The FDA has approved updated labeling for capecitabine (Xeloda) tablets, making it the first agent to be granted a labeling update under Project Renewal.

Under the updated label, capecitabine is now approved for the adjuvant treatment of patients with stage III colon cancer as monotherapy or in combination with a chemotherapy regimen. Additionally, the agent is approved for the perioperative treatment of adults with locally advanced rectal cancer as a part of chemoradiotherapy and for patients with unresectable or metastatic colorectal cancer, either as a monotherapy or as a component of a combination chemotherapy regimen. In the breast cancer space, capecitabine is approved for patients with advanced or metastatic breast cancer as a single agent if anthracycline- or taxane-containing chemotherapy is not indicated, as well as in combination with docetaxel following disease progression on anthracycline-containing chemotherapy.

For patients with unresectable or metastatic gastric, esophageal, or gastroesophageal junction (GEJ) cancer capecitabine is now indicated as part of a combination chemotherapy regimen and as a part of a combination regimen for patients with HER2-overexpressing disease who have not received prior treatment for metastatic disease. The agent is also indicated as a component of a combination chemotherapy regimen for the adjuvant treatment of adult patients with pancreatic adenocarcinoma.

The Oncology Center of Excellence initiated Project Renewal with the ultimate aim of updating labeling information for oncology agents, especially those that are older and commonly prescribed, by evaluating relevant scientific evidence from published literature. The program utilizes external oncology experts and early-career scientists to review the existing published literature.

The initiative was conceived to address outdated labeling that exists on many oncology agents and applying new information that comes to light in the post-marketing setting that could potentially warrant labeling changes and indication updates. The key goals of Project Renewal are to: develop repeatable processes, use published data, engage with the oncology community, and foster educational experiences.

The recent labeling update also revised and updated the dosing regimen for multiple indications, including allowing for a reduced starting dose for patients with metastatic breast cancer. Under the revision, severe renal impairment was removed as a contraindication, information on risks from exposure to crushed tablets was added in the warnings and precautions section, and more information was given regarding the relationship between treatment with capecitabine and dihydropyrimidine dehydrogenase deficiency. The FDA also updated and revised clinical pharmacology information, the Patient Counseling Information section, and thePatient Information document.

According to the updated label, capecitabine can be given for the adjuvant treatment of patients with colon cancer as monotherapy at a dose of 1,250 mg/m

 twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles or at a dose of 1000 mg/m

 twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m

. For the perioperative treatment of rectal cancer, the agent should be administered at a dose of 825 mg/m

 twice daily for patients who are being treated with concomitant radiation therapy or without radiation therapy, respectively.

Patients with unresectable or metastatic colorectal cancer can be given capecitabine 1250 mg/m

 for the first 14 days of each 21-day cycle as monotherapy or at a dose of 1000 mg/m

 twice daily for the first 14 days of each 21-day cycle when used in combination with oxaliplatin 130 mg/m

 given on day 1 of each cycle. In pancreatic cancer, the agent can be administered at a dose of 830 mg/m

 twice daily for the first 21 days of each 28-day cycle for a maximum of 6 cycles in combination with gemcitabine 1,000 mg/m

 given on days 1, 8, and 15 of each cycle.

Patients with advanced or metastatic breast cancer can be treated with capecitabine monotherapy at a dose of either 1,000 mg/m

 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. The agent can also be administered at either dosing schedule in combination with docetaxel 75 mg/m

 on day 1 of each cycle in this patient population.

Finally, capecitabine is indicated at a dose of 625 mg/m

 twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy or at a dose of 850 mg/m

 twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m

 on day 1, for patients with unresectable or metastatic GEJ cancer. Patients with HER2-overexpressing metastatic GEJ cancer can be treated with the agent at a dose of 1000 mg/m

 twice daily for the first 14 days of each 21-day cycle.

FDA approves updated drug labeling including new indications and dosing regimens for capecitabine tablets under Project Renewal. News release. FDA. December 14, 2022. Accessed December 16, 2022. 

Project renewal. Updated February 15, 2022. Accessed December 16, 2022. 

Xeloda. Prescribing information. Genentech; 2022. Accessed December 16, 2022. 

Articles

The FDA has approved updated labeling for capecitabine under Project Renewal, an Oncology Center of Excellence initiative aimed at updating labeling information for certain older oncology drugs.

Label Update for Capecitabine Expands and Updates Indications

Pain management is essential in cancer care, especially in surgical oncology settings. Oncology RNs may administer narcotic pain killers to their patients on either a prn (“pro re nata” or as needed basis) or a scheduled basis. Unfortunately, this also opens the door to nurse abuse of high-risk medications, and other issues. Although the popular Netflix series 

 has brought attention to a specific nurse intending to cause harm, there are statistics which suggest that inappropriate handling of high-risk medications is a relevant problem for many institutions.

The rate of substance abuse in the United States is 6% to 8%.

According to the American Nurses Association, this figure has held true for the past 3 decades, and the percentage rate is comparative to the substance abuse rate in the country overall.

However, the general population does not typically have access to the same medications that nurses have access to.

RNs must chart on the electronic medication administration record, MAR, that the medication was given to their patient. However, it is possible to pretend to give an intravenous (IV) push medicine by trading it for saline or sterile water. The liquid pain medication can be extracted with a needle and compatible flushes and vials are readily available in the hospital. This scenario happens despite the advent of the computerized drug dispensers, known as the Pyxis or Omnicell. 

Drug diversion is defined as when a drug, in this case a narcotic, does not reach the patient. It is then used by the nurse, or may even be sold by the health care professional. Drug diversion includes drug theft, or tampering (adulteration or substitution). 

 Moreover, it is a felony that can result in a nurse’s criminal prosecution and loss of license.

What happens when a nurse tampers with narcotics? First of all, the patient suffers. Their pain is not controlled. The patients on the floor or unit experience what is described as “inadequate care from impaired health care workers.”

 Patients may also be at risk of infections from contaminated syringes.”

 The hospital or health care setting does not escape unscathed neither. They can accrue fines and may lose Medicare funding. The nurse with substance abuse disorder may also experience hardship as he or she could find themselves facing both legal and medical consequences of their addiction.

I work in surgical oncology and sometimes a dose is ordered that is less than what is dispensed. There are cameras in the med room to document what has transpired. Despite this safeguard, drug diversion continues.

 When a nurse signs off on a waste that was not witnessed, a note in the system can be added and an incident report can be created as a prompt for patient safety concerns not as a punitive measure.

 One potential solution to this problem may lay with pharmacy—if wider dose ranges are available it may become more difficult to make excuses for differences between ordered and administered doses.

 Having a designated bin where all witnessed narcotic waste is discarded is another potential strategy. In any case, unapproved Environmental Protection Agency methods of disposing drugs—such as discarding meds down a sink or in a sharps container—must be avoided.

I am in Florida, and there is a mandatory reporting law in this state for nurses with substance abuse problems. Different states have individual reporting requirements, so these processes can depend on where you are employed, but in Florida, hospital or medical facilities should report nurses suspected of experiencing substance abuse disorder to the Department of Health or Intervention Project for Nurses (IPN). The IPN was created in 1983 with the purpose of protecting the public by helping nurses with substance abuse disorders. The IPN gives them the tools to cope with substance abuse.

The IPN is contracted by the Florida Department of Health to help nurses through “state-wide education, support and monitoring to nurses with impairing conditions such as substance use disorders.”

 Florida statute 456.076 is the legal basis for this project.

, streaming on Netflix, based on the book by Charles Graeber tells the story of convicted serial killer Charles Cullen, RN.

He repeatedly took out Digoxin and Insulin and spiked IV bags with these high-risk medications. Cullen would also take out medication and then cancel the removal before closing the Pyxis. A nurse on the unit, one of his coworkers and friends, risked her safety to pull all his Pyxis and Cerner records—which showed his documentation—to bring him to justice. He is now serving multiple life sentences.

These issues and the buzz around this series, 

, suggest that inappropriate handling of high-risk medications is an issue which is not going away soon. This has been the topic of the day in many nurses’ stations nationwide. The oncology nurse should be aware of the issues regarding impairment to effectively function in the healthcare setting.

Pavlovich-Danis SJ. The nurse with substance use disorder: moving past the “impaired” nurse label. June 18,2019

https://cedirect.continuingeducation.com/Aspx/CourseContent.aspx?uniqueid=38817892&topicid=601&page=1&IsAnthology=1

Webster A. Drug and alcohol rehab for nurses near you. American Addition Centers. September 14, 2022. Accessed December 5, 2022. 

Alunni-Kinkle S. Identifying substance use disorder in nursing. 

. 2015;46(12):53-54. doi:10.1097/01.NUMA.0000473512.38679.ca

Nyhaus, J. Drug diversion in healthcare: prevention and detection for nurses. 

About us. IPN: Intervention Project for Nurses. March 2022. Accessed November 28, 2022. 

Nicholson A.‘The Good Nurse’ review: Bad medicine. 

. October 27, 2022. Accessed November 28, 2022. https://nyti.ms/3VMSzMS



Sometimes nurses inappropriately handle high-risk medications. It is important that other nurses, especially those who work in pain management, hold colleagues accountable to promote patient safety. 

Opinion: The Good Nurse Brings Safe Narcotic Handling to the Forefront of Nursing Minds

As safety considerations for immunotherapy agents continue to be investigated, institutions have been developing safe handling approaches based on perspectives and anecdotal experience, according to representatives from Allegheny Health Network Seon Jo Park, PharmD, BCOP; and Heather Kennihan, MSN, RN, OCN.

“There’s a difference between traditional chemotherapy compared with checkpoint inhibitors,” Park said. “The checkpoint inhibitors are a more recent development, they started coming out approximately 7 or 8 years ago, and [more] keep coming out.”

For many institutions, standard procedures for administering chemotherapy have been adapted for immunotherapy drugs out of caution.

®, Kennihan, a professional development specialist with the AHN Cancer Institute, and Park, an oncology faculty member in the Department of Pharmacy Management and Clinical Specialists at AHN, highlighted the safety precautions used in their experience, the challenges with at-home infusions, and notable toxicities to keep in mind when using these agents.

®: How do immune checkpoint inhibitors compare with chemotherapy in terms of risk when administering these agents?

Kennihan: [When] immune checkpoint inhibitors and these new medications started coming out, we treated them just like we did regular anticancer therapy, regular chemotherapies. There was a lot of discussion of are these hazardous agents, do they pose risks for our staff?

[At AHN], we still err on the side of caution for our nursing staff, our mixers, and our pharmacy staff. They still apply PPE [personal protective equipment] just like they would for chemotherapy. We educate [our staff on] safe handling precautions. Is there more risk for hazardous precautions if the patient is only [receiving] immunotherapy vs combination therapy? I don’t think so. However, we do still treat them the same. We handle the medications the same way [and] we educate the patients similarly on safe handling precautions.

Park: The way the checkpoint inhibitors work is a little bit different than traditional chemotherapy, [which] binds to the patient’s DNA and then [essentially] damages their DNA. Checkpoint inhibitors [interact with the patient’s] immune systems and boosts it. In terms of hazardous drugs, one of the institutions that looks at [the category of] hazardous drugs is called the National Institute for Occupational Safety and Health [NIOSH]. That organization, with ASHP [American Society of Health-System Pharmacists], looked at checkpoint inhibitors and did not see all those hazardous components. The definition of hazardous characteristics [include] carcinogenicity, teratogenicity, reproductive toxicity, organ toxicity, and genome toxicity. [NIOSH and ASHP] didn’t see many of the [toxicities] with checkpoint inhibitors, so they didn’t list them under their hazardous drug list.

That’s the difference, [but] how should we handle them? According to the [determination by NIOSH and ASHP]: they’re not harmful, they’re not hazardous. But at the same time, because immune checkpoint inhibitors are a recent development, we believe that [limited] research has been done. There’s some animal data on reproductive toxicity and teratogenicity of checkpoint inhibitors, so if you look at the package insert of, [for example,] pembrolizumab [Keytruda] and nivolumab [Opdivo], it does have a warning that the animal data showed some reproductive toxicity. A lot of institutions want to be a little more cautious when they handle these drugs just because there’s not much data compared with chemotherapy just yet.

At AHN, do you allow visitors to be with patients in the infusion room during immunotherapy infusion? Are there special precautions?

Kennihan: As far as having a visitor or a family member or caregiver at chairside when [patients are] getting infusions, we absolutely allow that in most of our facilities where space allows.

We’re covering all the bases; we still [perform] all the safe handling precautions that we do for standard chemotherapy. We educate the patients [and] provide them with written instructions. [For example,] we ensure that pregnant women aren’t handling their excretions for a couple of days after they’ve had treatment and those types of things.

Some centers and institutions have been exploring options for at-home infusions. What risk do at-home infusions potentially pose for individuals? Where do you think the field is headed?

Park: I don't think that’s a very central issue. We administer immunotherapy and checkpoint inhibitors in satellite cancer centers. That has been going on ever since they came out. For home infusion, [there are] a lot of different issues that come with it. Not only that we need to train the home infusion nurses on the safety for the hazardous drugs, but we also have to coordinate when patients are going to see an oncologist and how health care staff are going to assess the patient when they’re at home and how often.

Storage of the medication [is another issue] because checkpoint inhibitors have expiration times. They have to be refrigerated, ones that [require] mixing can only be used within certain hours. How about the exposure at home? Who are the [patients] living with? [We need to consider] insurance coverage as well: are agencies going to cover home administration vs when a patient comes into the institution?

There’s a lot of different questions that we have to answer before we start doing this. I’m not sure about in the US but I know some home infusion has already started in Europe. I think that’s a little bit easier because their insurance system is different than in the US and they had pretty good success coordinating with the oncologist doing assessment. But it all depends on the patient’s specific environment. As long as we can coordinate all different pieces and the insurance issues, I think it is possible, but I don't think it’s going to be anytime soon for our own institution just yet.

Kennihan: I completely agree with Seon Jo on that. One good factor about immunotherapy is [the patient’s] risk for reactions is lower, so that’s a positive for at-home infusion. There needs to be a lot of coordination, assessments need to be done on these patients. It’s not like you can go in and say, “How are you feeling today? Are you okay to get your medication and hang [the IV bag]?” We have lots of questions and assessments we need to do, and it needs to be [an individual] who’s trained and skilled in doing that.

Park: In terms of infusion reactions, we have so many different patients who are on checkpoint inhibitors and I saw maybe a handful—approximately 5 patients or less—who had an [infusion-related] reaction over the past 7 years. The reaction risk is definitely lower, but the scary thing about this reaction is that this can happen at any point. For some of the agents, it’s more a risk to have an infusion reaction with their first dose and once they don’t react from the first dose, you can relax, it’s not going to happen. But with an immunotherapy reaction—what I’ve seen in my experience is that— it can happen at any point. It happened with 1 patient in cycle 40, which was so random. I don’t think we have enough data about checkpoint inhibitor reactions either.

What does proper storage look like with immunotherapy? Are there any safety precautions you would like to highlight?

Park: Because [immunotherapy drugs are not on the] hazardous drug list, you can store them in a nonhazardous section, just like with any other nonchemotherapy agent. At AHN, they store them with the hazardous for workflow, and they take all the precautions just as the chemotherapy. Most of our checkpoint inhibitors must be refrigerated.

Kennihan: I think it’s important to make sure your staff are educated on the medications and the reasons why they’re getting the safe handling. Educating the patient is important to keep them informed of what’s going on and why they’re getting the medications that they are.

Park: One thing that I wanted to point out is if you look at all [immunotherapy] labels and their package insert, they all have a warning for pregnancy. If patients are receiving these agents, they must use contraception during therapy and for at least 4 to 8 months after the treatment to make sure that they’re not getting pregnant. I think that’s one thing that a lot of staff forget to mention with the immunotherapy checkpoint inhibitors, but those are the official recommendations as of right now.

Wiley K. What Safe Handling and Administration Requirements Apply to Immunotherapy? Oncology Nursing Society. June 27, 2017. Accessed September 9, 2022. 

Seon Jo Park, PharmD, BCOP and Heather Kennihan, MSN, RN, OCN, discuss the best practices that their institution uses to ensure the safe handling of immunotherapy. 

Experts Provide an Institutional Perspective on the Safe Handling of Immunotherapy Treatments

Because of the risks associated with handling chemotherapy drugs, safety guidelines surrounding their proper use have existed since 1981.

 The Oncology Nursing Society (ONS) and the National Institute for Occupational Safety & Health (NIOSH) have both recommended oncology nurses receive hazardous drug education, including safe storage, preparation, labeling, transportation, administration, and disposal of hazardous drugs and proper use of personal protective equipment (PPE).

In 2016, the United States Pharmacopeial Convention (USP) updated the General Chapter 

<800> to set standards for the safe handling of hazardous drugs, with implementation of the new standards set scheduled for December 2019. Almost 3 years after 

 <800> became the recommended standard, some hospitals have improved their compliance, but Seth Eisenberg, ASN, RN, OCN, BMTCN, a retired oncology nurse now working as a consultant in Saint George, Utah, believes implementing 

 <800> is still a work in progress for many hospitals.

<800> requires pharmacies to store hazardous drugs in an externally ventilated, negative-pressure room with at least 12 air changes per hour,” Eisenberg said in an interview with 

®. “For pharmacies that were housed in the basement of a hospital, this entail[ed] expensive modifications. In some cases, it was more cost-effective to build a new pharmacy rather than retrofit an old one.”

 <800> compliance entails increasing education about proper handling of hazardous drugs, implementing closed system drug-transfer devices (CSTDs), and using requisite PPE, according to Eisenberg. “One of the biggest changes in 

 <800> is the requirement to use CSTDs when administering drugs,” he said. “Although ONS and NIOSH had recommended these devices, they weren’t required.”

CSTDs can prevent or minimize drug leakage, but Eisenberg said the cost can be prohibitive for some hospitals and clinics. “[Because] some components of CSTDs are meant for single use, it increases the overall cost of the medication,” he said. “The average price of a CSTD ranges from $8-$12 a dose.”

 <800> requires nurses to double-glove and wear chemotherapy gowns, when administering chemotherapy drugs, which is consistent with ONS guidelines.

“NIOSH has provided best practice guidance for more than 2 decades. But 

 <800> is an enforceable standard with far-reaching implications for all facilities that handle hazardous drugs,” Eisenberg says.

Although guidelines for safe handling of hazardous oncology drugs aren’t new, 

 <800> introduced safety standards that could be enforceable on a state level.

 <800> gave teeth and enforceability to safety practices that already existed,” AnnMarie Walton, PhD, MPH, RN, OCN, CHES, FAAN, assistant professor in the School of Nursing at Duke University in Durham, North Carolina, explained in an interview with 

 <800> is still a work in progress for many oncology units. Some of the oncology units that weren’t already using CSTDs are adopting them now that suppliers are able to meet the demand. Enforceability of the 

 <800> requirement is being decided and regulated at the state level.”

Walton said oncology nurses are in a good position to advocate for safety changes and encourage adoption of 

 <800> if their unit hasn’t already implemented them. In addition, oncology nurses can educate patients and their caregivers on safety measures that should be followed while chemotherapy is administered in the hospital or at home after the patient is discharged.

MiKaela M. Olsen, DNP, MS, APRN-CNS, AOCNS, FAAN, clinical program director for oncology at The Johns Hopkins Hospital in Baltimore, Maryland, works at a hospital that began offering a curbside injection clinic to oncology patients in 2020, during the height of the pandemic. 

“We had to find a way to ensure our patients could safely continue receiving chemotherapy while also protecting them from the coronavirus,” Olsen told 

Johns Hopkins initially conceived curbside injection clinics as a precaution during the pandemic. But Olsen said Johns Hopkins plans to continue these clinics for patients receiving chemotherapy, and other hospitals have taken notice. “For many oncology patients, the curbside injection clinic offers both increased safety and convenience,” Olsen said. “They still have the option of our indoor injection clinic, but for patients with transportation and mobility issues, the curbside clinic is easier. They can have a family member drive them or take an Uber or Lyft to their appointment.”

Nurses staffing the curbside injection clinic wear full PPE, follow safety protocols, and offer services including symptom assessment, port flushes, dressing changes, and chemotherapy. To date, the curbside injection clinic has seen over 7000 patients. Although large health systems such as Johns Hopkins have embraced 

<800>, Olsen acknowledged that some smaller community hospitals are still working to implement 

 <800> safety requirements. One way for hospitals to do this is to request a Health Hazard Evaluation from NIOSH. This evaluation identifies potential health hazards and recommends ways to reduce exposure. There is no cost for the evaluations, but they pay off by providing peace of mind.  “Compliance challenges vary from one health care setting to the next, but nurses can help identify areas in need of improvement,” Olsen said. 

Bernabeu-Martínez MA, Ramos Merino M, Santos Gago JM, Álvarez Sabucedo LM, Wanden-Berghe C, Sanz-Valero J. Guidelines for safe handling of hazardous drugs: a systematic review. 

. 2018;13(5):e0197172. doi:10.1371/journal.pone.0197172

USP<800> Compliance: A Hazardous Drug Safe-Handling Quality Improvement Project for Ambulatory Care Infusion Nurses

. Doctor of Nursing Practice thesis. University of San Francisco; 2020.https://repository.usfca.edu/dnp/218

Powerful chemicals used in chemotherapy may pose safety hazards for oncology nurses, pharmacists, and other health care providers if not handled properly.

USP <800>: Still a Work in Progress?

The implementation of a verification process for the distribution of investigational agents to patients to take orally on their own has proven efficacious at Smilow Cancer Hospital, according to a presentation at the 47th Annual Oncology Nursing Society (ONS) Congress.

“Independent verification of documentation is paramount to patient safety. With high-risk medications, verification administration and documentation of oral investigational chemotherapy and immunotherapy agents had not been in alignment with our policy,” Jeramy Tabuzo BSN, RN, OCN, clinical trials oncology nurse, Smilow Cancer Hospital, Yale New Haven Health in Connecticut, said during her presentation at the Congress.

“Pulling together an interdisciplinary team has created a new process that we developed and implemented to ensure patient safety and practice according to our institutional standards.”

At Smilow, a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, Tabuzo and colleagues administer oral investigational chemotherapy drugs as part of their ongoing phase 1 trials. Through the administration process, patients receive their drug bottle on day 1 of the study, and are responsible for taking the agent at specific time points thereafter.

Their phase 1 clinical trial infusion unit is comprised of 12 infusion chairs, where they see 12 to 20 patients per day, across 142 active trials. Among these trials, there are approximately 64 oral investigational trials.

“In 2018, our nursing policy on chemotherapy verification was revised and required nurses to practice independent verification at the bedside, or chairside,” explained Tabuzo. “However, the infrastructure of our electronic medication administration record does not support our practice and policy.”

For example, she added, the oral drug released to the patient is not on electronic Medication Administration Record (eMAR) and has not allowed for barcode scanning at the time of disbursement and administration.

Therefore, Tabuzo and her colleague aimed to safely administer oral investigational chemotherapy and immunotherapy agents in accordance with current nursing policies; in particular, through completing dual independent nurse verification and appropriately scanning and documenting oral drug administration.

To do so, they had a committee of 6 individuals, comprised of the EPIC/Beacon coordinator, a pharmacy application IT specialist, an oncology pharmacist, an investigational drug services manager, a nursing professional development specialist, and an infusion nurse. The committee identified components that needed to be changed for new processes to improve workflow and dispense and administer oral medications that allow for independent 2-nurse verification through barcode scanning.

In turn, once these processes were developed, the committee educated and dispersed the new processes to nurses, pharmacists, and physicians. Lastly, the process was then implemented across the Smilow ambulatory units and 15 infusion care centers.

Ordering for oral investigational medication in the treatment plan.

Once released, transferring the order to eMAR.

The pharmacy creating a process to generate the barcode label for scanning the oral investigational drug bottle.

At the chairside, 2-nurse verification process occurring.

If there are no discrepancies, nurse 2 signing off MAR, and nurse 1 proceeding to dispense the drug bottle.

The patient self-administering from the bottle dispensed on day 1 of treatment.

Documenting the patient self-administered the agent, using the smart phrase, “.oralinvestigational” in the nurse’s note.

“Smart phrase is a function in EPIC that we utilize to create the standardized text that can be inserted into the nurse’s notes,” explained Tabuzo. “In our case, if you type in ‘.oralinvestigational’ that will populate the notes with the treatment cycle, the HIC number, the drug name, the dose, and the time that the patient took the medication. The standard documentation supports consistency and efficiency for research data collection.”

Compliance to the new workflow was evaluated by monitoring the number of safety events reported through the electronic event reporting system at Smilow. The system evaluated incorrect bottles dispensed, incorrect doses, and incorrect medication labels. Moreover, barcode scanning compliance was audited using an automated report.

“We also saw direct feedback from nurses, pharmacists, physicians, and clinical trials office staff. To date, nursing has been [satisfied] with [the] policy and no safety events have been reported,” Tabuzo said.

Tabuzo J, Mancini KA. Oral Investigational Chemotherapy/Immunotherapy Verification Process. Presented at: 47th Annual ONS Congress; April 27 – May 1; Anaheim, California. Presentation O26.

Independent verification of documentation is paramount to patient safety.

Independent 2-Nurse Verification Process in Distribution of Oral Investigational Chemo/Immunotherapy Proves Helpful

The Food and Drug Administration (FDA) has approved luspatercept-aamt (Reblozyl) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

The approval is based on findings from the phase III BELIEVE study, which showed that treatment with luspatercept-aamt led to significant reductions in RBC transfusion burden in those with beta-thalassemia—associated anemia.

 Results specifically showed that 21.4% of patients who received luspatercept-aamt achieved a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units, during weeks 13 to 24 after randomization compared with 4.5% of patients who received placebo (risk difference, 17.0; 95% CI, 10.4-23.6; 

“When patients receive multiple blood transfusions, there is a risk for iron overload, which can affect many organs,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release.

 “Today’s approval provides patients with a therapy that, for the first time, will help decrease the number of blood transfusions. This approval is an example of our continued progress for rare diseases and providing important new drugs to patients earlier.”

Beta thalassemia is a rare blood disorder that is caused by a genetic defect in hemoglobin; it is also associated with ineffective erythropoiesis, which leads to a production of fewer and less healthy RBCs and often leads to severe anemia. Luspatercept-aamt is a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation. 

In the double-blind, placebo-controlled, multicenter, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept-aamt in adult patients with beta thalassemia who regularly required RBC transfusions. To be eligible for enrollment, patients had to be aged ≥18 years, had beta thalassemia or hemoglobin (Hb) E/beta thalassemia, and required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.

A total of 336 patients were randomized 2:1 to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 weeks; 332 patients were treated. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

The primary endpoint of this trial was a ≥33% reduction in transfusion burden, with a reduction of ≥2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period. Secondary endpoints included ≥33% reduction in RBC transfusion burden at weeks 37 to 48, ≥50% reduction in transfusion burden at weeks 13 to 24, ≥50% reduction in transfusion burden at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24. Moreover, achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.

The median age was 30 years (range, 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. B0/B0 genotype was observed in 30.4% and 31.3% of patients in the luspatercept-aamt and placebo arms, respectively.

Additional results showed that 19.6% patients on luspatercept-aamt achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 compared with 3.6% of those receiving placebo (

 <.0001). Moreover, 7.6% and 10.3% achieved a ≥50% reduction in RBC transfusion burden at weeks 13 to 24 and 37 to 48, respectively, versus 1.8% and 0.9% of those on placebo (

Regarding safety, thromboembolic events occurred in 3.6% of patients on the luspatercept-aamt arm, and hypertension was reported in 10.7% of luspatercept-aamt—treated patients across the clinical development program. Serious adverse events (AEs) occurred in 3.6% of patients receiving luspatercept-aamt, and serious AEs in 1% of patients were cerebrovascular accident and deep vein thrombosis. There was 1 death due to an unconfirmed case of acute myeloid leukemia. The most common AEs were headache (26% with luspatercept-aamt vs 24% with placebo), bone pain (20% vs 8%, respectively), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%).

Treatment discontinuation due to an AE in grades 1 through 4 occurred in 5.4% of patients who received luspatercept-aamt. The most frequent AEs that required discontinuation in the luspatercept-aamt arm included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%). Furthermore, dose reductions due to an AE occurred in 2.7% of patients who received luspatercept-aamt, the most common were due to hypertension and headache. Dose interruptions due to AEs occurred in 15.2% of those on luspatercept-aamt; the most frequent AEs that led to dose interruptions were upper respiratory tract infection, alanine transaminase increase, and cough.

“Today’s approval is an important milestone and underscores our continued commitment to patients with hematology disorders,” Nadim Ahmed, president, Global Hematology and Oncology for Celgene, the developer of luspatercept-aamt, stated in a press release. “There are very limited options for patients living with anemia due to beta thalassemia who are dependent on long term red blood cell transfusions. We are pleased to make Reblozyl available as a new therapy for these patients to help address their anemia, a significant clinical complication of beta thalassemia.”

A version of this article appeared on OncLive

FDA Approves Luspatercept for Beta Thalassemia—Associated Anemia

FDA approves REBLOZYL® (luspatercept-aamt) for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. Celgene. Published November 8, 2019. https://bit.ly/33vOhPo. Accessed November 8, 2019.

FDA approves first therapy to treat patients with rare blood disorder. FDA. Published November 8, 2019. https://bit.ly/2JZQeLZ. Accessed November 8, 2019. 

Cappelini MD, Viprakasit V, Taher A, et al. The BELIEVE Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. 

. 2018;132:163. doi: 10.1182/blood-2018-163.

The therapy is now approved for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

Luspatercept Approved by the FDA to Treat Anemia in Patients With Beta Thalassemia

The FDA has approved the pegfilgrastim (Neulasta) biosimilar LA-EP2006 (pegfilgrastim-bmez; Ziextenzo) as a treatment to decrease the incidence of infection, exhibited from febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer therapy that is associated with a clinically significant incidence of febrile neutropenia.

The approval is based on analytical, preclinical, and clinical studies, including data from the pivotal three-way pharmacokinetics (PK) and pharmacodynamics (PD) LA-EP06-104 trial comparing Sandoz's pegfilgrastim biosimilar with US-sourced reference pegfilgrastim; the pegfilgrastim biosimilar with European Union—sourced reference pegfilgrastim; and US- with EU-sourced reference pegfilgrastim.

Results showed that PK and PD similarity were demonstrated in all three comparisons, and there were no clinically meaningful differences observed in safety and immunogenicity among the groups.

"When a cancer patient with febrile neutropenia gets an infection, it can have serious consequences such as delays or dose reductions of chemotherapy," Carol Lynch, president of Sandoz Inc., the developer of the biosimilar, stated in a press release.

Pegfilgrastim is a long-acting version of filgrastim (Neupogen), which is indicated for select patients with cancer undergoing chemotherapy to enhance the production of infection-fighting white blood cells. The indication is specific to those receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

In April 2019, Sandoz resubmitted a biologics license application to the FDA for LA-EP2006 to decrease the incidence of infection from febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer therapy.

 The resubmission addressed a complete response letter issued by the FDA in June 2016.

The resubmitted application included updated data from the LA-EP06-104 study, methodology of which was presented at the 2018 ESMO Congress. The study was sufficiently powered (90%) to achieve confidence intervals within margins 0.8 to 1.25 in co-primary endpoints pairwise comparisons. The investigators noted that due to historically known high intra- and inter-subject variabilities with reference biologic in area under the serum concentration-time curve (AUC)0-inf, the study, in healthy volunteers, is appropriate and establishes the scientific bridge to demonstrate similarity of PK/PD, safety, and immunogenicity between LA-EP2006, EU reference pegfilgrastim, and US reference pegfilgrastim. As of October 2018, the trial was ongoing in 5&thinsp;US and 1 Dutch study sites.

The European Commission approved LA-EP2006, known as Ziextenzo, as a treatment to reduce the duration of neutropenia and incidence of febrile neutropenia that is associated with anticancer chemotherapy in November 2018. With that approval, the biosimilar became indicated for use in the same proposed indications as reference pegfilgrastim, which is to prevent febrile neutropenia in patients receiving myelosuppressive chemotherapy, those with acute myeloid leukemia receiving induction or consolidation chemotherapy, patients with cancer undergoing bone marrow transplantation, those undergoing autologous peripheral blood progenitor cell collection and therapy, and those with severe chronic neutropenia.

The European approval was based on comprehensive analytical, preclinical and clinical data demonstrating the similarity between Ziextenzo and pegfilgrastim regarding safety, efficacy, and quality. Part of the submitted data was from a single-dose, double-blind, randomized, two-way crossover, phase I study, in which the biosimilar demonstrated similar PD, PK, immunogenicity, and safety as reference pegfilgrastim.

The study consisted of 2 treatment periods separated by an 8-week washout period. A total of 169 patients between the ages of 18 and 45 years were randomized to either the biosimilar or pegfilgrastim. Each treatment was administered at a 6-mg subcutaneous dose on day 1 of each treatment period.

PK/PD similarity was claimed if 90% PK and 95% PD confidence intervals (CIs) for geometric mean ratios of AUC from time of dosing and extrapolated to infinity (AUC0-inf), or to the last measurable concentration (AUC0-last), maximum observed serum concentration (Cmax), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last), and ANC maximum effect attributable to the therapy under investigation (Emax) were completely contained within the predefined margin (0.8-1.25).

Results showed that similar PK/PD data were demonstrated: 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (0.9737-1.0169) were contained within the predefined margin.

Moreover, the biosimilar and reference pegfilgrastim demonstrated similar safety profiles and were well tolerated, and there was no detection of neutralizing or clinically relevant antibodies.

FDA approved the first pegfilgrastim biosimilar CHS-1701

 (pegfilgrastim-cbqv; Udenyca) for patients with cancer receiving myelosuppressive chemotherapy.

A version of this article originally appeared on OncLive

FDA Approves Sandoz’s Pegfilgrastim Biosimilar

Sandoz receives US FDA approval for long-acting oncology supportive care biosimilar Ziextenzo™ (pegfilgrastim-bmez). Sandoz. Published November 5, 2019. https://bit.ly/2PP20Nh. Accessed November 5, 2019.

Nakov R, Schussler S, Schier-Mumzhiu S, et al. A large multi-center, randomized, double-blind, crossover study in healthy volunteers to compare pharmacokinetics and pharmacodynamics of a proposed biosimilar pegfilgrastim with EU and US reference pegfilgrastim: methodological approach. Ann Oncol. 2018;29(suppl 8; abstr 1796P). doi: 10.1093/annonc/mdy300.110.

Sandoz resubmits biosimilar pegfilgrastim application to US FDA. Sandoz. Published April 2, 2019. https://bit.ly/2FQQsCu. Accessed April 2, 2019.

Nakov R, Gattu S, Wang J, et al. Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects [published online August 5, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13731.

The FDA has approved the biosimilar pegfilgrastim for treatment to decrease the incidence of infection exhibited from febrile neutropenia.

Pegfilgrastim Biosimilar Approved By FDA

The FDA has expanded the approval of aprepitant (Cinvanti) injectable emulsion for intravenous (IV) use to include the 130-mg single-dose regimen for patients receiving moderately epigenetic chemotherapy (MEC).

The label expansion standardizes the aprepitant 130 mg single-dose regimen for patients receiving highly emetogenic cancer chemotherapy (HEC) and/or MEC as an injection over 2 minutes or an infusion over 30 minutes, which eases the dosing and administration and eliminates the need to take oral aprepitant on days 2 and 3 following MEC administration.

The expansion also builds on the prior label expansion that introduced the 2-minute IV push, which enables physicians to utilize the operational advantages of this administrative method of and contributes to a reduction in total patient time spent at the infusion site, according to Heron Therapeutics, Inc., the developer of aprepitant, in a press release.

"This most recent label expansion to offer a simplified dosing regimen for MEC adds to the important advantages Cinvanti provides to patients as the only FDA-approved, IV NK

 RA available as a convenient 2-minute IV push for MEC and HEC," Rudolph M. Navari, MD, PhD, University of Alabama, Birmingham School of Medicine, Division of Hematology and Oncology, stated in a press release. "The simplified dosing in MEC removes the need for patients to take oral aprepitant on days 2 and 3, which can improve compliance and reduce costs. These benefits continue to improve the overall patient experience with Cinvanti."

Aprepitant is a polysorbate 80-free, IV formulation of an NK1 receptor antagonist, which is designed to significantly reduce CINV in both the acute and delayed phases following chemotherapy. The FDA previously approved aprepitant as a 30-minute IV infusion on November 2017, making it the first IV formulation to directly deliver aprepitant (Emend). In February 2019, the FDA has expanded the approval of aprepitant injectable emulsion to include a 2-minute IV use for the prevention of acute and delayed CINV.

The decision of the earlier approval is based on results of a two-part, phase I study that demonstrated bioequivalence and a similar safety profile for patients who received aprepitant as a standard 30-minute IV infusion compared with a 2-minute IV injection, which is also referred to as an IV push.

Part A of the study randomized 24 patients to receive aprepitant at 130 mg IV via injection over 15 minutes (cohort 1), 5 minutes (cohort 2), or 2 minutes (cohort 3). The primary endpoint was tolerability and safety of single doses of aprepitant across the 3 cohorts. Patients then progressed to Part B of the trial, which was a two-sequence crossover study, following the establishment of acceptable tolerability in cohorts 2 and 3.

In Part B, 50 patients were randomized to receive a 2-minute injection of 130 mg aprepitant at 9 ml/min or a 30-minute infusion at 296 ml/h. The primary endpoint was pharmacokinetics of plasma aprepitant following a single dose as an injection or infusion; secondary endpoints were safety and tolerability. The mean age of patients was 34; 19 patients were female and 31 were male.

The FDA has expanded the approval of aprepitant to include in its label the use of a single dose regimen in patients receiving moderately epigenetic chemotherapy.   

Drug Safety