a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee to discuss the new drug application for Hydexor, a fixed-dose combination oral tablet, submitted by Õlas Pharma, Inc., that contains hydrocodone, acetaminophen, and promethazine, for the short-term (not to exceed 3 days) management of acute post-operative pain severe enough to require an opioid analgesic and the prevention of opioid-induced nausea and vomiting in patients who are at risk for or have a history of nausea and vomiting.

December: On December 23, the FDA finalized modifications to the transmucosal immediate-release fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) to address the persistence of concerning prescribing practices and improve the agency’s ability to monitor for adverse events and ensure safe use of these medicines.

February: On February 1, the FDA provided an update on the pilot program with the National Telecommunications and Information Administration (NTIA) and three domain name registries to help reduce the availability of unapproved opioids illegally offered for sale online.

February: On February 16, the FDA issued a warning letter to AcelRx Pharmaceuticals, Inc. for the false and misleading promotion of Dsuvia (sufentanil sublingual tablet), a potent opioid analgesic.

March: On March 1, the FDA approved Hydrocodone bitartrate (reference listed drug: Hysingla ER), the first FDA-approved generic opioid with an abuse-deterrent formulation (ADF)—meaning the product has properties that are expected to reduce, though not totally prevent, abuse of the drug when chewed and then taken orally or crushed and snorted or injected.

March: On March 24, the FDA issued a white paper, Introduction to FDA’s Opioid Systems Model, which introduces FDA’s opioid systems modeling effort, discusses potential uses of the model, provides an overview of the model’s scope and structure, highlights preliminary areas for potential policy analysis and outlines on-going work.​


States and Their Admission to the Union

The thirteen original colonies in North America could officially be admitted to the United States after the U.S. Constitution was written and signed by the delegates to the Constitutional Convention, on Sep. 17, 1787. Article IV, Section 3 of that document reads:

The main part of this article grants the U.S. Congress the right to admit new states. The process usually involves Congress passing an enabling act that authorizes a territory to convene a constitutional convention, draft a constitution, and formally apply for admission. Then, assuming they meet any conditions set forward in the enabling act, Congress accepts or denies their new status.

Between Dec. 7, 1787, and May 29, 1790, each of the colonies became states. Since that time, 37 additional states have been added. Not all states were territories before they became states, however. Three of the new states were independent sovereign states at the time they were admitted (Vermont, Texas, and California), and three were carved out of existing states (Kentucky, part of Virginia Maine part of Massachusetts West Virginia out of Virginia). Hawaii was a sovereign state between 1894 and 1898 before it became a territory.

Five states were added during the 20th century. The last states to be added to the US were Alaska and Hawaii in 1959. The following table lists each state with the date it entered the union, and its status before they were states.


Transitioning Toward Transistors

The first modern computers were nothing like the commercial products used by consumers today. They were elaborate hulking contraptions that often took up the space of an entire room. They also sucked enormous amounts of energy and were notoriously buggy. And since these early computers ran on bulky vacuum tubes, scientists hoping to improve processing speeds would either have to find bigger rooms—or come up with an alternative.

Fortunately, that much-needed breakthrough was already in the works. In 1947, a group of scientists at Bell Telephone Laboratories developed a new technology called point-contact transistors. Like vacuum tubes, transistors amplify electrical current and can be used as switches. More importantly, they were much smaller (about the size of an aspirin capsule), more reliable, and they used much less power overall. The co-inventors John Bardeen, Walter Brattain, and William Shockley would eventually be awarded the Nobel Prize in physics in 1956.

While Bardeen and Brattain continued doing research work, Shockley moved to further develop and commercialize transistor technology. One of the first hires at his newly founded company was an electrical engineer named Robert Noyce, who eventually split off and formed his own firm, Fairchild Semiconductor, a division of Fairchild Camera and Instrument. At the time, Noyce was looking into ways to seamlessly combine the transistor and other components into one integrated circuit to eliminate the process in which they had to be pieced together by hand. Thinking along similar lines, Jack Kilby, an engineer at Texas Instruments, ended up filing a patent first. It was Noyce’s design, however, that would be widely adopted.

Where integrated circuits had the most significant impact was in paving the way for the new era of personal computing. Over time, it opened up the possibility of running processes powered by millions of circuits—all on a microchip the size of a postage stamp. In essence, it’s what has enabled the ubiquitous handheld gadgets we use every day, that are ironically, much more powerful than the earliest computers that took up entire rooms.


Watch the video: 2,000 Years of Chinese History! The Mandate of Heaven and Confucius: World History #7 (July 2022).


Comments:

  1. Sandy

    I'm sorry, of course, but this doesn't suit me. I will look further.

  2. Molar

    This is the fun play

  3. Emyr

    you can infinitely discuss it.

  4. Edel

    It is seen, not the destination.



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