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

In 2021, regulators at the FDA’s Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research worked with manufacturers to prevent 317 drug shortages, according to a new 

 issued by the agency. Last year, the number of new drug shortages was 41, compared with a peak of 251 in 2011.

Regulatory officials said 2021 was a challenging year for shortages, with manufacturers in the United States and abroad struggling with both quality issues and capacity constraints.

The FDA continues to work closely with manufacturers to mitigate and prevent shortages as the COVID-19 situation evolves, an FDA spokesperson said. In 2021, the FDA expedited the review of 274 submissions and prioritized 29 inspections to address drug shortages.

The agency is currently focusing its shortage efforts on the drugs used in the hospital intensive care unit setting for patients on ventilators, including sedatives, opioid analgesics, neuromuscular blocking agents, vasopressors, anticoagulants, dialysis agents, antibiotics, beta-2 agonist inhalers, and intravenous fluids.

One such case involved cisatracurium, a drug that is used for patients on mechanical ventilators and went into shortage due to the increase in hospitalized patients early in the pandemic. Additional manufacturers were approved under expedited assessment and the shortage was able to be resolved in July 2021.

Additionally, the FDA issued 15 enforcement discretion decisions to increase supplies of the bronchodilator albuterol, oxygen, the anesthetic propofol and other critically needed medications.
“One urgent request covering the distribution of industrial grade oxygen for medical use due to significant shortages in Texas and increased demand due to COVID-19, was considered and approved in less than eight hours on the condition that oxygen distributors met several key quality and safety conditions, including testing for impurities prior to distribution and immediately reporting any serious adverse events,” the spokesperson said.

The Food and Drug Administration Safety and Innovation Act (FDASIA) enacted in 2012 gave regulators new 

 to address drug shortages and ensure quality in the global drug supply chain. It required manufacturers to notify the FDA about discontinuation of manufacturing or a temporary interruption that could impact supply.

Additionally, the CARES Act, signed into law on March 27, 2020, to help ease the economic impact of the COVID-19 pandemic provided additional authority to the FDA in this area, including allowing the agency to prioritize and expedite reviews and inspections that could help ease or prevent shortages.

Agency officials believe the requirements related to early notification of interruptions and discontinuances in manufacturing and the FDA’s own actions are helping to reduce the impact of drug shortages.

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Increased demand for certain medications used to treat hospitalized patients with COVID-19 had a significant impact on medication supply last year.

COVID-19 had an Impact on Drug Supply

Purdue Pharma has introduced nalmefene hydrochloride injection, which is an opioid antagonist indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids, and in the management of known or suspected opioid overdose.

“We believe nalmefene will be an important treatment option to help address the growing and continuing crisis of opioid overdose deaths, including those due to fentanyl and other synthetic opioids,” Craig Landau, M.D., president and CEO, Purdue Pharma, said in a press release. “We decided to provide this medication without market exclusivity because it is in the best interest of the public that other companies also have the ability to quickly introduce similar products if approved by FDA.”

Additionally, Purdue will distribute nalmefene for no profit as part of its commitment to help abate the opioid crisis. This is part of the company’s 

 and settlement with 20 states to address the opioid crisis that the company, in part, helped to create. Purdue developed OxyContin (oxycodone). The company’s aggressive marketing, which incorrectly indicated that the pain reliever was not addictive, is seen as a major contributor to the abuse of this and other opioids.

The company and the Sackler family, which owned Purdue Pharma, have agreed to a settlement that would create a trust of about $6 billion to pay for claims from states, hospitals, and those impacted by addition. A judge in March 2022 

As part of the reorganization plan, Purdue will cease to exist. A 

, called Knoa Pharma, will be owned by National Opioid Abatement Trust, the trust that is being established to fund any claims brought by states. The new company will provide millions of doses of a generic version of buprenorphine and naloxone sublingual tablets, a treatment for opioid dependence. The FDA approved a generic version of buprenorphine and naloxone tablets, in 2020. The company will continue to support the development of a low-cost, nonprescription naloxone intranasal spray.

The company will take no profit, which is part of the company’s bankruptcy filing and settlement with states.

Purdue Launches Opioid Reversal Nalmefene

The FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting is tentatively 

 for Nov. 16, 2022, to discuss the new drug application for Ardelyx’s Xphozah (tenapanor) for the control of serum phosphorus in adult patients with chronic kidney disease (CKD) who are on dialysis.

As part of its response to Ardelyx’s appeal of the complete response letter received on July 28, 2021, the FDA’s Office of New Drugs stated that additional input from an advisory committee, including the addition of input from expert clinicians who care for patients on dialysis, would be valuable in further considering the clinical meaningfulness of the phosphate lowering effect observed in Ardelyx’s phase 3 clinical program in order to reach a decision on the company's formal dispute resolution request. A response from the OND to Ardelyx’s appeal is expected within thirty calendar days after the conclusion of the Advisory Committee meeting.

FDA to Hold Advisory Committee for Xphozah in Kidney Disease

Hyperphosphatemia is a serious condition resulting in an abnormally elevated level of phosphorus in the blood that is estimated to affect the vast majority of the 550,000 patients in the United States with chronic kidney disease on dialysis. When kidney function is impaired, phosphorus is not adequately eliminated from the body.

 of morbidity and mortality in patients with chronic kidney disease.

Xphozoh is a first-in-class phosphate absorption inhibitor that acts locally in the gut to inhibit the sodium hydrogen exchanger 3, reducing phosphate absorption through the paracellular pathway, the primary pathway of phosphate absorption.

 in April. Ardelyx has completed three phase 3 pivotal trials, and two phase 4 clinical trials (OPTIMIZE and NORMALIZE) for Xphozah. In the OPTIMIZE phase 4 trial, Xphoza as monotherapy helped 63% of patients with uncontrolled hyperphosphatemia who were naïve to phosphate binder therapy to achieve target serum phosphate levels. For those with uncontrolled hyperphosphatemia despite being on treatment with phosphate binders, switching to Xphozah or adding Xphozah to a reduced binder dose enabled 34% to 38% of these patients to achieve target levels.

In the NORMALIZE phase 4 trial, up to 49.4% of patients treated with Xphozah monotherapy or in combination with sevelamer achieved a serum phosphate level within the normal range during the 18-month treatment period.

The Cardiovascular and Renal Drugs Advisory Committee meets Nov. 16, 2022, to discuss Xphozah for patients with kidney disease.

FDA Announces Advisory Committee Meeting for Xphozah

 to the FDA a supplemental new drug application for Qulipta (atogepant) to support the preventive treatment of chronic migraine in adults. If approved, Qulipta would be the first gepant (oral calcitonin gene-related peptide receptor antagonist) approved for the broad indication of the preventive treatment of migraine, including episodic and chronic.

“Having one oral medication to treat both episodic and chronic migraine would be an important advancement for health care providers and patients,” Michael Gold, M.D., therapeutic area head, neuroscience development, AbbVie, said in a press release. “This sNDA approval would also diversify AbbVie's migraine portfolio and make it the only company to offer two approved preventive treatments for those living with chronic migraine. No two migraine patients are alike, so having multiple treatment options with unique mechanisms of action is critical.”

AbbVie also markets Botox (onabotulinumtoxinA).

The sNDA submission for Qulipta includes data from the pivotal phase 3 PROGRESS trial in patients with chronic migraine, which supplements the existing data in episodic migraine. People living with chronic migraine experience headaches for 15 or more days per month, which, on at least eight of those days per month, have the features of migraine.

The trial met its primary endpoint of statistically significant reduction from baseline in mean monthly migraine days compared with placebo across the 12-week treatment period in adults with chronic migraine. The trial also demonstrated that treatment Qulipta resulted in statistically significant improvements in all six secondary endpoints. This includes a key secondary endpoint that measured the proportion of patients that achieved at least a 50% reduction in mean monthly migraine days across the 12-week treatment period.

The most common adverse events were constipation and nausea.

The FDA approved Qulipta in September 2021 for the preventive treatment of episodic migraine in adults.

If approved, Qulipta would be the first oral calcitonin gene-related peptide receptor antagonist with a broad preventive treatment of both chronic and episodic migraine.

AbbVie Submits Supplemental NDA for Qulipta for Chronic Migraine

The Centers for Medicare and Medicaid Services has issued a product specific J-Code for Xipere (triamcinolone acetonide) effective July 1, 2022. J-Codes are reimbursement codes used by both commercial insurers and government payers to identify therapies that are administered by a healthcare professional incident to the office visit.

“The issuance of the permanent J-Code will help facilitate access to XIPERE for Americans suffering from macular edema associated with uveitis and help streamline the reimbursement process,” Yolande Barnard, senior vice president and general manager, U.S. Pharmaceuticals, Bausch + Lomb, said in a press release.

The FDA approved Xipere in October 2021 for treatment of macular edema associated with uveitis, a form of eye inflammation. Developed by Bausch + Lomb and Clearside Biomedical, Xipere provides a targeted delivery to the retina and choroid. Macular edema is the buildup of fluid in the macula, which causes retinal swelling and distorted vision, and if left untreated, may lead to permanent vision loss.

Related: FDA Approves Targeted Therapy for Macular Edema

Xipere became commercially available in March 2022. The new J-Code is J3299 “Injection, Triamcinolone acetonide (XIPERE).”

Xipere became commercially available in March 2022. It is the first therapy for patients with macular edema that provides a targeted delivery to the retina.

CMS Issues J-Code for Xipere to Treat Macular Edema

Accord Healthcare releases generic of Viibryd

Accord Healthcare has launched vilazodone tablets. The drug is therapeutically equivalent to Allergan’s Viibryd and is approved to treat major depressive disorder (MDD) in adults. Accord’s product, offered in 10 mg, 20 mg, and 40 mg tablets, is currently available to ship.

Depression is a leading cause of disability worldwide. It is a serious mood disorder that affects how people think, feel, and handle daily activities like sleeping and eating. Globally, roughly 5% of adults suffer from MDD.

FDA approves Ani’s generic of Tranxene.

 the abbreviated new drug application for Ani Pharmaceuticals’ clorazepate dipotassium tablets, the generic version of Tranxene. It is a benzodiazepine is used to treat patients with anxiety, alcohol withdrawal and as an add-on for seizures. Executives from Ani said the launch of its generic is imminent.

Amring receives approval and launches generic of Timoptic

Amring Pharmaceuticals has received FDA approval for generic timolol maleate ophthalmic solution, which is the generic equivalent of Merck’s Timoptic in Ocudose. Timolol maleate ophthalmic solution is supplied in a 60 pack of 0.3mL single-dose vials. It is indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Generics of Viibryd, Tranxane and Timoptic have recently been approved and launched. 

New Generic Approvals

 the warnings and precautions section of the label for AstraZeneca’s Byetta (exenatide) to include a new subsection about the risk of gallbladder disease. Byetta is used to improve glycemic control in people with type 2 diabetes.

The change was made based on results from the EXSCEL trial of Bydureon (exenatide extended-release), another AstraZeneca therapy used for glycemic control, an FDA spokesperson said. EXSCEL was a multinational study that evaluated cardiovascular outcomes during treatment in 14,752 patients with type 2 diabetes and any level of cardiovascular risk when added to the current usual care (NCT01144338).

That study found that 1.9% of Bydureon-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis (gallstones) or cholecystitis (inflammation of the gallbladder).

The labeling of Byetta has been updated to include this data as well. The new subsection reads:

“Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.”

Byetta is used to control blood sugar in patients with diabetes. A new warning includes the risk of gallstones and gallbladder inflammation.

FDA Updates Safety Label of Byetta

Plan sponsors know members are struggling with the barriers placed on them through utilization management and drug benefit design, according to a new 

 of benefits leaders. The Trends in Drug Benefit Design Report was sponsored by Rx Savings Solutions and conducted by conducted by PSG.

“One of the big findings is the importance of member engagement and member satisfaction that we see that coming through across different topics,” Morgan Lee is the senior director of research & strategy, PSG, said in an interview with 

. “It’s encouraging to see that benefit leaders care about their members’ experience.”

PSG surveyed benefits leaders about their perceptions and challenges around high deductible health plans, the role of member experience, formulary strategy, and how the pandemic have shifted plan design priorities.

But while 57% of respondents cited member acceptance as a barrier to trend and utilization management programs, 33% said reducing inappropriate utilization is their top goal outside of managing trend. Additionally, 69% of respondents cited member dissatisfaction as their top challenge with formulary exclusions but 81% use formulary exclusions.

Within high-deductible plans, 22% respondents recognized that affordability of medications prior to deductible being met is challenges. Other challenges included lack of member understanding of health savings account, cited by 19% of respondents, members delaying or foregoing needed care due to deductible amounts, cited by 16% of respondents, and member confusion about deductibles, cited by 12% of respondents. Additionally, only 35% of respondents agreed that high deductible plans were an effective way to manage overall drug trend.

Respondents are not surprised by the friction utilization management and formulary exclusions cause for members, Michael Lonergan, president of PSG, said in an interview. But he pointed to the efforts by benefit plans to become more transparent and help member navigate their plans.

“We’re seeing a two-fold increase in the use of cost-sharing transparency tools,” he said. “This has accelerated through the use of digital tools. Communication with both members and providers is increasing, especially at the point of deciding which treatment to select through the EHR. This can help doctors to know a prior authorization is required or whether there is an alternative.”

In fact, 57% of respondents in the survey promote the use of cost-sharing transparency tools, up from 28% in 2018. Large employers were more likely than smaller employers to promote these tools.

Lonergan said that tools such as Rx Savings Solutions and GoodRx are positive for patients to help provide them information about drug costs.

“Healthcare costs are too high. Plan sponsors are going to continue to be asking members to share in those costs and then empower the members and their provider to make decisions to optimize both the cost and, hopefully, the outcomes,” he said.

Lonergan said that in high deductible plans especially, many people are not engaging their benefit because they may not meet their deductible. “Plans are trying to help those patients navigate the process and make the best decisions.”

Benefits leaders surveyed in PSG’s Trends in Drug Benefit Design Report say the importance of the member experience has increased since the start of the pandemic.


Survey: Patient Satisfaction is a Barrier to Utilization Management of Drug Plans

 a new drug application (NDA) to the FDA for elacestrant in patients with ER+/HER2- advanced or metastatic breast cancer. The companies are requesting priority review.

If approved, elacestrant it would be the first oral therapy in a class of medications called selective estrogen receptor degraders (SERDs), which binds to the estrogen receptor and causes it to be downregulated. As a result, SERDs are being 

 in breast cancers that have become resistant to aromatase inhibitors or those with tamoxifen resistance.

AstraZeneca’s Faslodex (fulvestrant) was the first SERD to be approved by the FDA in 2017. It is an injection therapy for patients with estrogen receptor positive breast cancer.

“We are excited about the potential for elacestrant to be approved for treatment of patients with advanced or metastatic ER+/HER2- breast cancer, which constitutes about 70% of breast cancer and remains an area of significant unmet medical need,” Elcin Barker Ergun, the chief executive dfficer of Menarini, said in a press release.

The elacestrant submission is based on positive phase 3 data from the EMERALD study, which showed that elacestrant met both of its primary endpoints, which were progression-free survival in the overall population and progression-free survival in the estrogen receptor 1 (ESR1) mutation subgroup compared with standard of care with the options of (Faslodex) fulvestrant or an aromatase inhibitor.

, among those who received elacestrant, there was a 31% reduction in the risk of progression or death and a prolonged median progression-free survival of 3.68 months compared 1.97 months in patients receiving standard of care. There was also a 46% reduction in the risk of progression or death in patients with a mutation of ESR1 and prolonged median progression-free survival of 5.32 months compared 1.91 months for those in the standard of care group. ESR1 mutation is one of the key resistance mechanisms that develops in later treatment lines of metastatic breast cancer.

Elacestrant is oral therapy that targets estrogen receptor 1, a key resistance mechanism in advanced breast cancer. 

Menarini Submits NDA Elacestrant for Advanced Breast Cancer

 accelerated approval for the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment. Both therapies were developed and marketed by Novartis.

Tafinlar + Mekinist is the first BRAF/MEK inhibitor to be approved with a tumor-agnostic indication for solid tumors carrying the BRAF V600E mutation. It is the only BRAF/MEK inhibitor approved for use in pediatric patients. Continued approval for this indication is on clinical benefit in a confirmatory trials.

“The combination of dabrafenib and trametinib demonstrated meaningful efficacy in multiple BRAF-positive tumor types, including in some patients with rare cancers who have no other treatment options available,” principal investigator Dr. Vivek Subbiah, M.D., said in a press release. He is associate professor of Investigational Cancer Therapeutics and center medical director of the Clinical Center for Targeted Therapy, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, Texas. “Physicians should consider a BRAF test as a routine diagnostic step that could enable a new option for treating patients with many solid tumors.”

The approval was based on clinical efficacy and safety demonstrated in three clinical trials. In the phase 2 ROAR (Rare Oncology Agnostic Research) basket study and the NCI-MATCH Subprotocol H study, Tafinlar + Mekinist resulted in overall response rates of up to 80% in patients with BRAF V600E solid tumors, including high- and low-grade glioma, biliary tract cancer and certain gynecological and gastrointestinal cancers. An additional study (Study X2101) demonstrated the clinical benefit and acceptable safety profile of Tafinlar + Mekinist in pediatric patients.

BRAF mutations have been identified as drivers of cancer growth across a wide range of solid tumors, including in rare cancer types that can be challenging to study in Phase III trials and often have limited treatment options. BRAF V600E is the most common type of BRAF mutation, accounting for up to 90% of BRAF-mutant cancers.

Both Tafinlar and Mekinst are approved as a single agent to treat metastatic melanoma, non-small cell lung cancer, and metastatic thyroid cancer.

The FDA approved the combination of Tafinlar and Mekinist for solid tumors with a BRAF V600E mutation. This is the first therapy to be approved that is tumor agnostic for patients with this mutation.



New Generic Approvals

FDA Updates Safety Label of Byetta

Survey: Patient Satisfaction is a Barrier to Utilization Management of Drug Plans

Menarini Submits NDA Elacestrant for Advanced Breast Cancer

FDA Approves Drug Combination for Tumor Agnostic Indication