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By ROB HAMILTON
Northmor got out to a fast start in Mid-Ohio Athletic Conference volleyball action on Tuesday and was able to hold on for a 25-12, 25-9, 11-25, 25-16 win.
After the first few points of the opening game were played evenly, the Knights got one point from Anna Donner and three more from Rayanna Loyer to jump out to an 11-5 advantage. Northmor's defense played a huge key in the win, as they only surrendered one offensive point to the Pirates during that first game.
Holding a 17-10 lead, the Knights got three points from Erica McElvain to reach 20. From there, two scores from Cristianna Boggs and one from Loyer, as well as a pair of defensive stops, gave Northmor the first game.
With a young team, Northmor coach Kara Wright is trying to keep her charges aggressive, both defensively and offensively — a strategy that worked for much of Tuesday's match.
"We're asking the girls to serve aggressively and shoot for holes and look to dominate," she said. "And we're just trying to teach them to hut very aggressively."
Northmor then got out to a fast start in the second game, getting five quick points from Jordyn Zoll, three from Karlee Carroll and two from Lindsey Wiseman to jump out to a 12-2 lead. The Pirates would not be able to recover from that deficit as the Knights continued to add to that lead on their way to taking a 2-0 lead in the best-of-five match.
"I don't know what was going on," said Cardington (3-4, 1-1 in league play) coach Kendra Mosher. "I thought we were beating ourselves. Finally (in the third game), they must have gotten tired of being beaten badly and came out and played."
That third game started out with a snafu, as Northmor erred in making their line-up card, turning a 1-1 game with the Knights holding serve into a 1-0 Cardington lead with the ball in their possession. After the lengthy discussion, Cardington was able to snag the momentum, getting two points from MaKenna McClure and three from Gracie Rees to jump out to a 7-1 advantage.
Cardington's earlier offensive woes vanished in this game, as eight straight girls scored at least once on their trips behind the line. Jordan Deskins tallied one point, followed by two from Samantha Brininger, one each by Rylie Partlow and Marissa Hall, four more from McClure and two more from Rees.
Those final Rees' points made the score 24-9 in favor of the Pirates. Northmor got the ball back and got one point from Wiseman, but a defensive stop by Cardington gave them the game and sent the match to a fourth.
"Northmor was doing a good job and not making many hitting errors," said Mosher. "I think we finally came together in the third set."
The Knights got two points from Zoll and two more from Wiseman in jumping out to a 7-2 lead in the fourth game, but the Pirates roared back to tie the score after a defensive stop and four points from Rees. However, with Northmor holding a scant 9-8 advantage, they would blow the game open behind seven consecutive points scored by Donner.
Cardington responded with three from Brininger to get within a 16-12 score, but after getting a stop, the Knights would then get seven more scores from Kelsie Fike to come one point from victory. Cardington would get a stop and three points from Kelsey Barker, but the Knights would be able to finish off the win.
Mosher, who noted this season has been a roller-coaster so far, noted that consistency is something her players will have to develop.
"That's our biggest thing — we beat ourselves some times and aren't mentally tough," she said. For the Knights, who improved to 2-0 in league play and 5-2 overall, getting off to a good start in league play during a week full of distractions due to the Morrow County Fair, was a huge positive.
"Losing six seniors, we knew we had a lot of holes to fill," she said. "To start 2-0 and during fair week, that's what we wanted to do."
Rob Hamilton can be reached at 419-946-3010, ext. 1807. Connect with him on Twitter at @SportsMCS


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Well well well how the tables have turned. Just kidding, these Democrats have always been shady with their mask wearing, they are just getting caught now. The newest to get caught with his metaphorical pants down is Democratic presidential nominee Joe biden. He was conspicuously without his trademark face mask and it was caught on video that was shared by ABC News "20/20" reporter Beatrice-Elizabeth Peterson.
I asked the former Vice President if the gloves were off against @realDonaldTrump? @JoeBiden said "yes."
He also added that when it comes to his support with Hispanic his numbers "are much higher" than Trump's. pic.twitter.com/6WYExKTb5d
— Beatrice-Elizabeth Peterson (@MissBeaE) September 14, 2020
Trending: Bisexual Horticulturalist with ADHD Goes Berserk in Video After Learning of RBG Death
Then only 4 days later this is what Biden tweeted:
"Do your part. Wear a mask," along with an eerie video of himself putting one on.
Do your part. Wear a mask. pic.twitter.com/pdnEecS49Q
— Joe Biden (@JoeBiden) September 10, 2020
Biden talks all the time about him and his "national mask mandate" which essentially mean him FORCING Americans to wear a mask when they are outdoors. BUT…even with all his talk about masks, he has still been seen more than once without one.
9/30: Ignoring social distancing guidelines, Biden walks up to a group of officers and speaks to them in very close proximity… while not wearing a mask. pic.twitter.com/nRUM2xbZFs
— Abigail Marone ?? (@abigailmarone) October 6, 2020
9/17: After Biden said he would mandate mask wearing as President, he went up to a group of people to talk to them… without a mask on. pic.twitter.com/oqo0w2jWc2
— Abigail Marone ?? (@abigailmarone) October 6, 2020
"Wearing your mask is your patriotic responsibility." — @JoeBiden pic.twitter.com/2Bq6e1x4ko
— Team Joe (Text JOE to 30330) (@TeamJoe) October 6, 2020
Joe Biden 5 days ago … no mask, no social distancing pic.twitter.com/051vWa6d6d
— Trump War Room – Text TRUMP to 88022 (@TrumpWarRoom) October 6, 2020
Now, we all know that he free to choose for himself if he will wear a mask or not, because…this is America. But, its a little shady for him to not wear one while using fear tactics in telling everyone else they need to.
Just look at what the candidate's Twitter account posted Monday when a COVID-19 positive President Donald Trump was readjusting to being back at the White House after a stint at Walter Reed National Military Medical Center:
Wear a mask. pic.twitter.com/TSuLuzAXEB
— Joe Biden (@JoeBiden) October 6, 2020
On Tuesday morning, he tweeted, "Folks, we can save nearly 100,000 lives by the end of the year if everyone wears a mask in public. Do your part. Protect your neighbors. Wear a mask."
Folks, we can save nearly 100,000 lives by the end of the year if everyone wears a mask in public.
Do your part. Protect your neighbors. Wear a mask.
— Joe Biden (@JoeBiden) October 6, 2020
Trump has tried not to make a big issue out of wearing masks amid the coronavirus pandemic.
And he hasn't needed to, as the establishment media and Democrats have done that for him.
They lost their collective minds Monday night when Trump took off his mask outside the White House, where he lives, while alone.
CNN's @ChrisCuomo who:
– Broke Quarantine while COVID Positive
– Got into a fight with a biker without a mask
– Likely infected his family with the Virus
– Faked his emergence from his basement on air..
Is offended that President Trump took his mask off on his balcony. pic.twitter.com/qlko8ifhK0
— Benny (@bennyjohnson) October 6, 2020
Democrat after democrat have been caught discrediting their own relentless mask messages.
A hot mic moment between two Pennsylvania Democrats last week gave us some pretty good insight into why some Democrats wear masks.
While speaking with Gov. Tom Wolf, State Rep. Wendy Ullman seemed to give away how some of our leaders really feel about masks.
"So Wendy, I'm going to, I'm going to take my mask off when I speak," Wolf told Ullman.
Ullman laughed, then told Pennsylvania's Democratic governor, "I will as well. I'm waiting so we can do a little political theater.
"So that it's on camera," she added, before the two politicians chuckled.
The video was quickly seized on by opponents of mandatory mask-wearing, as it should have been.
I hope every person in Pennsylvania sees this video! The Governor is killing your states economy for "political theater." https://t.co/u5srZrmPYK
— Eric Trump (@EricTrump) September 29, 2020
With Democrats getting caught maskless, their hypocrisy can be frustrating, especially when they are likely the cause of panic that are in many other Americans when it comes to masks. Even to the point of taking away anothers freedom….to enforce them to wear a mask.
For instance this recent story that happened in Idaho…
A high school football game in Idaho was cancelled during half-time after a parent who was there to watch his son play refused to wear a mask. Ammon Bundy, who is most known for a 2016 standoff at an Oregon wildlife refuge was there and just wanted to watch his son play football. However, he was turned away at the gate for refusing to adnere to Caldwell's coronavirus policy on masks.
He was refused at the entrance and proceeded to try and watch the game from the parking lot outside the stadium instead. Once again he was approached and asked to leave by the game hosts, despite peacefully agreeing to no entrance and settling at watching his son play from the parking lot. When he didn't comply with their demand to leave, Caldwell administrators decided to call the game off and send everyone home. It was Emmett High School Huskies (Bundy's Son's team) vs the Caldwell Cougars and Emmett was winning 35-0 when the game was cancelled.
Emmett High School does not enforce a policy that requires fans to wear masks. Bundy has been able to attend his son's football games mask-less before this incident in Caldwell.
Bundy explained why he refused to wear the mask:
"I have a strong belief in my right to choose to wear a mask or not," Bundy said. "And If they think somehow there's a safety issue, then they need to section off a part of the bleachers to accommodate for those of us who believe differently than others."
As for the winner of the cancelled game, it has not been declared yet. Despite Emmett's lead on the scoreboard, the win could go to host Caldwell Cougars as winners by forfeit, if it is found that Caldwell administrators enforced their policy on Bundy correctly, making their policy clear to him.
"It depends on what was directed to Mr. Bundy and who is the offended team was here," Jones said.
Emmett Independent School District Superintendent, Craig Woods had this to say:
"This is incredibly sad for the Emmett High School football team, high school and community. They were winning the game," Woods said in a statement over the weekend.
"They've been having a great season, and they've worked hard. We were the visitors. We should respect the host's policies and procedures. Whether you agree or not when it comes to masks, the football team should not have to suffer the consequences. I'm proud of the Huskies. They did not ask for this."
According to People's Rights FB Page:
"Now Caldwell High School administrators are actively seeking to take the win away from Emmett High School in what appears to be an attempt to persuade the Emmett community to socially punish Ammon & his family for a non-compliance to their demands."
People's Rights Public Statement:
October 2, 2020
Friday evening, Ammon Bundy & his family went to watch their son and brother play football at Caldwell High School. They were denied access into the football stadium because of a masks policy. The family moved far away from the ticket booth and began to watch the game from the parking lot. Ammon went back to the ticket booth and offered to pay for full admission to watch the game outside the stadium fence. He then returned to his family. The family did nothing to bring attention to the situation, they only wished to watch and support their son and brother playing in the game. Caldwell High School administrators would not allow Ammon or his family to pay for or watch the game from the parking lot. Caldwell Police were called in to remove the family from the property but they refused to enforce the will of the Caldwell High School administrators because the family was not causing a disruption or posing a threat to anyone. Ammon & his family were peacefully watching the game outside the stadium fence from the west parking lot. Out of desperation to enforce their demands, Caldwell High School administrators ended the football game at halftime. The reason given to Ammon and his family was, "They would not comply with their (the administrators) demands."
Caldwell High School administrators are now actively seeking to take the win away from Emmett High School in what appears to be an attempt to persuade the Emmett community to socially punish Ammon & his family for non-compliance to their demands.

subset: commoncrawl


text: We apologize for multiples copies. Please circulate this CFP among your colleagues and students. ---------------------------------------------------------------------- IFIP/IEEE IM 2015 The 14th IFIP/IEEE Symposium on Integrated Network and Service Management Ottawa, Ontario, Canada, 11-15 May 2015 http://www.ieee-im.org/ (Paper Submission Date: September 15, 2014) "Integrated Management in the Age of Big Data" ---------------------------------------------------------------------- The 14th IFIP/IEEE Symposium on Integrated Network and Service Management (IM 2015) will be held 11-15 May 2015 in Ottawa, Ontario, Canada and hosted by the Ottawa Convention Centre. Held in odd-numbered years since 1989, IM 2015 follows the 27 years tradition of NOMS and IM as the primary IEEE Communications Society's forum for technical exchange on management of information and communication technology focusing on research, development, integration, standards, service provisioning, and user communities. IM 2015 will focus on the theme "Integrated Management in the Age of Big Data" presenting recent, emerging approaches and technical solutions for dealing with Big Data as well as using it for management solutions. IM 2015 will offer five types of sessions: technical, experience, poster, panel and dissertation. High quality will be assured through a well qualified Technical Program Committee and stringent peer review of paper submissions. A special call for demonstrations is organized to allow industry partners and researchers to demonstrate early products and prototypes. TOPICS OF INTEREST Authors are invited to submit papers that fall into or are related to the topic areas that are listed below. In addition, we invite submissions of proposals for demonstrations, exhibits, technical panels, tutorials and workshops. Papers can be submitted as technical session full papers, technical session short papers, experience session papers and dissertation papers. Network Management & Operational Experience - Software Defined Networks (SDN) - Smart Cities, Smart Grids - Internet of Things (IoT) - Future Internet - Content Distribution Networks (P2P, CDN, ICN) - Virtual and Overlay Networks - Data Centers, Storage Area Networks - Cyber-Physical Systems - Wireless and Mobile Networks (Ad-Hoc, Mesh, Sensor, Vehicular) - Smart Devices and Home Networks - Broadband Access Networks - Cognitive Radio Networks - IP/MPLS Networks - Optical Networks - Heterogeneous Networks Service Management - Cloud Services (IaaS, PaaS, SaaS) - IT Service Management - Multimedia and Data Services - QoE-Centric Management - Service Discovery, Migration and Orchestration - Resource Provisioning and Management - Hosting and Virtualized Infrastructures - OTT Service Management - Management as a Service Business Management - Legal and Ethical Issues - Process Management Functional Areas - Deployment - Fault Management - Diagnostics, Tracing, Troubleshooting - Configuration Management - Accounting and Billing Management - Performance Management - Service Level Management - Security Management, IDS, IPS Management Approaches - Centralized management - Distributed management - Autonomic and self-management - Policy-based management - Federated Management - Pro-Active Management - Energy-Aware Management - Management Architectures Management Enablers & Technologies - Network Programmability - Cloud Computing - Network Function Virtualization (NFV), Service Chaining - (Big) Data, Information and Semantic Modeling - Protocols and Languages - Message and Software Buses - Middleware, Grids - Mobile Agents - Social Networking - Human-Machine Interactions - Operations and Business Support Systems (OSS/BSS) Methodologies for Network Operations and Management - (Big) Data Analytics and Data Mining - Monitoring and Measurements - Control Theories - Optimization Theories - Economic Theories - Machine learning and Genetic Algorithms - Probability, Stochastic Processes, and Queuing Theory - Design and Simulation - Experimental Studies - Visualization SUBMISSION INSTRUCTIONS Authors are invited to submit original contributions (written in English) in PDF format through the IM 2015 web site. Only original papers that have not been published or submitted for publication elsewhere can be submitted. Each submission will be limited to 8 pages (full papers) or 4 pages (short papers) in IEEE 2-column style. Papers exceeding these limits, multiple submissions, and self-plagiarized papers will be rejected without further review. The authors of the IM 2015 top papers will be encouraged to extend their work and submit to IEEE TNSM (IEEE Transactions on Network and Service Management. These extended papers will undergo the normal TNSM peer-review process. IMPORTANT DATES Paper submission: September 15, 2014 Notification of acceptance: November 30, 2014 Camera ready submission: February 1, 2015 GENERAL CO-CHAIRS - Raouf Boutaba, University of Waterloo, Canada - Wahab Almuhtadi, Algonquin College, Canada TPC CO-CHAIRS - Shingo Ata, Osaka City University, Japan - Remi Badonnel, TELECOM Nancy - LORIA/INRIA, France - Jin Xiao, IBM T.J. Watson, USA TECHNICAL PROGRAM COMMITTEE - Abdelkader Lahmadi, ENSEM, France - Adarsh Sethi, University of Delaware, USA - Adel El-Atawy, Google, USA - Aiko Pras, University of Twente, Netherland - Akihiro Nakao, The University of Tokyo, Japan - Alberto Gonzalez, Cisco Systems, USA - Aldri dos Santos, Universidade Federal do Paraná, Brazil - Alexander Clemm, Cisco Systems, USA - Alexander Keller, IBM Global Technology Services, USA - Alva Couch, Tufts University, USA - Anna Sperotto, University of Twente, Netherlands - Anwar Haque, Bell Canada, Canada - Arosha Bandara, The Open University, UK - Artur Ziviani, LNCC, Brazil - Bradley Simmons, York University, Canada - Brendan Jennings, TSSG - Waterford Institute of Technology, Ireland - Burkhard Stiller, University of Zurich and ETH Zurich, Switzerland - Carlos Westphall, Federal Uiversity of Santa Catarina, Brazil - Carol Fung, Virginia Commonwealth University, USA - Chonggang Wang, InterDigital Communications, USA - Choong Seon Hong, Kyung Hee University, South Korea - Christopher Ward, SiriusXM, USA - Clarissa Marquezan, Duisburg-Essen University, Germany - Danny Raz, Technion, Israel - David Breitgand, IBM - Haifa Research Lab, Israel - David Hausheer, TU Darmstadt, Germany - Deep Medhi, University of Missouri-Kansas City, USA - Edmundo Madeira, UNICAMP, Brazil - Emil Lupu, Imperial College, UK - Fetahi Wuhib, Ericsson Research, Sweden - Filip De Turck, Ghent University - iMinds, Belgium - Gabi Dreo Rodosek, University of Federal Armed Forces, Munich Germany - George Pavlou, University College London, UK - Gerard Parr, University of Ulster, UK - Giovane Moura, Delft University of Technology, Netherlands - Guillaume Doyen, UTT, France - Hanan Lutfiyya, University of Western Ontario, Canada - Helmut Reiser, Leibniz-Supercomputing Centre, Germany - Henning Sanneck, Nokia Siemens Networks GmbH & Co KG, Germany - Hongtaek Ju, Keimyung University, South Korea - Isabelle Chrisment, Université de Lorraine, France - Iyad Katib, King Abdulaziz University Saudi, Arabia - James Hong, POSTECH, South Korea - Javier Baliosian, University of the Republic, Uruguay - Jérôme François, INRIA Nancy Grand Est, France - Jean-Philippe Martin-Flatin, EPFL, Switzerland - Jeroen Famaey, Ghent University - iMinds, Belgium - Jerry Rolia, HP Laboratories, USA - Jiahai Yang, Tsinghua University, China - Joan Serrat, Universitat Politècnica de Catalunya, Spain - Joe Betser, The Aerospace Corporation, USA - John Strassner, Huawei Technologies (US), USA - Jorge López de Vergara, Universidad Autónoma de Madrid, Spain - Jorge Lobo, Universitat Pompeu Fabra, Spain - José De Souza, UFC, Brazil - Jose-Marcos Nogueira, Universidade Federal de Minas Gerais, Brazil - Juergen Schoenwaelder, Jacobs University Bremen, Germany - Kazuhiko Kinoshita, Osaka University, Japan - Liam Fallon, Ericsson, Ireland - Lisandro Zambenedetti Granville, UFRGS, Brazil - Luca Deri, ntop.org, Italy - Luciano Paschoal Gaspary, UFRGS, Brazil - Lucy Cherkasova, Hewlett Packard Labs, USA - Malgorzata Steinder, IBM T. 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As I traveled through the middle of nowhere the other day, the car's radio dial rested upon a National Public Radio Program titled, "The Takeaway." Part of the show focused upon the procedure to ban books. The show's host discussed the topic with three guests:
- Mike Holzknecht, a lawyer and parent who was part of the opposition to the book "The Absolutely True Story of a Part-Time Indian" by Sherman Alexi.
- Sarah Pacheco, Public Information Officer for the Sierra Vista Unified School District; and
- Amy Crump, Library Director at Homewood Public Library in Illinois.
While the program was interesting, I became fixated upon the segment discussing censorship, including of the book "The Absolutely True Story of a Part-Time Indian" by Sherman Alexi." In truth, I never heard of this banned book, so a quick internet search revealed a few schools who've banned this publication.
According to well published sources, censorship may have begun around 2010 in Stockton, MO where a resident(s) supported banning The Absolutely True Story of a Part-Time Indian for containing material too mature for children. The New York Daily News reported middle schoolers at Public School 114 in Rockaway, Queens, wouldn't be reading Sherman Alexie's prized illustrated novel either. The school caved to pressure from at least one angry parent and phone calls from a tabloid (newspaper). The book was also removed from reading lists in Oregon and Washington as well. It was banned by Washington's Richland School District—until board members actually read the book and reversed their decision.
In Stockton, MO, local media outlets indicated the author's book may not have reflected community values. And while specific citations remain elusive, reports indicate supporters citing "… Biblical references." Stockton residents also listed book descriptions of masturbation, sexual language and foul jokes, along with themes encompassing racism, alcoholism and violence.
Man … that must be one badass book.
Some may justifiably argue that not every child is emotionally mature to handle the content. Thus, it should be a parent's decision of how much information is provided to their children. Fair enough. While those with such opposing views may have a point, I remember a similar badass book a lot of parents freely give their children. Here are just a few themes:
- 4 Kings 2:23-24 – Don't make fun of bald people or two female bears may eat you
- Genesis 38:8-10 – Neologism – hidden reference to onanism, an archaic term for masturbation
- Judges 19:22-30 – Unwilling to let guests be rapped, so owner throws his daughters to the crowd
- Found in: 1 Kings 18:25-27 – David kills two hundred men to gather foreskins
- Exodus 33:23 – Exhibitionism, God exposed his back parts to Moses
- Numbers 22:28-30 – A talking donkey
- Genesis 1:28 – God blessed them and said to them, "Be fruitful and increase in number; fill the earth and subdue it." So (1 Chronicles 1) Adam begat Seth, Seth begat Enosh, Enosh begat Kenan, Mahalaleel, Jered … etc., etc. Question, who did Cain and Able marry? Maybe … sisters?
- Genesis 19:30-36 – Lot has drunken sex with daughters (i.e., incest)
- Genesis 29:21-28 – Jacob takes a job where payment is a woman (so much for women's rights)
- Judah 38:8-10 – Judah said to Onan, go marry your brother's wife and get her pregnant
- Genesis 38:15-16 – The prostitute I has sex with turned out to be my daughter (i.e., another quality relationship)
- Solomon's Song: A complete sexual love letter
- 2 Kings 6:24–7:20 – Cannibalism
- Exodus 21 – Gives advice on how to sell your daughter (so much for women's rights)
- 2 Samuel 11 – King David's Adultery and Murder of Uriah just to get Uriah's wife
- Ephesians 6:5 – Slaves, obey your earthly masters with deep respect and fear. Serve them sincerely as you would serve Christ (So your master is Christ?)
- Leviticus 19:20-22 – If a man rapes his female slave … the woman gets punished and the man's sins are forgiven
- 1 Corinthians 11:3-9 – God over Christ, Christ is over man, and man is over woman. After all man was not created for woman, but woman was created for man
- Judges 21:12 – Basically, young virgins are considered a spoil of war and can be taken for the use of the victors
- Deuteronomy 25:10 – Ladies, a man has an obligation to produce a child for his widowed sister-in-law (ladies, I guess you just have to deal with it)
- Mark 10:29 – Man who leaves his house, wife, brothers, parents, or children for the sake of the kingdom of God will receive special rewards
In complete transparency, I admit to having never read Sherman Alexi's book. And in truth, I'll be damned if I could find any published articles reflecting Stockton, MO's community values. A Google keyword search of "Stockton, MO community values" revealed little. But I didn't spend a lot of time researching either.
Still … should one go to their local community and demand the Bible be banned from all schools and public libraries? I mean the "Good Book" does have "… hidden references to masturbation, rape, murder, sexual language, racism, alcoholism and violence." Or should we just allow future generations to ask their parents how to properly spill their seed on the ground ("onanism?)" Bet you never hear that sermon Sunday morning. Ah … there's nothing like having your children snuggle up with a good book on a rainy day!
Seriously, let's stop hiding and call it what it is: censorship. And some forms of censorship can be filled with cocky snide remarks, intemperance and self-congratulatory smiles. When this occurs, it's a play to the gallery. While some believe proper censorship protects the community, many forms of censorship are simply subjective intolerance and self-imposed righteousness.
It's strange how liberal conservatives are in applying the First Amendment and how conservative they become in applying the Second.


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Heal the sick, raise the dead, cure those with leprosy, and cast out demons. Give as freely as you have received! Matthew 10:8 (NLT)
Two days ago, I posted a ridiculous prayer request. Yes, it is ridiculous because I asked you to pray for a child's resurrection. Faith is ridiculous. People will ridicule you for having the audacity to believe God can make an exception for you. The momma who lost her 2 year old daughter does not want to let her daughter go. She has chosen to believe that the God she serves can resurrect her daughter. As her sister in Christ and a fellow momma, my duty is to support her, not to mock her faith or stay silent. She is not believing God for something unscriptural. Whether she is asking for prayer from a place of grief or faith is not mine to determine or judge. I will continue to pray along.
What if the baby doesn't resurrect? That's not my expectation. I will still give glory and praise to God. We are limited in our understanding of God's ways. We keep growing in faith. Our commitment to God should not be on the basis of circumstances but from a place of love for the one who loved us first. When we don't get that healing or miracle we prayed for, it is never because God did not honor his word. It is always based on our human limitations. I pray like I have never been hurt. I put all my eggs in one basket and give it to God.
Are you that Christian Momma who would stand in the gap for the resurrection of another momma's child?
Are you that Christian Momma who would pray for the healing of another momma's child?
Are you that Christian Momma who doesn't mock the ridiculous faith of another momma?
Are you that Christian Momma who is mama bear for other mommas' children?
Are you that Christian Momma who cares about other momma's children?
Are you that Christian Momma with ridiculous faith?
Carry each other's burdens, and in this way you will fulfill the law of Christ. Galatians 6:2 (NIV)
I am thrilled that people have the audacity to believe God for the dead to rise. Oh what hope!


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There are a number of different ways to prevent bed bugs and decisions that you can make in your everyday lives that will help decrease your likelihood of running into bed bugs. First off, all of your mattresses and box springs should be encased in encasements that have designed specifically to protect against bed bugs. The spread of bed bugs is often attributed to an increase in travel. Prior to traveling, make sure to check websites such as http://www.bedbugregistry.com/ to see if your vacation location has been affected by bed bugs. Always use the luggage rack in hotel rooms and thoroughly check the beds and furniture for bed bugs in each hotel room prior to settling in.
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text: Ryan Patrix's skin displays his total dedication to the tattoo needle. Swirling colors and patterns sweep up his arms, across his chest, and down to his big, fat dick, which hovers above a mouth-watering pair of low-hanging bull balls. In front of Ryan stands scruffy Jake Jammer, whose mushroom-headed cock struggles to emerge from the confines of his Levis. Ryan lays Jake out on the table and, in a single, swift motion, tears off Jake's jeans and inhales his cock. However, Jake wants more than a blowjob. 'Fuck me with that big dick; get it in there,' he demands, and Ryan delivers with rudee strength. The intensity spirals: the harder Ryan fucks, the harder Jake wants it, and soon they're rebounding off the table after each thrust. At the limit of his endurance, Ryan relents, and Jake services Ryan's crack and sack with his tongue. In an unexpected twist, Jake assumes control and drills Ryan's ass deep, commanding him, 'Squeeze my dick!' They blow their loads together, marking Ryan's inked torso with massive white dots of cum.


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Die Another Day – latest movies streaming
Pierce Brosnan gives one last mission as James Bond. Starting off in North Korea, Bond is betrayed and captured. 14 months later, Bond is set free, but traded for Zao who was captured by MI6. When back in his world, Bond sets off to track down Zao. Bond gets caught up in yet another scheme which sends him to millionaire Gustav Graves. Another MI6 agent known as Miranda Frost is also posing as a friend of Graves. Bond is invited to a presentation held by Graves about a satellite found in space which can project a huge laser beam. Bond must stop this madman with a fellow American agent, known as Jinx. Whilst Bond tries to stop Graves and Zao, will he finally reveal who betrayed him?
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Also, it's quite possible that I have ridiculously high standards. I can't count the number of times I'll comment about this or that during a show or movie and my wife just looks at me with this are-you-kidding-me" look. She points out that no one else in the world would see the things I see when it comes to pointing out discrepancies or flat-out mistakes during movies.
I beg to differ. I think there are many people out there, just like me, who see the same things I do and grit their teeth and bare it just like I do. I mean, there has to be right? Tell me I'm not the only one!
Oh, God…am I the only one?
Herro? Greorge?
Alllllrighty then, moving on.
I consider myself an educated Sci-fi fan and in my considerable educated opinion, I thought Defiance sucked a big fat huge one. I mean seriously, horrible. I laughed. My daughter can write better dialogue with a crayon...and she has.
Okay, it might not be their fault, they had crap plots and flat, uninspired characters to work with, but come on! At what point do you tell the dude with the money...that's stupid...sci-fi fans are smart...let's not have the hero fight some abnormally large guy we all know he's going to punch in the nuts to win. Geesh, once Kirk does something...
How does crap like this get picked up for a second season and Firefly gets the boot!? I miss you Mal!
So that brings me to my Thought O' The Day: Don't eat a bowl of Cinnamon Toast Crunch in bed while watching a crappy-over-budget-lazily-written-sci-fi-knock-off-of-every-other-lazily-written-sci-fi-show-ever-made. Milk and cereal is hard to soak up.


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Sweet potato nachos are a delicious and healthy twist on traditional nacho recipes! Potato nachos are a quick and easy gluten free appetizer to make for game day, or for a healthy snack.
Jump to:
My New Year's resolution was to try to make some of my favorite foods healthier. Mr. Fearless Dining often says I could live on nachos...and he is right. What better recipe to make healthier than my favorite nachos recipe?
These potato nachos are healthy, delicious, and full of protein. They are also vegetarian and naturally gluten free so I will be able to enjoy them anytime. This recipe is also perfect for a party!
If you love nachos, don't forget to check out my easy 3 ingredients homemade bean dip and nachos recipes.
When you watch the big game, do you put out a table full of appetizers like a buffet? You may like these BBQ Chicken Nachos.
You will love how crispy the potatoes get without frying...and they have fewer calories because they are baked.
How do I thinly slice potatoes?
The first step to making these sweet potato nachos is to thinly slice the potatoes. You can slice your potatoes a few different ways:
- With a mandolin slicer. I love my slicer but do make sure to use the vegetable grip so you don't accidentally cut your finger!
- You can also use a food processor if you have one that will slice.
- If you don't have either of these machines, a simple sharp knife will do. Just be careful of those fingers!!
Can I fry the potato slices?
You can definitely fry the potatoes if you want your potato nachos to be really crispy!
My little secret "hack" to get crispy potatoes is to brush olive oil onto each slice, and then bake them for 10 minutes before topping them.
For this baked sweet potato nacho recipe, I used Ro*TEL spicy tomatoes and refried beans.
Feel free to use your favorite refried beand and chunky salsa if you prefer."
To create these nachos, all you need are sweet potatoes, shredded cheese, Ro*TEL or salsa, refried beans, and cilantro. Garnish with sour cream, guacamole, and/or scallions!
Take a large sweet potato and slice it thinly. Brush olive oil on each slice then bake the sweet potato slices for 15 minutes.
Remove the sweet potatoes from the oven. Top with beans and Rotel. You can verify if Rotel is Gluten Free.
Finally, top with cheese and bake an additional 8-10 minutes.
When should I serve nachos?
These nachos are best hot right out of the oven! These nachos make a delicious appetizer for game day or any party!
More Delicious Potato Recipes To Try:
- Sloppy Joe Pie with a Mashed Potato Crust
- Mashed Potato Pie with Bacon Roses
- Pizza Stuffed Hasselback Potatoes
- Cheesy Scalloped Potatoes
- A mandolin vegetable slicer
- A brush to spread the olive oil onto the sweet potato slices
📖 Recipe
Sweet Potato Nachos
- 1-2 large sweet potatoes skins washed and sliced thinly
- 1 can Rosarita Refried Beans
- 1 can RO*TEL
- 1 cup shredded cheese
- 1 tablespoon olive oil
- cilantro
- Preheat the oven to 375 degrees.
- Spray olive oil on a cookie sheet.
- Lay sweet potato slices across pan.
- Brush olive oil on each slice.
- Bake 10 minutes.
- Remove from the oven and top with beans, Ro*TEL, and cheese.
- Return these to the oven for 5-8 minutes.
- Serve hot.
Please know that every gluten free flour blend has a different starch to grain ratio. If you use a blend I didn't test, you may need to adjust your moisture levels in your baked goods.
Nutrition Disclaimer
Nutritional information is an estimate provided to you as a courtesy. You should calculate the actual nutritional information with the products and brands you are using with your preferred nutritional calculator.
Fearless Dining
Looking for more? Get my FREE Gluten Free Lemon Desserts E-Cookbook when you sign up for my weekly recipe newsletter!


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More about the Keynote speakers
World Learning Summit, 2016
Peter Norvig is known to many from his pioneering work on Massive Open Online Courses, or so-called MOOCs. With his colleague Sebastian Thrun, he set up an open course at Stanford University, in Artificial Intelligence in 2011, finding to his surprise that 165000 students signed up. How does one deal with those numbers? What is that experience like? And how does he understand the future of learning and education in a mediatized world?
At the World Learning Summit in 2016, you will have a chance to hear for yourself. Peter is the chief scientist at Google, in Silicon Valley. He was employer number 8 in the company. He has also taught extensively, among other places at UC Berkeley. He was part of our 2015 conference at Stanford University, where he summarised his general impression after having heard how education leaders from a dozen US universities now approach online learning.
"The weight is off my shoulders", he said. Teachers and education leaders are finding their various ways to make sensible use of available education tools. In the future discussions about technology, learning and education will be less about technology and more about the coming changes in education materials and interactions.
Michael Shanks is professor of Archeology at Stanford University and a long-time participant in various Stanford centers and labs focused on design, digital media, and technology. Co-teaching a course in design history with David Kelley, founder of Stanford'sD.School, Mike keeps an ear close to the ground on matters relating technology to human interaction.
He has worked extensively with colleagues at the now closed Stanford Humanities Lab, and he travels frequently to Europe to work with city managers and companies who share his interest in urban development and design thinking.
Mike has been part of our Future Learning network these past few years and we are incredibly fortunate to have him join us in Norway for the kind of big and small venue activities that we are planning. There will be ample time to hear a very good speaker, and also time to reflect together with an engaged colleague in smaller group settings.
At our 2015 summit on the beautiful Stanford campus, Mike gave a speech performance that is still talked about, and believe us when we say this: You will very seldom hear as much wisdom on the question of technology and human interaction as you will get from listening to Mike for one single hour.
Keith Devlin is the Executive Director of H-Star Institute at Stanford University and a contributing member to the Future Learning Lab team, behind the Wold Learning Summit. We are heavily indebted top Keith for all his time spent with us and his generosity in opening up doors at Stanford University as well as in the Silicon Valley community that he is part of.
In May 2015, Keith helped us launch a fantastic conference at Stanford, gathering education thought leaders from all over the country and some from as far away as Japan, the UK and the Nordic countries. In 2016 we will step up the activities in the Word Learning Summit together.
Author of numerous books, Keith is also the founding president of the company eed, where his mathematics background also finds an outlet in entrepreneurship creating video games in math. He has found several companies before that, He travels frequently, and he knows the Nordic Education Technology field like few others. He is also known on National Public Radio in the United States as the "Math Guy". At the 2016 summit, Keith till both be a keynote speaker and a co-director of several workshops.
Catherine Casserley is currently the VP of Learning Networks at EdCast in Mountain View, California. She is a former CEO of Creative Commons. She is an adviser to the Aspen Institute on matters relating to Education and Technology. She is adviser to the (US) National Science Foundation, as well.
She is passionate about how openness and global knowledge sharing can promote learning. An early architect of the open educational resources (OER) field, she managed investments totaling more than $100M for the William and Flora Hewlett Foundation. Cathy spearheaded work in the areas of transparency and technology as Vice President of Innovation and Open Networks at the Carnegie Foundation for the Advancement of Teaching. She is a founding board member of the Digital Public Library of America and Peer-2-Peer University. Cathy earned her Ph.D. in the economics of education from Stanford University
Early in her career Cathy was a teacher of mathematics in Kingston, Jamaica. She earned her Ph.D. in the Economics of Education from Stanford University and holds a B.A. in Mathematics from Boston College. Cathy is a founding board member of the Digital Public Library of America and Peer-2-Peer University. Cathy is also a part of 2015 National Educational Technology Plan Face-to-Face Technical Working Group Meeting.
Karl Mehta´s presentation to WLS has already been received, and will also me made available to the conference attendees during WLS 2016. Consequently, we will leave his profile up among the speakers - hoping for a visit at some later occasion. In his place: VP Catherine Casserley, EdCast.
Karl Mehta is a serial entrepreneur, author, investor, engineer, and civil servant with over 20 years of experience in founding, building, and funding technology companies in the U.S. and international markets. Karl came into our little world by coincidence -- as we were having a meeting with one of his co-workers at his current company in Mountain View, Silicon Valley. We shook hands, introducing ourselves. It took less than a half hour to decide to pursue the 2015 Future Learning Summit at Stanford University, together. Karl and his associates became crucial team pillars, in a collaboration that now extends to the 2016 World Learning Summit and hopefully beyond.
Karl is currently Founder & CEO of EdCast Inc., a next-generation knowledge platform company. He is former venture partner at Menlo Ventures, a leading VC firm of Silicon Valley with over $4B under management.
Previously, he was the Founder & CEO of PlaySpan Inc., acquired by Visa Inc. (NYSE:V), the world's largest payment network. Karl also served as a White House Presidential Innovation Fellow, selected by the Obama Administration during the inaugural 2012-13 term. He was recently appointed by Governor Brown to the Workforce Investment Board of the State of California. In 2010, Karl won the "Entrepreneur of the Year" award from Ernst & Young for Northern California. Karl is on the boards of Simpa Networks and on the advisory board of Intel Capital and Chapman University's Center of Entrepreneurship.
Karl is founder of several non-profit's including Code For India (http://CodeforINDIA.org) and Grassroots Innovation (http://grassrootsinnovation.org ). He is author of 'Financial Inclusion at he Bottom of the Pyramid"(http://www.openfininc.org) -http://www.amazon.com/dp/1460265513


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BENDEKA (bendamustine hydrochloride) injection is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2 • HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula:
BENDEKA (bendamustine hydrochloride) injection is supplied as a sterile, clear, and colorless to yellow ready-to-dilute solution in a multiple-dose clear glass vial. Each milliliter contains 25 mg of bendamustine hydrochloride, 0.1 mL of Propylene Glycol, USP, 5 mg of Monothioglycerol, NF, in Polyethylene Glycol 400, NF. Sodium hydroxide may have been used to adjust the acidity of polyethylene glycol 400.
Chronic Lymphocytic Leukemia (CLL)
BENDEKA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.
Non-Hodgkin Lymphoma (NHL)
BENDEKA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximabcontaining regimen.
Dosing Instructions For CLL
Recommended Dosage
The recommended dosage is 100 mg/m2 administered intravenously over 10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
Dose Delays, Dosage Modifications And Reinitiation Of Therapy For CLL
Delay BENDEKA administration in the event of Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], reinitiate BENDEKA (bendamustine hydrochloride) injection at the discretion of the treating physician. In addition, consider dose reduction. [see WARNINGS AND PRECAUTIONS] Dosage modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.
Dosage modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.
Consider dosage re-escalation in subsequent cycles at the discretion of the treating physician.
Dosing Instructions For NHL
Recommended Dosage
The recommended dose is 120 mg/m2 administered intravenously over 10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
Dose Delays, Dosage Modifications And Reinitiation Of Therapy For NHL
Delay BENDEKA administration in the event of a Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], reinitiate BENDEKA at the discretion of the treating physician. In addition, consider dose reduction. [see WARNINGS AND PRECAUTIONS]
Dosage modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Dosage modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Preparation For Intravenous Administration
BENDEKA is a hazardous drug. Follow applicable special handling and disposal procedures.1 BENDEKA is in a multiple-dose vial. At room temperature, BENDEKA is a clear, and colorless to yellow ready-to-dilute solution. Store BENDEKA at recommended refrigerated storage conditions (2°C to 8°C or 36°F to 46°F). When refrigerated, the contents may freeze. Allow the vial to reach room temperature (15°C to 30°C or 59°F to 86°F) prior to use. Do not use the product if particulate matter is observed after achieving room temperature.
Intravenous Infusion
- Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution as per Table A below and immediately transfer the solution to a 50 mL infusion bag of one of the following diluents:
- 0.9% Sodium Chloride Injection, USP; or
- 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or
- 5% Dextrose Injection, USP.
The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 0.49 mg/mL to 5.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear, and colorless to yellow solution.
No other diluents have been shown to be compatible. The 5% Dextrose Injection, USP, offers a sodium-free method of administration for patients with certain medical conditions requiring restricted sodium intake.
Table A: Volume (mL) of BENDEKA required for dilution into 50 mL of 0.9% saline, or 0.45% saline/2.5% dextrose or 5% dextrose for a given dose (mg/m2) and Body Surface Area (m2)
|Body Surface Area (m2)
|Volume of BENDEKA to withdraw (mL)
|120 mg/m2
|100 mg/m2
|90 mg/m2
|60 mg/m2
|50 mg/m2
|25 mg/m2
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.
Admixture Stability
BENDEKA contains no antimicrobial preservative. Prepare the admixture as close as possible to the time of patient administration.
If diluted with 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2°C to 8°C or 36°F to 46°F) or for 6 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Administration of diluted BENDEKA (bendamustine hydrochloride) injection must be completed within this period of time.
In the event that 5% Dextrose Injection, USP is utilized, the final admixture is stable for 24 hours when stored refrigerated (2°C to 8°C or 36°F to 46°F) or for only 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Administration of diluted BENDEKA must be completed within this period of time.
Retain the partially used vial in original package to protect from light and store refrigerated (2°C to 8°C or 36°F to 46°F) if additional dose withdrawal from the same vial is intended.
Stability Of Partially Used Vials (Needle Punched Vials)
BENDEKA is supplied in a multiple-dose vial. Although it does not contain any antimicrobial preservative, BENDEKA is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2°C to 8°C or 36°F to 46°F). Each vial is not recommended for more than a total of six (6) dose withdrawals.
After first use, store the partially used vial in the refrigerator in the original carton at 2°C to 8°C or 36°F to 46°F and then discard after 28 days.
Dosage Forms And Strengths
100 mg/4 mL (25 mg/mL) as a clear and colorless to yellow ready-to-dilute solution in a multiple-dose vial.
Storage And Handling
Safe Handling and Disposal
BENDEKA (bendamustine hydrochloride) injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 Care should be exercised in the handling and BENDEKA® (bendamustine hydrochloride) injection preparation of solutions prepared from BENDEKA (bendamustine hydrochloride) injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of BENDEKA (bendamustine hydrochloride) injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If BENDEKA (bendamustine hydrochloride) injection contacts the mucous membranes, flush thoroughly with water.
BENDEKA (bendamustine hydrochloride) injection is supplied in individual cartons of 5 mL clear multiple-dose vials containing 100 mg of bendamustine hydrochloride as a clear, and colorless to yellow ready-to-dilute solution.
- NDC 63459-348-04, 100 mg/4 mL (25 mg/mL)
Store BENDEKA (bendamustine hydrochloride) injection in refrigerator, 2°C to 8°C (36°F to 46°F). Retain in original carton until time of use to protect from light.
1. OSHA Hazardous Drugs. OSHA. [http://www.osha.gov/SLTC/hazardousdrugs/index.html]
Manufactured For: Teva Pharmaceuticals, 400 Interpace Parkway #3, Parsippany, NJ 07054. Revised: Oct 2021.
The following clinically significant adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the prescribing information.
- Myelosuppression [see WARNINGS AND PRECAUTIONS]
- Infections [see WARNINGS AND PRECAUTIONS]
- Progressive Multifocal Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
- Anaphylaxis and Infusion Reactions[see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Skin Reactions [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Other Malignancies [see WARNINGS AND PRECAUTIONS]
- Extravasation Injury [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to bendamustine hydrochloride in 329 patients who participated in an actively controlled trial (N=153) for the treatment of CLL and two single arm studies (N=176) for the treatment of indolent B cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of BENDEKA administered IV as a 50 mL admixture over a 10-minute infusion is supported by clinical trials using bendamustine hydrochloride administered IV as a 500 mL admixture over 30-60 minutes infusion time, as well as an open-label, crossover study in 81 'end-of-life' cancer patients treated with BENDEKA. In total, safety data from clinical studies are available from over 400 cancer patients exposed to bendamustine hydrochloride at doses in the range used in the treatment of CLL and NHL.
No clinically significant differences in the adverse reaction profile were noted among bendamustine hydrochloride administered as a 500 mL admixture over standard infusion time (30-60 minutes) and BENDEKA administered as a 50 mL admixture in a 'short-time' infusion over 10 minutes.
The safety and tolerability of BENDEKA was evaluated in an 8-week clinical study of BENDEKA in 81 'end-of-life' cancer patients, diagnosed with solid tumors and hematologic malignancies (excluding CLL). The population was 40-82 years of age, 58% females, 84% white, 12.3% Black, 1.2% Asian and 2.5% were classified as 'other'. BENDEKA was administered IV at a 120 mg/m2 dose as a 50 mL admixture over 10 minutes. Patients in the study received BENDEKA (50 mL IV, over 10 minutes) or bendamustine hydrochloride (500 mL IV, over 60 minutes) on Days 1 and 2 every 28 days for two consecutive 2-day cycles.
Adverse reactions (any grade) that occurred with a frequency greater than 5% during BENDEKA infusion and within one hour post-infusion were nausea (8.2%) and fatigue (5.5%).
Adverse reactions (any grade) that occurred with a frequency greater than 5% within 24 hours of BENDEKA were nausea (10.9%) and fatigue (8.2%).
Adverse reactions leading to study withdrawal in 4 patients receiving BENDEKA were pyrexia (1.2%), nausea (1.2%), vomiting (1.2%), pneumonia (1.2%) and fatigue (1.2%).
Chronic Lymphocytic Leukemia (CLL)
The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled randomized trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.
Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).
Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.
Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.
The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%).
Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients
|Number (%) of patients
|Bendamustine Hydrochloride
|Body System
Adverse Reaction
|All Grades
|Grade 3/4
|All Grades
|Grade 3/4
|Total number of patients with at least 1 adverse reaction
|121 (79)
|52 (34)
|96 (67)
|25 (17)
|Gastrointestinal disorders
|31 (20)
|1 (<1)
|21 (15)
|1 (<1)
|24 (16)
|1 (<1)
|9 (6)
|14 (9)
|2 (1)
|5 (3)
|General disorders and administration site conditions
|36 (24)
|6 (4)
|8 (6)
|2 (1)
|14 (9)
|2 (1)
|8 (6)
|13 (8)
|6 (4)
|9 (6)
|1 (<1)
|Immune system disorders
|7 (5)
|2 (1)
|3 (2)
|Infections and infestations
|10 (7)
|12 (8)
|9 (6)
|3 (2)
|1 (<1)
|1 (<1)
|Herpes simplex
|5 (3)
|7 (5)
|Weight decreased
|11 (7)
|5 (3)
|Metabolism and nutrition disorders
|11 (7)
|3 (2)
|2 (1)
|Respiratory, thoracic and mediastinal disorders
|6 (4)
|1 (<1)
|7 (5)
|1 (<1)
|Skin and subcutaneous tissue disorders
|12 (8)
|4 (3)
|7 (5)
|3 (2)
|8 (5)
|2 (1)
The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil.
Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received bendamustine hydrochloride or Chlorambucil in the Randomized CLL Clinical Study
|Laboratory Abnormality
|All Grades
n (%)
|Grade 3/4
n (%)
|All Grades
n (%)
|Grade 3/4
n (%)
|Hemoglobin Decreased
|134 (89)
|20 (13)
|115 (82)
|12 (9)
|Platelets Decreased
|116 (77)
|16 (11)
|110 (78)
|14 (10)
|Leukocytes Decreased
|92 (61)
|42 (28)
|26 (18)
|4 (3)
|Lymphocytes Decreased
|102 (68)
|70 (47)
|27 (19)
|6 (4)
|Neutrophils Decreased
|113 (75)
|65 (43)
|86 (61)
|30 (21)
In the randomized CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with bendamustine hydrochloride may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur.
Non-Hodgkin's Lymphoma (NHL)
The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received bendamustine hydrochloride at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.
The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with bendamustine hydrochloride by System Organ Class and Preferred Term (N=176)
|Body System
Adverse Reaction
|Number (%) of patients*
|All Grades
|Grade 3/4
|Total number of patients with at least 1 adverse reaction
|176 (100)
|94 (53)
|Cardiac Disorders
|13 (7)
|Gastrointestinal disorders
|132 (75)
|7 (4)
|71 (40)
|5 (3)
|65 (37)
|6 (3)
|51 (29)
|1 (<1)
|27 (15)
|1 (<1)
|Abdominal pain
|22 (13)
|2 (1)
|20 (11)
|Gastroesophageal reflux disease
|18 (10)
|Dry mouth
|15 (9)
|1 (<1)
|Abdominal pain upper
|8 (5)
|Abdominal distension
|8 (5)
|General disorders and administration site conditions
|101 (57)
|19 (11)
|59 (34)
|3 (2)
|24 (14)
|Edema peripheral
|23 (13)
|1 (<1)
|19 (11)
|4 (2)
|Chest pain
|11 (6)
|1 (<1)
|Infusion site pain
|11 (6)
|10 (6)
|Catheter site pain
|8 (5)
|Infections and infestations
|Herpes zoster
|18 (10)
|5 (3)
|Upper respiratory tract infection
|18 (10)
|Urinary tract infection
|17 (10)
|4 (2)
|15 (9)
|14 (8)
|9 (5)
|Febrile neutropenia
|11 (6)
|11 (6)
|Oral candidiasis
|11 (6)
|2 (1)
|11 (6)
|Weight decreased
|31 (18)
|3 (2)
|Metabolism and nutrition disorders
|40 (23)
|3 (2)
|24 (14)
|8 (5)
|Decreased appetite
|22 (13)
|15 (9)
|9 (5)
|Musculoskeletal and connective tissue disorders
|Back pain
|25 (14)
|5 (3)
|11 (6)
|Pain in extremity
|8 (5)
|2 (1)
|Bone pain
|8 (5)
|Nervous system disorders
|36 (21)
|25 (14)
|13 (7)
|Psychiatric disorder
|23 (13)
|14 (8)
|1 (<1)
|10 (6)
|Respiratory, thoracic and mediastinal disorders
|38 (22)
|1 (<1)
|28 (16)
|Pharyngolaryngeal pain
|14 (8)
|1 (<1)
|8 (5)
|Nasal congestion
|8 (5)
|Skin and subcutaneous tissue disorders
|28 (16)
|1 (<1)
|11 (6)
|Dry skin
|9 (5)
|Night sweats
|9 (5)
|8 (5)
|Vascular disorders
|10 (6)
|2 (1)
|*Patients may have reported more than 1 adverse reaction.
NOTE:Patients counted only once in each preferred term category and once in each system organ class category.
Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).
Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received bendamustine hydrochloride in the NHL Studies
|Hematology Variable
|Percent of Patients
|All Grades
|Grade 3/4
|Lymphocytes Decreased
|Leukocytes Decreased
|Hemoglobin Decreased
|Neutrophils Decreased
|Platelets Decreased
In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.
Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic systems disorders: Pancytopenia.
Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.
General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).
Immune system disorders: Anaphylaxis.
Infections and infestations: Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy (PML)
Respiratory, thoracic and mediastinal disorders:Pneumonitis.
Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
Effect Of Other Drugs On BENDEKA
CYP1A2 Inhibitors
The coadministration of BENDEKA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with BENDEKA [see CLINICAL PHARMACOLOGY]. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with BENDEKA.
CYP1A2 Inducers
The coadministration of BENDEKA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of BENDEKA [see CLINICAL PHARMACOLOGY]. Consider alternative therapies that are not CYP1A2 inducers during treatment with BENDEKA.
Included as part of the "PRECAUTIONS" Section
Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies [see ADVERSE REACTIONS]. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
BENDEKA causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs occurred predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see DOSAGE AND ADMINISTRATION]
Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride [see ADVERSE REACTIONS]. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following BENDEKA treatment to contact a physician immediately if they have symptoms or signs of infection.
Patients treated with BENDEKA are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.
Progressive Multifocal Leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab [see ADVERSE REACTIONS]. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold BENDEKA treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Anaphylaxis And Infusion Reactions
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials [see ADVERSE REACTIONS]. Symptoms include fever, chills, pruritus and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue BENDEKA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care.
Tumor Lysis Syndrome
Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in postmarketing reports [see ADVERSE REACTIONS]. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly. [see Skin Reactions]
Skin Reactions
Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens- Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash [see ADVERSE REACTIONS]. Events occurred when bendamustine hydrochloride injection was given as a single agent and in combination with other anticancer agents or allopurinol.
Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue BENDEKA.
Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients [see Infections]. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during BENDEKA therapy.
Other Malignancies
There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma [see ADVERSE REACTIONS].
Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with BENDEKA.
Extravasation Injury
Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain [see ADVERSE REACTIONS]. Assure good venous access prior to starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BENDEKA.
Embryo-Fetal Toxicity
Based on findings from animal reproduction studies and the drug's mechanism of action, BENDEKA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with BENDEKA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the last dose. [see Use In Specific Populations and CLINICAL PHARMACOLOGY]
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (the lowest dose tested, approximately 0.3 times the maximum recommended human dose [MRHD]) and 75 mg/m2/day (approximately 0.6 times the MRHD) for 4 days, peritoneal sarcomas in female AB/Jena mice were produced. Oral administration at 187.5 mg/m2/day (the only dose tested, approximately 1.6 times the MRHD) for 4 days induced mammary carcinomas and pulmonary adenomas.
Bendamustine is a mutagen and clastogen. In a bacterial reverse mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2, (the lowest dose tested, approximately 0.3 times the MRHD).
Bendamustine induced morphologic abnormalities in spermatozoa in mice. Following tail vein injection of bendamustine at 120 mg/m2 or a saline control on days 1 and 2 for a total of 3 weeks, the number of spermatozoa with morphologic abnormalities was 16% higher in the bendamustine-treated group as compared to the saline control group.
Use In Specific Populations
Risk Summary
In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data
Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride to mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration.
Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.
Risk Summary
There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with BENDEKA, and for 1 week after the last dose.
Females And Males Of Reproductive Potential
BENDEKA can cause embryo-fetal harm when administered to a pregnant woman [see Pregnancy].
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiation of BENDEKA [see Pregnancy].
Advise female patients of reproductive potential to use effective contraception during treatment with BENDEKA and for 6 months after the last dose.
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the last dose [see Nonclinical Toxicology].
Based on findings from clinical studies, BENDEKA may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances, spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Advise patients of the potential risk to their reproductive capacities.
Based on findings from animal studies, BENDEKA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of BENDEKA on male fertility, including the reversibility of adverse effects, have not been studied (see Nonclinical Toxicology].
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1 to 19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safety profile in these patients was consistent with that seen in adults, and no new safety signals were identified.
The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.
Geriatric Use
No overall differences in safety were observed between patients ≥65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receiving bendamustine hydrochloride based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was also longer in younger patients with CLL receiving bendamustine (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.
Renal Impairment
Do not use BENDEKA in patients with creatinine clearance (CLcr) < 30 mL/min [see CLINICAL PHARMACOLOGY].
Hepatic Impairment
Do not use BENDEKA in patients with AST or ALT 2.5-10 × upper limit of normal (ULN) and total bilirubin 1.5-3 × ULN, or total bilirubin > 3 × ULN [see CLINICAL PHARMACOLOGY].
The intravenous LD50 of bendamustine hydrochloride is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.
Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.
No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.
BENDEKA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. [see WARNINGS AND PRECAUTIONS]
Mechanism Of Action
Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.
Based on the pharmacokinetics/pharmacodynamics analyses of data from adult patients with NHL, nausea increased with increasing bendamustine Cmax.
Cardiac Electrophysiology
The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab at 375 mg/m2 intravenous infusion followed by a 30-minute intravenous infusion of bendamustine at 90 mg/m2/day. No mean changes greater than 20 milliseconds were detected up to one hour post infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.
Following a single dose of 120 mg/m2 of bendamustine hydrochloride over 10-minute infusion, the mean Cmax achieved was 35 μg/mL (range 6 to 49 μg/mL), occurring typically at the end of infusion. Little or no accumulation in plasma is expected for bendamustine administered on Days 1 and 2 of a 28-day cycle.
The protein binding of bendamustine ranged from 94 to 96% and was concentration independent from 1 to 50 μg/mL. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 μg/mL.
The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20 to 25 L.
After a single intravenous dose of 120 mg/m2 of bendamustine over 1 hour, the intermediate halflife (t1/2) of the parent compound is approximately 40 minutes. The mean terminal elimination t1/2 of two active metabolites, γ-hydroxybendamustine (M3) and N desmethylbendamustine (M4) are approximately 3 hours and 30 minutes, respectively. Bendamustine clearance in humans is approximately 700 mL/min.
Bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxybendamustine (HP2) metabolites with low cytotoxic activity in vitro. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2 in vitro. M3 and M4 concentrations of these metabolites in plasma are 1/10th and 1/100th that of the parent compound, respectively.
Following IV infusion of radiolabeled bendamustine hydrochloride in cancer patients, approximately 76% of the dose was recovered. Approximately 50% of the dose was recovered in the urine (3.3% unchanged) and approximately 25% of the dose was recovered in the feces. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.
Specific Populations
No clinically meaningful effects on the pharmacokinetics of bendamustine were observed based on age (31 to 84 years), sex, mild to moderate renal impairment (CLcr ≥ 30 mL/min), or hepatic impairment with total bilirubin 1.5 < ULN and AST or ALT < 2.5 × ULN. The effects of severe renal impairment (CLcr < 30 mL/min), or hepatic impairment with total bilirubin 1.5-3 × ULN and AST or ALT 2.5-10 × ULN or total bilirubin > 3 × ULN on the pharmacokinetics of bendamustine is unknown.
Exposures in Japanese subjects (n=6) were 40% higher than that in non-Japanese subjects receiving the same dose. The clinical importance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.
Drug Interaction Studies
In Vitro Studies
Effect of Bendamustine on CYP Substrates
Bendamustine did not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5.
Effect of Transporters on Bendamustine Hydrochloride
Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).
Clinical Studies
Chronic Lymphocytic Leukemia (CLL)
The safety and efficacy of bendamustine hydrochloride were evaluated in an open-label, randomized, controlled multicenter trial comparing bendamustine hydrochloride to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukemia were excluded from the study.
The patient populations in the bendamustine hydrochloride and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), "B" symptoms (51% vs. 53%), lymphocyte count (mean 65.7x109/L vs. 65.1x109/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).
Patients were randomly assigned to receive either bendamustine hydrochloride at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.
The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for bendamustine hydrochloride compared to chlorambucil (see Table 5). Survival data are not mature.
Table 5: Efficacy Data for CLL
|Response Rate n (%)
|Overall response rate
|90 (59)
|38 (26)
|(51, 66.6)
|(18.6, 32.7)
|Complete response (CR)*
|13 (8)
|1 (<1)
|Nodular partial response (nPR)**
|4 (3)
|Partial response (PR) †
|73 (48)
|37 (25)
|Progression-Free Survival††
|Median, months (95% CI)
|18 (11.7, 23.5)
|6 (5.6, 8.6)
|Hazard ratio (95% CI)
|0.27 (0.17, 0.43)
|CI = confidence interval
* CR was defined as peripheral lymphocyte count ≤ 4 x 109/L, neutrophils ≥ 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 110g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤ 1.5 cm, < 30% lymphocytes without nodularity in at least a normocellular bone marrow and absence of "B" symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days.
** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.
† PR was defined as ≥50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils ≥ 1.5 x 109/L or 50% improvement over baseline, platelets >100 x 109/L or 50% improvement over baseline, hemoglobin >110g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.
†† PFS was defined as time from randomization to progression or death from any cause.
Kaplan-Meier estimates of progression-free survival comparing bendamustine hydrochloride with chlorambucil are shown in Figure 1.
Figure 1: Progression-Free Survival Survival Distribution Function
|Progression – Free Survival (months)
|Study Treatment
|Bendamustine Hydrochloride
Non-Hodgkin Lymphoma (NHL)
The efficacy of bendamustine hydrochloride was evaluated in a single arm study (NCT00139841) of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received bendamustine hydrochloride intravenously at a dose of 120 mg/m2, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles. The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.
Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6.
Table 6: Efficacy Data for NHL*
|Bendamustine Hydrochloride
|Response Rate (%)
|Overall response rate (CR+CRu+PR)
|(64.3, 82.3)
|Complete response (CR)
|Complete response unconfirmed (CRu)
|Partial response (PR)
|Duration of Response (DR)
|Median, months (95% CI)
|9.2 months (7.1, 10.8)
|CI = confidence interval
* IRC assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that a persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.
Inform patients of the likelihood that BENDEKA (bendamustine hydrochloride) injection will cause a decrease in white blood cells, platelets, and red blood cells. They will need frequent monitoring of these parameters. They should be instructed to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see WARNINGS AND PRECAUTIONS].
Progressive Multifocal Leukoencephalopathy (PML)
Inform patients to immediately contact their healthcare provider if they experience confusion, memory loss, trouble thinking, difficulty talking or walking, vision loss or other neurological or cognitive symptoms [see WARNINGS AND PRECAUTIONS].
Anaphylaxis And Infusion Reactions
Inform patients of the possibility of serious or mild allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see WARNINGS AND PRECAUTIONS].
Skin Reactions
Advise patients that a mild rash or itching may occur during treatment with BENDEKA (bendamustine hydrochloride) injection. Advise patients to immediately report severe or worsening rash or itching [see WARNINGS AND PRECAUTIONS].
Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see WARNINGS AND PRECAUTIONS].
Advise patients that BENDEKA (bendamustine hydrochloride) injection may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect [see ADVERSE REACTIONS].
Nausea And Vomiting
Advise patients that BENDEKA (bendamustine hydrochloride) injection may cause nausea and/ or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided [see ADVERSE REACTIONS].
Advise patients that BENDEKA (bendamustine hydrochloride) injection may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided [see ADVERSE REACTIONS].
Non-Melanoma Skin Cancer (NMSC)
Advise patients to undergo regular skin cancer screenings, and to report any suspicious skin changes to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and Nonclinical Toxicology]. Advise female patients of reproductive potential to use effective contraception during treatment with BENDEKA and for 6 months after the last dose [see Use In Specific Populations]. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the last dose [see Use In Specific Populations and Nonclinical Toxicology].
Advise females not to breastfeed during treatment with BENDEKA and for 1 week after the last dose [see Use In Specific Populations].
Advise males of reproductive potential that BENDEKA may impair fertility [see Use In Specific Populations].
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.