Denise Myshko is your editorial contact for the Formulary Watch. She joined Formulary Watch as editor is June 2021 from Oncology Live. Prior to that, she was managing editor of PharmaVOICE, a trade publication in the pharmaceutical industry. Email: dmyshko@mjhlifesciences.com

 the warnings and precautions section of the label of Imbruvica (ibrutinib) to include information about the possibility of cardiac failure and sudden death.

Imbruvica is a once-daily oral medication that is jointly developed and commercialized by Janssen Biotech and Pharmacyclics, an AbbVie company, and used to treat patients with B-cell blood cancers.

A Janssen spokesperson said the update was made to further characterize the uncommon risk of potential cardiac events and provide more specific guidance related to dose modifications for patients receiving therapy. “We continually monitor patient safety and, working closely with the FDA, update our label guidance accordingly as additional clinical trial data and real-world experience are accumulated,” the spokesperson said.

Imbruvica blocks the Bruton's tyrosine kinase (BTK) protein, which is needed by normal and abnormal B-cells, including specific cancer cells, to multiply and spread. By blocking BTK, Imbruvica may help inhibit their proliferation.

The FDA first approved Imbruvica in November 2013, and today is indicated for adult patients in six disease areas, including five hematologic cancers. These include indications to treat adults with CLL/SLL with or without 17p deletion (del17p), and adults with Waldenström’s macroglobulinemia (WM), and adult patients with previously treated mantle cell lymphoma (MCL), as well as to treat adult patients with previously treated marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy, and adult patients with previously treated chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

“We are confident in the benefit/risk profile of Imbruvica, which has been used to treat more than 250,000 patients worldwide with B-cell blood cancers,” the spokesperson said. “Imbruvica is the most comprehensively studied and prescribed medicine in its class and is the only BTKi with 11 approvals across 6 indications, including five hematologic cancers and chronic graft-versus-host disease.”

The warnings and precautions section now reads (changes are underlined):

“Fatal and serious cardiac arrhythmias and cardiac failure have occurred with Imbruvica. 

Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received Imbruvica in clinical trials, including in patients who received Imbruvica in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

“Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received Imbruvica in clinical trials, including in patients who received Imbruvica in unapproved monotherapy or combination regimens.

“These events have occurred particularly in patients with cardiac risk factors 

, a previous history of cardiac arrhythmias, 

 at baseline, and monitor patients for cardiac arrhythmias and cardiac 

 (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, 

. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued Imbruvica treatment.”

Articles

The label for Imbruvica now includes information about the possibility of cardiac failure, which has occurred in 1% of patients. Imbruvica is used to treat B-cell blood cancers.

Janssen Updates Warnings Section of Imbruvica Label

The FDA has updated the prescribing information of two Parkinson’s disease therapies to include a new section warning about the risk of hemolytic anemia, a condition that can result in red blood cells being destroyed faster than they can be made.

The two products — Supernus Pharmaceuticals’ 

 — contain apomorphine hydrochloride. Both are used to treat short-term, intermittent “off” episodes in people with Parkinson’s disease. Apokyn is a subcutaneous injection and Kynmobi, which launched in October 2020, is a sublingual film formulation of apomorphine.

An FDA spokesperson said the agency became aware of adverse event reports and reports in the published literature of patients experiencing apomorphine-associated hemolytic anemia. “We determined that apomorphine products represent a class of products that have the potential for the same serious risk of hemolytic anemia,” he said.

Supernus has also developed an apomorphine infusion device (SPN-830) for the continuous treatment of motor fluctuations (off episodes) in Parkinson’s disease that is being reviewed by the FDA. The agency has provided a PDUFA date in October 2022, and the company is prepared for launch in the first quarter of 2023.

The new section within warnings and precautions reads:

“Hemolytic anemia requiring hospitalization has been reported with apomorphine treatment in the postmarketing setting. Many of the reported cases included a positive direct antiglobulin test (Coombs test), suggesting a potential immune-mediated hemolysis. Severe anemia, angina, and dyspnea have occurred with hemolytic anemia. Some patients were treated with high dose glucocorticoids or blood transfusions. Hemolytic anemia can appear at any time after apomorphine treatment. If a patient develops anemia, consider a workup for hemolytic anemia. If hemolytic anemia occurs, consider discontinuing treatment.”

Apokyn and Kynmobi contain apomorphine hydrochloride, which can cause hemolytic anemia that requires hospitalization. The products both treat the loss of muscle movement control caused by Parkinson’s disease.

FDA Updates Warning Labels on Parkinson’s Therapies

Sandoz has launched the generic pirfenidone, the first fully substitutable equivalent to Genentech’s Esbriet, to treat patients with idiopathic pulmonary fibrosis (IPF). IPF is a progressive rare disease with no cure, which causes irreversible lung scarring and makes it difficult to breathe. It primarily affects adults over age of 50 and is more common in men. About 140,000 Americans live with IPF.

The generic pirfenidone is immediately available via specialty pharmacies. It is available as an oral therapy with two dosages: 267 mg and 801 mg. Sandoz is offering a $0 co-pay program for eligible patients.

“We developed this medicine in-house and continue to build our expertise and infrastructure to support our long-term commitment to grow our respiratory portfolio.,” Keren Haruvi, president of Sandoz said in a press release.

Pirfenidone is used to treat patients with idiopathic pulmonary fibrosis, a progressive rare disease that make it difficult to breathe. 

Sandoz Launches First Generic of Esbriet

 Radicava ORS (edaravone) oral suspension for the treatment of adults with amyotrophic lateral sclerosis (ALS). Radicava ORS, developed by Mitsubishi Tanabe Pharma America, is an orally administered version of Radicava, which was originally approved in 2017 as an intravenous (IV) infusion to treat ALS.

"ALS is a progressive disease that, due to its heterogenous nature, impacts patients at different rates with varying symptoms," Tulio Bertorini, M.D., Professor of Neurology, The University of Tennessee Health Science Center, said in a press release. "Therefore, it is crucial that patients have treatment and formulation options that accommodate their own unique needs, and RADICAVA ORS provides HCPs who have prescribed their ALS patients edaravone with an alternate delivery option.

Radicava ORS can be taken orally or administered through a feeding tube. The oral medication has the same dosing regimen as Radicava—an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

The effectiveness of Radicava ORS is based on a study that showed comparable levels of Radicava ORS in the bloodstream to the levels from the IV formulation of the therapy. The efficacy of Radicava for the treatment of ALS was previously demonstrated in a six-month clinical trial that served as the basis for approval in 2017. In that trial, 137 participants were randomized to receive Radicava or placebo. At Week 24, individuals receiving Radicava declined less on a clinical assessment of daily functioning compared to those receiving placebo.

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing, and talking. ALS causes the nerves to lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is a progressive disease that continues to get worse over time.

Radicava ORS has the same dosing regimen as the IV form of the ALS therapy, with a treatment cycle followed drug-free periods.


FDA Approves Oral Form of ALS Therapy

The FDA has launched a new program that is aimed to increase the development of drugs for people with rare diseases. Called Accelerating Rare Disease Cures (ARC), the 

 is managed by Center for Drug Evaluation and Research’s (CDER) Rare Diseases Team and will provide coordination across the agency’s efforts in this area.

This new effort continues the regulator agencies effort to provide support for the development of rare diseases. One effort, developed in collaboration with the Critical Path Institute, is the Rare Disease Cures Accelerator-Data and Analytics Platform. The platform provides a database designed to promote the secure sharing of existing patient-level data and encourage the standardization of new data collection.

There are about 7,000 rare diseases and conditions, which affect about 30 million people. Developing new therapies for rare diseases can be complex. Established trial designs may not work with these potential treatments, and endpoint selection can be challenging if there is a limited understanding of the natural history of the disease. Additionally, because of small patient populations, there may not be enough people available to participate in rare disease clinical trials.

Progress is being made for some rare diseases. In 2021, 26 of the 50 novel drugs approved by the FDA were for orphan diseases. And in the first few months of 2022, the FDA approved four new drugs for people with rare diseases in the areas of oncology and hematology. These drugs:

 (a rare cancer that develops in a part of the eye called the uvea) that has spread to other parts of the body or cannot be surgically removed.

first therapy to decrease the need for red blood cell transfusion

 due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease, a rare type of anemia.

first therapy to treat anemia in adults with pyruvate kinase deficiency

, an inherited disorder that causes premature red blood cell destruction.

drug for adults with intermediate or high-risk primary or secondary myelofibrosis

, a rare bone marrow disorder, who have low platelet (blood clotting cells) levels.

“However, despite an increase in the approval of novel drugs to treat rare diseases and conditions, there is still a tremendous unmet need for FDA approved therapies,” Kerry Jo Lee, M.D., associate director for rare diseases, Office of Rare Diseases at the FDA, said in a video introducing the new program.

“Through scientific and regulatory innovations and engagement, we believe the ARC program will help accelerate the availability of treatments for patients with rare diseases,” she said.

More than 700 drugs are in development for rare diseases, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents biopharmaceutical companies.

The goal of the new program is to help increase the development new treatments for patients with rare diseases.

FDA Launches New Rare Disease Program

The FDA has amended the emergency use authorization (EUA) for the Pfizer/BioNTech COVID-19 vaccine, authorizing the use of a single booster dose for administration to individuals 5 through 11 years of age. The booster is given at least five months after completion of a primary series and is the same dose of the Pfizer-BioNTech COVID-19 vaccine.

To date, more than 8 million 5- to 11-year-olds in the United States have completed a primary series, and 4,500 children this age have participated in the companies’ COVID-19 vaccine clinical trial, according to a 

“While it has largely been the case that COVID-19 tends to be less severe in children than adults, the omicron wave has seen more kids getting sick with the disease and being hospitalized, and children may also experience longer term effects, even following initially mild disease,” FDA Commissioner Robert M. Califf, M.D., said in a press release.

 from the phase 2/3 clinical trial, which showed that a booster dose of the Pfizer-BioNTech COVID-19 vaccine elicited a strong immune response in this age group, generating neutralizing antibodies against both the omicron variant and wild-type SARS-CoV-2 virus regardless of prior SARS-CoV-2 infection. No new safety signals were observed.

The safety of a single booster dose of the Pfizer-BioNTech COVID-19 vaccine in this age group was assessed in about 400 children who received a booster dose at least five months (range 5 to 9 months) after completing a two-dose primary series. The most commonly reported side effects were pain, redness and swelling at the injection site, as well as fatigue, headache, muscle or joint pain and chills and fever.

The companies have already submitted an application to the European Medicines Agency for a booster dose in this age group and are planning to file with other regulatory agencies around the world.

The vaccine is authorized for use as a two-dose primary series for those 5 years and older, and a three dose primary series for those with certain kinds of immunocompromise. The vaccine is also authorized as a single booster for those 5 years and older, and as a second booster for those 50 years and older and as a second booster for those 12 years and older with certain immunocompromise.

The booster is given at least five months after completion of a primary series.

FDA Expands EUA for Pfizer/BioNTech COVID-19 Booster to Children 5 to 11 Years

FDA okayed the first direct-to-consumer multi-analyte COVID-19 test that can detect SARS-CoV-2, influenza A and B, and respiratory syncytial virus (RSV) simultaneously.

The Labcorp Seasonal Respiratory Virus RT-PCR DTC Test is available without a prescription, so people can self-collect a nasal swab sample at home and then send the sample to Labcorp for testing, FDA said in a 

Results are delivered through an online portal, with follow up from a healthcare provider for positive or invalid test results.

“While the FDA has now authorized many COVID-19 tests without a prescription, this is the first test authorized for flu and RSV, along with COVID-19, where an individual can self-identify their need for a test, order it, collect their sample and send it to the lab for testing, without consulting a health care professional,” said Jeff Shuren, M.D., J.D., director of FDA’s Center for Devices and Radiological Health.

“The rapid advances being made in consumer access to diagnostic tests, including the ability to collect your sample at home for flu and RSV without a prescription, brings us one step closer to tests for these viruses that could be performed entirely at home,” Shuren added.

The home sample collection kit can be purchased online or in a store.

“This will enable consumers to more easily determine whether they may be infected with COVID-19, flu, or RSV, which can aid in determining if self-isolation (quarantine) is appropriate and to assist with healthcare decisions after discussion with a healthcare professional,” the FDA said.

The FDA emergency use authorization allows the nonprescription test to use at-home sample collection with testing performed in a laboratory.


FDA Clears First At-Home Combo COVID-19, RSV and Flu Test

 a request for an emergency use authorization made by a physician for the use of fluvoxamine to treat adults with COVID-19 to prevent hospitalization. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the FDA to treat patients with obsessive-compulsive disorder and depression.

The rationale for fluvoxamine’s use in patients with COVID-19 is based on models that found the drug binds to the sigma-1 receptor on immune cells, reducing inflammatory cytokines.

The EUA request was based on the results of several studies, including one 

 conducted in Brazil (the TOGETHER trial) and published in 

 that showed a 5% risk reduction in hospitalization. 

David R. Boulware, M.D., is an infectious disease physician with the University of Minnesota who submitted the EUA requestion, suggests in a 

 in the same publication that fluvoxamine seems an effective low-cost therapy that provides benefit.

“There are no FDA-approved or EUA authorized medicines which have shown benefit in vaccinated populations or who are not ‘high risk,' ” Boulware wrote in a letter to the FDA about the agency’s refusal to issue the EUA. “There remains a clinical need of effective medications and possible options. More horse memes by the FDA are not helpful for those of us who are serious clinical trialists,” he said, referring to a tweet the FDA issued last year about why ivermectin shouldn’t be used to treat COVID-19.

But the FDA in a memorandum explaining its decision said based on the available evidence, the data don’t support the use of fluvoxamine for treating non-hospitalized patients with COVID-19 to prevent hospitalization. The regulatory agency indicated that while the TOGETHER study met its primary endpoint, the results were primarily driven by a reduction in the emergency department visits lasting greater than six hours. Regulators indicated there are uncertainties about whether that is a meaningful threshold.

The agency pointed out that this endpoint has not be used to support regulatory decisions about other treatments for nonhospitalized patients with COVID-19. The endpoint used in other decisions about COVID-19 therapies include “proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28” and “percentage of subjects who were hospitalized or died through Day 29 due to any cause.”

The FDA wrote: "acknowledging that retention in an emergency setting for six hours or longer was intended to serve as a proxy for hospitalization in this study, it is uncertain how accurately the study captured recommended retention time for observation, who determined the length of observation, and whether the six-hour timepoint represents a clinically meaningful threshold.”

The FDA also questioned whether the results are generalizable to patients in United States.

Boulware, in a letter to the FDA about the agency’s refusal to issue the EUA, said progression to severe disease is a valid clinical trial endpoint that was used in vaccine trials. “The EUA application noted the 36% reduction in progression to severe Covid-19 as per FDA’s definition of severe Covid-19,” he wrote.

The FDA also pointed out that other studies, STOP COVID, STOP COVID 2, and COVID-OUT, did not demonstrate a benefit of fluvoxamine in adults with COVID-19. Two of those studies were stopped for futility.

“More guidance on the choice of clinical endpoints for outpatient trials in 2022 would be useful,” Boulware wrote in his letter. “As a clinical trialist, there remains a need for greater two-way communication between FDA and the research community. FDA’s current guidance for trial endpoints for outpatient early treatment of COVID-19 pretends as if it is circa 2020. A medication is beneficial for many reasons, including shortening duration of illness or preventing progression to severe Covid-19. Progression to hospitalization/death is substantially lower in vaccinated populations and/or those with prior infection. This is no longer a realistic trial primary endpoint.”

Additionally, regulators said there are limited 

 data to support the proposed mechanism of action of fluvoxamine for the treatment of COVID-19. “There is no evidence to date that an anti-inflammatory therapeutic would be beneficial at an early stage of infection when COVID-19 disease severity is mild and that anti-inflammatory therapies are currently recommended only for hospitalized individuals requiring supplemental oxygen,” the FDA said.


FDA regulators said the data to support the EUA, which was submitted by a physician, is not sufficient to support the use of the antidepressant fluvoxamine for the treatment of patients with COVID-19.


FDA Declines EUA for Fluvoxamine for COVID-19

Payers, regulators and clinicians are increasingly looking to health economics and outcomes research (HEOR) and real-world evidence (RWE) as a valuable source for patient-level data, and the demand for this information about patients and their medications will only increase, according to a 

 in which Trinity Life Sciences interviewed experts in the economics and outcomes field. The paper aims to better understand how these capabilities can be best leveraged across the life-sciences industry to improve patient outcomes.

The demand for outcomes research continues to grow. The growth not only comes from value, access and pricing teams, but from cross-functional teams across life-sciences companies, according to Trinity Life Sciences.

There is a focus on generating evidence, and this is both a top-down and bottom-up effort, Nandini Hadker, partner, evidence strategy at Trinity Life Sciences, said in an interview with 

“The FDA has embraced economics and health outcomes research. They have given the green light to not just use randomized clinical trials, but also to use real-world data and real-world evidence,” she said. “Pharmaceutical companies want to differentiate their therapies and show the value that they bring to the market and how they improve the clinical paradigm.”

At the same time, there has been an evolution in the health economics and outcomes research industry. The data and analytics industry has grown and matured, with new companies forming and new sources of data now available, as well as new methods for capturing data, such as wearable technologies, which track patient physiological measures over time. “There has been an evolution in evidence generation, moving from the slow and academic studies to a much more strategic, more real-time effort to assess value,” Hadker said.

Additionally, she said, the timeline for beginning to assess patient outcomes of new therapies has shifted. “Pharmaceutical companies are not waiting for the product to get market approval before doing these assessments. They are starting two years before approval, looking at unmet needs today to create a regulatory submission that includes real-world evidence,” she said.

Important elements of these studies now include quality of life, activities of daily living, pre- and post-therapy survey questions. “There is an economic angle to this,” Hadker said. “Patients who are doing better on therapy, that would show up in the system. Patients wouldn’t see doctors as much or go the emergency room.”

Payers, however, want these benefits to be quantified. “Health economics and outcomes research is here to stay. In the future, it’s going to be an integral part of decision making for pharmaceuticals, and even for devices and diagnostics.”

Over the next decade, the paper points out, there will be greater data availability and more high-quality data and will likely include more patient-specific and personalized value narratives. In addition, practices more common in Europe, such as health technology assessments, cost-effectiveness analyses and cost-utility analyses, will likely become more common in the United States and include impact on quality of life.

The role of health economic and real-world evidence has become, and will continue to be, an important aspect of healthcare decision-making.

Demand for Real-World Evidence of Medications is Growing

The FDA has approved Eli Lilly’s Mounjaro (tirzepatide) injection — the first drug of its type — to treat type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes.

The once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist is the first and only FDA-approved GIP and GLP-1 receptor agonist, Lilly said in a 

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly's auto-injector pen with a pre-attached, hidden needle.

Mounjaro was effective at improving blood sugar and was more effective than the other diabetes therapies with which it was compared in clinical studies. The FDA said in a 

“Given the challenges many patients experience in achieving their target blood sugar goals, today’s approval of Mounjaro is an important advance in the treatment of type 2 diabetes,” Patrick Archdeacon, M.D., associate director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research, said in the press release.

The approval of Mounjaro is “an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials," said Juan Pablo Frías, M.D., medical director at the National Research Institute and investigator in the SURPASS program, the clinical trials assessing Mounjaro in type 2 diabetes.

Three different doses of Mounjaro (5 mg, 10 mg and 15 mg) were evaluated in five clinical trials, as either a stand-alone therapy or as an add-on to other diabetes medicines. The efficacy of Mounjaro was compared with placebo, a GLP-1 receptor agonist (semaglutide, brand names Ozempic, Wegovy) and two long-acting insulin analogs.

On average, patients randomized to receive the maximum recommended dose of Mounjaro (15 mg) realized lowering of their hemoglobin A1c (HbA1c) level by 1.6% more than placebo when used as stand-alone therapy, and 1.5% more than placebo when used in combination with a long-acting insulin.

In trials comparing Mounjaro with other diabetes medications, patients who received the maximum recommended dose of Mounjaro had lowering of their HbA1c by 0.5% more than semaglutide, 0.9% more than insulin degludec and 1.0% more than insulin glargine, the FDA said.

In addition, among patients randomized to the maximum recommended dose, the average weight loss with Mounjaro was 15 pounds more than placebo when neither were used with insulin and 23 pounds more than placebo when both were used with insulin.

The average weight loss with the maximum recommended dose of Mounjaro was 12 pounds more than semaglutide, 29 pounds more than insulin degludec and 27 pounds more than insulin glargine. Those patients receiving insulin without Mounjaro tended to gain weight during the study.

The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2, Lilly said.

Mounjaro can cause nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain, according to the FDA.

Mounjaro is a first-in-class medicine that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.


FDA Expands EUA for Pfizer/BioNTech COVID-19 Booster to Children 5 to 11 Years

FDA Clears First At-Home Combo COVID-19, RSV and Flu Test

FDA Declines EUA for Fluvoxamine for COVID-19

Demand for Real-World Evidence of Medications is Growing

FDA Okays Lilly’s Novel Diabetes Drug