46 minute read
TJC expects big things from pharmacist surveyor
Med Errors Communication Preserves Patient Trust
By Karen Blum
Phoenix—Effective communication with patients and their family members is a critical but uncomfortable step that pharmacists and other care team members must take after a harm event. Done well, it can preserve trust in the healthcare system and potentially reduce clinician stress and legal or disciplinary actions, speakers said at the 2022 ASHP Summer Meetings and Exhibition.
Communication and resolution programs (CRPs)—principled, comprehensive, systematic and compassionate programs for preventing and responding to harm events—are an emerging best practice, said Thomas H. Gallagher, MD, MACP, a professor and an associate chair of the Department of Medicine at the University of Washington, in Seattle.
“In healthcare, all of us aspire to be open and honest with patients and families when there’s been a problem,” said Dr. Gallagher, also the director of the UW Medicine Center for Scholarship in Patient Care Quality and Safety. “It’s certainly what we would expect as patients. But there are all sorts of reflexes and challenges that get in the way of turning that principle into practice.”
CRPs should involve several elements, he said, including immediate reporting of an incident by clinicians and ongoing transparent communication with patients and families. Events should be thoroughly analyzed and used for quality improvement. For the subset of harm events that occur because of error or system failure, health-system personnel should make CRPs a proactive offer of financial resolution rather than waiting for them to file a malpractice claim.
These efforts shouldn’t just be focused on patient and family members, the speakers stressed: Involved caregivers also should immediately be offered some type of care or peer support.
Error Fallout Goes ‘On and On’
Patient and family advocates hate the term “resolution,” Dr. Gallagher noted, because for many of them, the events are never over. “They go on and on and affect multiple members of the family,” he said. “So, the notion that we’ve written a check, or we fix some little system problem, … that’s not at all how it works for the patients and families.”
The benefits of CRPs, when done well, are several, he added. They preserve trust and meet patient/family expectations, reduce clinical distress, reduce the likelihood of litigation or of disciplinary action by regulators, promote learning within and across institutions, strengthen institutional culture and climate, and increase the public’s trust in healthcare.
A big challenge, however, is that organizations use CRPs inconsistently, applying them to some cases but not others, Dr. Gallagher said. Health systems might use the full approach for some cases or just some elements, such as telling a family what happened or what they plan to do to prevent recurrences, and then assume if a patient’s family is interested in financial compensation, they can just ask. “That’s not consistent with having a highly reliable CRP,” he said.
The way organizations respond initially to harm events is “absolutely critical,” he said. “Oftentimes we just want to go in and tell them what happened, and then run out of the room,” Dr. Gallagher said. “That’s not the approach we want to take. We want to hear what’s on their mind and give them timely responses.”
The work is a team effort, he added, with everyone needing to be on the same page about what to tell patients and families about the error. As such, it’s important that all front-line clinicians receive some training in communication about harm events.
Truthful and Transparent
Being truthful and transparent about harms or medical errors as soon as possible is important not just for the families but also for practitioners, commented Natasha Nicol, PharmD, FASHP, moderator for the session and the director of global patient safety affairs at Cardinal Health in Houston. She speaks from experience, having been part of a team involved in a medication error years ago that resulted in the death of a 2-year-old girl.
Silence, or an attitude of keeping errors quiet or thinking what families don’t know won’t hurt them, “is so much more damaging to a practitioner in moving forward and being able to stay in the profession,” Dr. Nicol said. “We really need to learn how to communicate effectively when events happen…It’s really about doing the right thing, and at the end of the day knowing that something really terrible happened but we gave the dignity and respect that people deserve.”
It’s crucial to communicate with families throughout the process of reporting and analyzing events, she added. You don’t have to wait to have all of the information before disclosing a harm event to families.
Drs. Gallagher and Nicol reported no relevant financial disclosures.
Pharmacist JC Surveyor a Benefit to NCCN
By PPN Staff
Phoenix—The Joint Commission’s addition of a pharmacist to the survey process for certain healthcare facilities has added a new level of expertise and insight to the review of standards compliance for medication-related processes, two leaders of the group announced at the 2022 ASHP Summer Meetings and Exhibition.
Only healthcare organizations that are registered with the National Comprehensive Cancer Network (NCCN) are subject to surveys staffed by a pharmacist, according to a Joint Commission spokesperson.
The decision to add the pharmacist surveyor “is a game changer,” said Jeannell Mansur, PharmD, the principal consultant, medication management and safety, Joint Commission Resources. The expertise of the pharmacist surveyor should reap many benefits, she noted, given the significance that medication processes play in patient safety.
As for why the pharmacist surveyor initiative is limited to NCCN hospitals, a Joint Commission spokesperson noted that the program “was the result of strong collaboration with the NCCN and their member organizations to better support our collective missions. As the Joint Commission continues to monitor this initiative, next steps will be determined.”
One challenging area that has come up during surveys is complex medication orders, Dr. Mansur noted. To ensure compliance with these medication orders, pharmacists should review policies to ensure they include the required elements for titration, range, taper and other orders for which the Joint Commission requires hospitals to maintain policies, she said.
Dr. Mansur pointed to block charting as one allowance that the Joint Commission has published for titration orders. Block charting allows for more abbreviated documentation during urgent situations when titration medications are used, but which should not extend beyond four hours, she explained.
Dr. Mansur added that the Joint Commission does not prohibit the adjustment of a titration infusion dose once the patient has met the titration end points. She also noted that the group does not require titration end points to maintain a maximum and a minimum.
Another Valued Team Member
Besides adding a pharmacist surveyor, Dr. Mansur underscored the important role played by a different pharmacist on the Joint Commission team: co-presenter Robert Campbell, PharmD, the director of the Joint Commission’s Standard Interpretation Group. With his pharmacy representation, there is a better understanding of hospital medication issues within the Joint Commission, Dr. Mansur noted, adding: “I have seen medicationrelated issues get addressed more timely” due to his involvement. “We receive a lot of medication-related frequently asked questions for which the Joint Commission provides direction.”
As for his own take on what health systems should expect during surveys, Dr. Campbell stressed that medication management—although critically important—isn’t the only compliance area on which to focus. Regulations from the Occupational Safety and Health Administration (OSHA), for example, prohibit food and drink in areas exposed to blood and infectious or toxic materials.
“[OSHA doesn’t] want to see you with one hand in a chest cavity and another eating a banana,” Dr. Campbell quipped.
Part 2
New and Emerging Options For Hypercholesterolemia Bempedoic acid, bempedoic acid plus ezetimibe, and inclisiran
This is a 2-part series designed to provide front-line pharmacists with knowledge of how to use antihyperlipidemic drugs to reduce low-density lipoprotein (LDL). C. MICHAEL WHITE, PHARMD, FCP, FCCP
Distinguished Professor and Chair, Pharmacy Practice University of Connecticut School of Pharmacy Storrs, Connecticut
The first installment described the most recent lipid guidelines from the American Heart Association/ American College of Cardiology, the role of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in therapy (bit.ly/3xHWhgp-PPN). This second installment explores 3 newer entrants that have been approved by the FDA for LDL cholesterol (LDL-C) reduction: bempedoic acid (Nexletol, Esperion), bempedoic acid plus ezetimibe (Nexlizet, Esperion), and inclisiran (Leqvio, Novartis). This article describes the pharmacologic mechanisms of action of these agents, as well as their pharmacokinetics/drug interaction potential, and reviews their lipoprotein effects and adverse events.
Pharmacologic Mechanisms
Bempedoic acid. Cholesterol in lipoproteins such as LDL and very low-density lipoprotein is created via the cholesterol cascade.1,2 Bempedoic acid blocks the enzyme ATP citrate lyase, which converts citrate into acetyl coenzyme A (CoA), which is subsequently converted into HMG-CoA (Figure). Statins block HMG-CoA reductase downstream, which prevents HMG-CoA from turning into mevalonate. Suppressing cholesterol synthesis with bempedoic acid, statins, or the combined agents triggers upregulation of LDL receptor expression by hepatocytes and increased clearance of circulating LDL.1,2
To exert their pharmacologic effects, bempedoic acid and its active metabolite (ESP15228) require activation by very long-chain acyl-CoA synthetase I (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively.1,2 ACSVL1 is present in hepatocytes but not myocytes, decreasing the risk for intramuscular suppression of the cholesterol cascade.1,2
Inclisiran. Inclisiran is a small interfering RNA (siRNA) product that contains antisense strands of RNA. The siRNA enters hepatocytes after binding to asialoglycoprotein receptors on the cell surface.3-5 Once in the cytoplasm, the antisense RNA binds first to an RNA-induced silencing complex and then binds the messenger RNA (mRNA) strands for PCSK9 produced by the DNA in the nucleus (Figure). Reducing the number of mRNA strands reaching the ribosomes diminishes the production of new PCSK9 molecules. Moreover, PCSK9 cross-links LDL-LDL receptor complexes, forcing the LDL receptor to be broken down instead of being recycled. The diminution of available PCSK9 prolongs LDL receptor functionality at the cell surface and reduces circulating LDL concentrations.6 PCSK9 inhibitors work downstream from inclisiran’s effects by blocking PCSK9 from binding LDLLDL receptor complexes so it cannot facilitate lysosomal destruction of the LDL receptor.
Cholesterol creation
ACL enzyme
HMG-CoA reductase
Net result:
Bempedoic acid and statins reduce formation of new cholesterol, and the body creates more LDLR on cell surface to pull more LDL out of circulation.
LDL receptor regulation
Net result:
Inclisiran and PCSK9 monoclonal antibodies decrease PCSK9 + LDL complexes, enhancing LDLR recycling and LDLR numbers on the cell surface, where more LDL can be removed from circulation.
Figure. Complimentary mechanism of action for bempedoic acid, inclisiran, statins, and PCSK9 inhibitors in hepatocytes.
Pharmacokinetics
Bempedoic acid. In published studies, the maximum plasma concentration (Cmax) and area under the curve (AUC) of bempedoic acid are approximately 12 mcg/mL and 202 mcg*h/mL, respectively.3-5,7,8 The median time to maximum concentration (Tmax) is 3.0 hours. Following multiple-dose administration of bempedoic acid monotherapy, the steadystate Cmax and AUC at 180 mg per day are approximately 21 mcg/mL and 289 mcg*h/mL, respectively. Bempedoic acid steady-state pharmacokinetics are generally linear over a range of doses, and steady state is achieved after 7 days. The combination product yields similar pharmacokinetic parameters for bempedoic acid; however, the ezetimibe in the combination product has a Cmax that is 22%
lower than ezetimibe monotherapy. Taking bempedoic acid with a highfat, high-calorie breakfast reduces the Cmax by 30% and the Tmax is delayed by 2 hours, but this is not clinically meaningful. The bempedoic acid apparent volume of distribution is 18 L, and bempedoic acid and its active metabolite, ESP15228, are both over 99% protein bound. The mean elimination half-life for bempedoic acid is approximately 21 hours at steady state.
Bempedoic acid is eliminated primarily through acyl glucuronide metabolism, but the medication also is reversibly converted to ESP15228 based on aldo–keto reductase activity, with a plasma AUC metabolite/ parent drug ratio for ESP15228 of 18%. ESP15228 is converted to inactive glucuronide conjugates in vitro by UGT2B7. Approximately 70% of the sum of bempedoic acid and its metabolites is recovered in urine and approximately 30% is recovered in feces. Less than 5% of bempedoic acid is eliminated unchanged in the urine and feces combined.3-5,7,8
Compared with patients who have normal renal function, the mean bempedoic acid exposures are 1.4- and 1.9-fold higher in patients with mild or moderate renal impairment versus those with normal renal function, respectively.3-5,7,8 These differences are not clinically significant. There are no data in severe renal impairment or end-stage renal disease on dialysis patients. Compared with patients who have normal hepatic function, the bempedoic acid mean Cmax and AUC are decreased by 11% and 22%, respectively, in patients with mild hepatic impairment, and by 14% and 16%, respectively, in patients with moderate hepatic impairment. This difference should not impede bempedoic acid’s efficacy. Bempedoic acid has not been studied in patients with severe hepatic impairment (Child-Pugh class C).7,8
Drug Interaction Potential
There are several important drug interactions with bempedoic acid or the bempedoic acid plus ezetimibe combination product (due to the ezetimibe constituent).7,8
Simvastatin and pravastatin.
Increased concentrations of simvastatin and pravastatin are associated with an increased risk for simvastatin- or pravastatin-related myopathy when used with bempedoic acid. Do not use more than 20 mg of simvastatin or 40 mg of pravastatin with bempedoic acid. Of note, there are no known issues with atorvastatin or rosuvastatin, regardless of FDAapproved dosage.
Cyclosporine. Cyclosporine increased exposure to ezetimibe in the combination product, which also could increase cyclosporine exposure. Monitor cyclosporine concentrations in patients receiving the combination product.
Fibrates. Coadministration of the combination product with fibrates other than fenofibrate is not recommended. Fenofibrate and the ezetimibe component may increase cholesterol excretion into the bile, leading to cholelithiasis.
Bile acid sequestrants. Cholestyramine may decrease ezetimibe concentrations, which may result in reduced efficacy. Administer the combination product either at least 2 hours before, or at least 4 hours after, bile acid sequestrants.
Inclisiran. Inclisiran exhibits approximately dose-proportional pharmacokinetics over the dose range of 24 to 756 mg following a single administration.3 Studies have shown that the medication’s Cmax is approximately equal to 4 hours after subcutaneous administration, with no detectable drug by 48 hours after single-dose administration. After multiple-dose administration, no accumulation was observed. Inclisiran is 87% bound to plasma proteins, with an apparent volume of distribution of approximately 500 L after subcutaneous administration of a single 284-mg dose to healthy adults.3
Inclisiran is metabolized primarily by nonspecific nucleases and is not a substrate, inhibitor, or inducer of the cytochrome P450 system.3 As such, no pharmacokinetic drug interactions with inclisiran are anticipated. Published data show no clinically meaningful interactions with atorvastatin or rosuvastatin. However, pharmacodynamic interactions, whereby lipoproteins are further reduced than with other cholesterol-lowering drugs, have been seen. Inclisiran has a terminal elimination half-life of approximately 9 hours, with only 16% being renally cleared.3
No dose adjustments are required in patients with mild (creatinine clearance [CrCl], 60-89 mL/min), moderate (CrCl, 30-59 mL/min), or severe (CrCl, 15-29 mL/min) renal impairment, with only 2.0- to 3.3-fold increases in inclisiran’s Cmax and 1.6- to 2.3-fold increases in AUC in severely impaired patients.3 LDL-C reductions were comparable across renal function groups. However, hemodialysis should be postponed for at least 72 hours after administration of inclisiran to prevent diminishing its effectiveness. In patients with mild to moderate hepatic impairment, no dose adjustments are required, with increases of only 1.1- to 2.1-fold for Cmax and 1.3- to 2.0-fold increases in AUC. Inclisiran was not studied in severe hepatic impairment (Child-Pugh class C), and therapy in these patients should be used with caution.3
Lipoprotein Concentrations
Bempedoic acid. The FDA approved bempedoic acid and bempedoic acid plus ezetimibe for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL after employing maximum tolerated statin therapy, which could mean no statins prescribed for the intolerant.1 The FDA-approved dose is 180 mg administered orally once daily with or without 10 mg of ezetimibe. This approval is supported by the results of several phase 3 clinical trials.1
CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) HARMONY was a randomized, placebo-controlled trial of 2,230 patients with HeFH, ASCVD, or both.9 The mean age was 66.1 years, with a baseline mean LDL level of 103.2 mg/dL. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. Patients had to be receiving maximally tolerated statin therapy, with an LDL level of at least 70 mg/dL. At 12 weeks, patients in the bempedoic acid group had their LDL level reduced 16.5% more than placebo (P<0.001).9
CLEAR WISDOM was a randomized, double-blind, placebo-controlled trial enrolling 1,049 patients with HeFH, ASCVD, or both.10 The mean age was 64.3 years, with a baseline mean LDL level of 120.4 mg/dL. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. Patients had to be receiving maximally tolerated statin therapy with a residual LDL of at least 70 mg/dL. The bempedoic acid treatment arm demonstrated a 15.1% reduction in LDL-C levels versus a 2.4% reduction with placebo (P<0.001). Non–high-density lipoprotein (non-HDL; –13.0%, P<0.001), total cholesterol (TC; –11.2%, P<0.001), and apolipiprotein B (apo B; –13.0%, P<0.001) were significantly reduced, as was the inflammatory marker highly specific C-reactive protein (hsCRP; –8.7%, P=0.04) compared with placebo.
CLEAR SERENITY was a double-blind, placebo-controlled trial of 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins.11 Patients with HeFH or ASCVD needed to have an LDL level of at least 100 mg/dL, but primary prevention patients could also be enrolled if their LDL-C level was at least 130 mg/dL. The mean age was 65.2 years, the baseline mean LDL level of 157.6 mg/dL, and 93% of patients had a history of statin-associated muscle symptoms. Patients were randomized 2:1 to 180 mg of bempedoic acid daily or placebo. The group receiving bempedoic acid had a 23.6% reduction in
LDL-C levels versus a 1.3% reduction in the placebo treatment arm (P<0.001). Non-HDL (–18.6%;
P<0.001), TC (–15.5%; P<0.001), apo B (–15.3%; P<0.001), and hsCRP (–28.1%; P<0.001) levels were significantly reduced versus placebo. CLEAR TRANQUILITY was a randomized, double-blind, placebocontrolled trial of 269 patients with a history of statin intolerance and an LDL level of at least 100 mg/dL.12 Overall, 20% of patients had ASCVD, the mean age was 63.8 years, and the mean baseline LDL-C level was 127.6 mg/dL. All patients received a 4-week run-in with 10 mg of ezetimibe daily and were then randomized to 180 mg of bempedoic acid daily or placebo. The bempedoic acid group had a 23.5% reduction in LDL levels versus a 5.0% increase with placebo (P<0.001). Non-HDL (–23.6%; P<0.001), TC (–18.0%; P<0.001), apo B (–19.3%; P<0.001), and hsCRP (–34.5%; P<0.001) were statistically lowered vs. placebo.
The final phase 3 study by Ballantyne et al was a double-blind, placebo-controlled trial of 301 patients with established HeFH, ASCVD, or multiple cardiovascular risk factors.13 Overall, 62.5% of participants had established ASCVD and/or HeFH, the mean age was 64.3 years, and most patients had a baseline LDL-C level greater than 130 mg/dL. All patients were randomized to the combination product of 180 mg of bempedoic acid plus 10 mg of ezetimibe daily, 180 mg of bempedoic acid
LIPIDS
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daily, 10 mg of ezetimibe daily, or placebo. The bempedoic acid plus ezetimibe group had a 36.2% reduction in LDL-C levels versus a 17.2% reduction in the bempedoic acid arm (P<0.001), a 23.2% reduction in the ezetimibe arm (P<0.001), and a 1.0% increase in the placebo treatment arm (P<0.001). For hsCRP, there was a 35.1% reduction with bempedoic acid plus ezetimibe versus 31.9% with bempedoic acid (P>0.05), 8.2% in the ezetimibe arm (P=0.002), and a 21.6% increase with placebo (P<0.001).13
Inclisiran. Inclisiran is FDA approved as a treatment to be used along with diet and maximally tolerated statin therapy for adults with HeFH or ASCVD who require additional lowering of LDL.14
ORION-9 was a randomized (1:1), double-blind, placebo-controlled trial of 482 adults who had HeFH and received 300 mg of inclisiran sodium subcutaneously or matching placebo on days 1, 90, 270, and 450.15 Overall, 90% of the patients were receiving statins, 75% received high-intensity statins, and over 50% received ezetimibe. The median age of the patients was 56 years, with a mean baseline level of LDL-C of 153 mg/ dL. At day 510, the LDL level was reduced by 39.7% in the inclisiran group and increased by 8.2% in the placebo group (P<0.001). Although statistical tests were not run, nonHDL (–43.6%), TC (–32.9%), and apo B (–36.9%) were reduced with only a slight reduction in hsCRP (–4.0%) versus placebo.15
The ORION-10 and ORION-11 trials were reported together.16 A total of 1,561 and 1,617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Patients (mean age, 64.8-66.4 years, depending on trial and group) were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg subcutaneously) or matching placebo on days 1 and 90, and every 6 months thereafter for 540 days. Mean LDL levels at baseline were 104.7 and 105.5 mg/dL, respectively. Inclisiran reduced LDL-C levels by 52.3% (P<0.001) in the ORION-10 trial and by 49.9% (P<0.001) in the ORION11 trial. Non-HDL (–47.4, P<0.001; –43.3%, P<0.001), TC (–33.1%, P<0.001; –29.8%, P<0.001), and apo B (–43.1%, P<0.001; –38.9%, P<0.001) levels were significantly reduced more with inclisiran versus placebo.16
Adverse Events
Bempedoic acid. The most common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials included upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.7,8 Bempedoic acid may increase blood uric acid levels inducing hyperuricemia. Hyperuricemia may occur early after initiation, persist throughout treatment, and lead to the development of gout. Clinicians should assess uric acid levels periodically as clinically indicated, especially in those with a history of hyperuricemia; monitor for signs and symptoms of hyperuricemia; and initiate treatment with urate-lowering drugs as appropriate. Bempedoic acid rarely induced tendon rupture (0.5% of patients treated) versus placebo (0%), and the tendons attached to the shoulder joint, biceps, or calf (Achilles tendon) have been affected. Tendon rupture may occur more frequently in patients over 60 years of age, patients taking corticosteroid or fluoroquinolone drugs, patients with renal failure, and patients with previous tendon disorders. Avoid bempedoic acid in patients who have a history of tendon disorders.7,8
Discontinue bempedoic acid products during pregnancy or breastfeeding because of its cholesterol cascade impeding mechanism of action.7,8 Like with statins, impeding the cholesterol cascade may be linked to fetal harm.
Inclisiran. Subcutaneous injection of inclisiran was generally safe and well tolerated.3 In the ORION-9,
ORION-10, and ORION-11 clinical trials, adverse reactions at the injection site were seen most commonly (8.2% of inclisiran recipients vs 1.8% of placebo recipients), which included inclisiran injection site irritation (3.1%), pain (2.2%), redness (1.6%), and rash (0.7%).16 However, adverse reactions at the injection site rarely led to treatment discontinuation (0.2% with inclisiran vs 0.0% with placebo).16 Serious adverse events occurred in 20% of inclisiran patients compared with 23% of placebo recipients in phase 3 trials.3,15,16 Treatment-emergent adverse events led to treatment discontinuation in 2.5% of inclisiran recipients compared with 1.9% of placebo recipients. During the pivotal clinical trials, 4.9% of patients tested positive for anti-inclisiran antibodies over 18 months of inclisiran treatment, but neither safety nor efficacy differed in any clinically significant manner.3,15,16
Place in Therapy
Bempedoic acid, bempedoic acid plus ezetimibe, and inclisiran offer new options for patients who require LDL lowering. Bempedoic acid works in the cholesterol cascade in a step preceding that of statins. Patients with HeFH or ASCVD require more intensive LDL lowering, and statins alone may not be able to achieve the patient’s goals due to their limited efficacy at maximum doses or from intolerance that precludes use or limits the statin doses that can be used. Bempedoic acid plus ezetimibe offers additional reductions in LDL levels with a similar safety profile to bempedoic acid alone and provides the convenience of a single pill instead of 2-pill therapy. While therapy is well tolerated, the risk for hyperuricemia requires uric acid monitoring; the rare risk for tendon rupture and risk for drug interactions need to be appreciated. LDL levels can be reduced by 15% to 24% with the addition of bempedoic acid and by 36% with the combination of bempedoic acid with ezetimibe.
Inclisiran works by suppressing the production of PCSK9, which is a complementary mechanism to the PCSK9 monoclonal antibodies that prevent PCSK9 from binding to LDL receptors. Patients with HeFH, ASCVD, or those who are statin intolerant can benefit from the potent 40% to 52% reductions in LDL that inclisiran provides, but without causing the same extent of inflammation suppression as seen with bempedoic acid and bempedoic acid plus ezetimibe. Inclisiran requires subcutaneous injection instead of oral therapy, which yields injection site reactions that should be heeded. However, inclisiran injections are only given periodically, there is a very low risk for pharmacokinetic drug interactions, and there is no increased risk for uric acid or tendon rupture associated with therapy.
References
1. Marrs JC, et al. Drugs Context. 2020; 9: 2020-6-5. 2. Di Minno A, et al. J Am Heart Assoc. 2020; 9: e01626. 3. Lamb YN, et al. Drugs. 2021; 81(3): 389-395. 4. Cupido AJ, et al. Cardiovasc Res. 2020; 116(11): e136-e139. 5. Jahangir A, et al. Cureus. 2021; 13(7): e16664. 6. Rashid S, et al. Proc Natl Acad Sci U S A. 2005; 102(15): 5374-5379. 7. Bendepoic acid [prescribing information].
Esperion Therapeutics; September 2021.
Accessed June 8, 2022. https: //pi.esperion. com/nexletol/nexletol-pi.pdf 8. Bempedoic acid with ezetimibe [prescribing information]. Esperion
Therapeutics; September 2021. Accessed
June 8, 2022. https: //pi.esperion.com/ nexletol/nexletol-pi.pdf 9. Ray KK, et al. N Engl J Med. 2019; 380(11): 1022-1032. 10. Goldberg AC, et al. JAMA. 2019; 322(18): 1780-1788. [Published correction appears in
JAMA. 2020; 323(3): 282]. 11. Laufs U, et al. J Am Heart Assoc. 2019; 8(7): e011662. 12. Ballantyne CM, et al. Atherosclerosis. 2018; 277: 195-203. 13. Ballantyne CM, et al. Eur J Prev Cardiol. 2020; 27(6): 593-603. 14. FDA. FDA approves add on therapy to lower cholesterol among certain high risk adults. December 22, 2021. Accessed June 8, 2022. https: //www.fda.gov/drugs/newsevents-human-drugs/fda-approves-addtherapy-lower-cholesterol-among-certainhigh-risk-adults 15. Raal FJ, et al. N Engl J Med. 2020; 382(16): 1520-1530. 16. Ray KK, et al. N Engl J Med. 2020; 382(16): 1507-1519.
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OUD Pharmacists
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Dr. Hagedorn and her colleagues want to increase access to buprenorphine and other OUD medications in the primary care setting as well as at pain and mental health clinics. “Traditionally, within the VA, medications for OUD have been provided in specialty care settings for people with substance use disorders,” she said. “But there’s a need to expand access as much as possible.”
Clinical pharmacists involved in the Minneapolis program are partnering with physicians who have buprenorphine prescribing powers under a collaborative care agreement, specifically managing patients with chronic pain. Under the agreement, pharmacists can prescribe naloxone but not buprenorphine, and they can prescribe nonopioid medications for pain as well as drugs for opioid withdrawal and alcohol use disorder. They also: • coordinate social services; • assess medication efficacy and safety; • make necessary drug adjustments; • order and address urine drug screens; • query the prescription drug monitoring program database to reduce the risk for opioid-related harms; and • provide medication education to patients.
“The pharmacists provide important support to physicians, who already have large caseloads and might not have the time to follow up and support buprenorphine recipients as much as they would like to,” Dr. Hagedorn said.
Clinical pharmacists perform initial patient questionnaire-based screenings, then refer patients who screen positive for OUD to the partner prescriber for a diagnosis of OUD and obtain a prescription for buprenorphine. The pharmacist can then initiate treatment and provide regular follow-up appointments with the patient.
“The pharmacist might check in with the patient every week or few weeks at the start of treatment and reduce the frequency as the patient stabilizes, and the prescriber would only need to follow up in the clinic every six months to a year,” Dr. Hagedorn said.
A feasibility study published in 2021 looked at the effectiveness of the program. The researchers found that the percentage of Minneapolis VA Health Care System primary care patients with OUD who received medical OUD treatment increased from 33.8% during a three-month period in 2017, to 46.7% during a three-month period in 2019, after the program was rolled out (Am J Health Syst Pharm 2021;78[4]:354-359). Of 109 patients managed by pharmacists during the post-implementation study period, 47 had their buprenorphine treatment initiated by the clinical pharmacist.
“The program demonstrated that clinical pharmacists can play a key and essential role in the management of patients with OUD,” Dr. Hagedron said. Not only does this benefit patients, “it allows for closer monitoring of patients than would otherwise fit within the prescriber’s scheduling capability,” Dr. Hagedorn noted. She added that the program’s success prompted the VHA to implement the model at other VA sites nationwide.
Transition of Care As an Opportunity
Although new models of outpatient access to medications for OUD are being investigated in the community pharmacy setting, health-system pharmacists in the emergency department can play an important role in helping patients with OUD access treatment, said Courtney Givens, PharmD, the mental health and pain clinical pharmacy program manager at the VA North Texas Health Care System, in Dallas. She told ASHP attendees that 5.5% of patients admitted to the emergency department for a nonfatal opioid overdose succumb to a subsequent overdose within 12 months of discharge, and the highest risk for fatal overdose is in the first two to 30 days after discharge (Ann Emerg Med 2020;75[1]:13-17).
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“It’s really important to act in a timely fashion and intervene in these patients, particularly to initiate buprenorphine in the emergency department,” Dr. Givens said. Doing so can increase levels of patient engagement in outpatient treatment more than when a patient is simply handed a referral for outpatient care and they leave the emergency department without starting buprenorphine and medications in hand, she noted (JAMA 2015;316[16]:1636-1644).
“Patients are often the most motivated during the transition of care, and we shouldn’t miss these opportunities for treatment engagement,” Dr. Givens stressed.
Reducing Stigma Another Care Component
Providing more low-barrier, pharmacy-based access to medications for OUD could change the OUD treatment landscape and help control the ongoing opioid epidemic, but “addressing stigma may just be as important as anything else that pharmacists can do in practice,” said Tera Moore, PharmD, the national program manager of integration and model advancement at the VA Administration, in Washington, D.C.
“We challenge you to be leaders in change to eliminate stigma,” Dr. Moore told ASHP meeting attendees. “Whether it’s family members, other healthcare providers or patients themselves, always remind people that opioid use disorder—and other substance use disorders—should be thought of the same as any physical chronic disease.”
Jeffrey Bratberg, PharmD, a clinical professor at the University of Rhode Island, in Kingston, and a coordinator of the initiative, echoed this call to action. Dr. Bratberg added that the quality of pharmacist–patient interactions can have a profound impact on a patient’s willingness to engage in treatment. “One friendly, empathetic pharmacist treating a patient with OUD— whether they’re getting medication or buying syringes—can go a long way in getting them to engage in treatment.”
The sources reported no relevant financial disclosures.
More on the Web
For a ‘no-barrier’ OUD community practice model, see expanded version on www. pharmacypracticenews.com.
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6 Tips on Transitioning To Outpatient OUD Care
Emergency department pharmacists and providers have a unique opportunity to help patients with opioid use disorder (OUD) receive treatment, according to Courtney Givens, PharmD, the mental health and pain clinical pharmacy program manager at the VA North Texas Health Care System, in Dallas. In addition to initiating buprenorphine in the emergency department, she shared some tips on how to increase the likelihood that patients will remain in treatment after their transition to the community or primary care setting. Arrange follow-up. This can take some work in getting to know what resources are available to the patients served in your practice area and which providers are available to prescribe buprenorphine or other medications for OUD. Provide education. Engage the patient and make sure they know what their treatment options are. Empowering them can increase the likelihood of treatment retention. Ensure continuity of treatment. If the patient is started on buprenorphine or other medications for OUD, make sure there’s a plan in place for how they will continue their therapy outside the hospital. Interruptions in therapy can be very detrimental and they increase the risk for overdose. Consider a harm reductionapproach. Ensure patients have the resources they need to protect themselves and prevent worst-case scenarios, rather than simply aiming to achieve opioid use abstinence. Provide a warm handoff, when possible. Personalizing the experience for the patient and making sure they are presented to other providers as a unique individual can go a long way in making them feel valued and respected. That positive regard assures them they’re receiving optimal care and can help retain them in care.
Make sure people in thepatient’s care support system have the facts.
Challenge stigmas and myths about OUD and related treatment so everybody involved—family, friends, physicians and outpatient pharmacists—can be on the same page and help reduce the risk for harm to the patient. Provide them with information on the importance of continuing medication use and of supporting the person experiencing the substance use disorder.
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Paxlovid: Know the Risks
continued from page 1
Jason Gallagher, PharmD, BCPS, a clinical professor at Temple University School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital, in Philadelphia, said there are, without a doubt, instances when not prescribing nirmatrelvir-ritonavir is completely justified. “Sometimes interactions exist that are manageable, and sometimes there are interactions that preclude the use of the combination altogether,” he said.
There are sufficient resources available to help practitioners make the right decisions about prescribing nirmatrelvir-ritonavir to the patients who may benefit, Dr. Gallagher noted. That position was echoed by Melanie Thompson, MD, the co-chair of the HIVMA/IDSA HIV Primary Care Guidance Panel, during the briefing.
Last December, the FDA issued an emergency use authorization for Pfizer’s oral tablets for adults and children 12 years of age and older and weighing at least 88 pounds who have tested positive for SARS-CoV-2 and are at high risk for hospitalization and death.
Nirmatrelvir-ritonavir should be administered within five days of symptom onset, and can be prescribed to people who have been vaccinated and boosted. The FDA issued a variety of videos and fact sheets on the regimen, including a healthcare provider fact sheet (bit.ly/3MgLlf4), which details interactions due to CYP3A4 drug metabolism (Table) and other considerations affecting medication management.
Dr. Gallagher said nirmatrelvirritonavir only works on the viral phase of the disease. The timing for dispensing the medication to reduce the severity of COVID-19 is crucial. The guidelines (bit.ly/3zgoMnL) help reduce confusion over nirmatrelvirritonavir to speed administration during the critical period following the presentation of symptoms.
Dr. Gallagher stressed the importance of the guidelines and education, because some patients may receive their routine medications from one pharmacy while receiving nirmatrelvirritonavir from another. And if “those two pharmacies aren’t talking to each other, there is obviously the concern that something could be missed.”
Of the top 100 prescribed drugs, the guidelines flag only two—rivaroxaban and salmeterol— that have interactions so severe that nirmatrelvir-ritonavir should be avoided altogether. Dr. Gallagher said the interaction
with these commonly prescribed medications might be managed by withholding them during the short course of nirmatrelvir-ritonavir treatment, if that can be done without severely adversely affecting the patient.
Dr. Thompson said drug interactions with nirmatrelvir-ritonavir are mostly manageable but not necessarily easy. “One of the things that IDSA has done so well with the guidance is to really spotlight the commonly used drugs. I think this will be very helpful to clinicians,” she said. However, she said, many of the less frequently prescribed medications also have very important interactions with nirmatrelvir-ritonavir. They are not listed in the IDSA guidelines, “which is where all the complexity really comes in,” she said.
Dr. Thompson said ritonavir boosts the levels of many drugs, which can cause side effects, such as toxicities. But some drugs are inducers instead of inhibitors that actually can diminish nirmatrelvir-ritonavir’s efficacy, and they are handled differently.
“Some of the drugs whose concentrations are increased by ritonavir can either be held or the dose can be reduced, so the side effects can be managed by holding the drug, changing the drug or dose reduction,” Dr. Thompson said. “There are a few drugs, the inducers, that will lower levels of nirmatrelvir-ritonavir and threaten its efficacy. Their activity lasts several weeks even after being stopped, so nirmatrelvir-ritonavir cannot be used if these drugs have been taken recently. Some seizure medications and tuberculosis medications are strong inducers.”
Dr. Thompson listed a variety of medications that are not among the top 100 prescribed drugs that have interactions with nirmatrelvir-ritonavir, such as antiarrhythmics, seizure medications, immunosuppressants, cancer drugs, migraine medications, treatments for gout, pulmonary hypertension medications and some mental health drugs. Even St. John’s wort, which is an herbal remedy often used for depression, is a strong inducer, and nirmatrelvir-ritonavir cannot be used within two weeks of the last dose of the herb, she said.
“Some drugs just can’t be used, while others can be managed with dose changes,” she said. “This is an area where I think clinicians are going to need help. We don’t want clinicians to say, ‘Oh, I’m not going to bother with it because it’s way too complicated.’ We can all learn this. It’s something that you don’t have to memorize. There are resources that are very helpful in terms of drug interactions.”
In addition to the IDSA guidelines, Dr. Thompson highlighted two additional valuable sources, both of which focus on COVID-19 drug interactions. One is from the University of Liverpool, England, which is famous for its pharmacology department (bit.ly/3ami7xQ). “It has a wonderful drug interaction website for COVID-19 drugs,” she said. The other, from the University of Waterloo in Ontario, Canada, “has a really good handout [bit.ly/3Nfux9C] that you can print out, preferably in color, to cover drug interactions.”
As for risk stratification, older patients need special attention, Dr. Thompson said, because “they [have] the most comorbidities and are precisely the population most likely to benefit from Paxlovid. But they’re also the most likely to be on the most drugs. This becomes very complicated.”
Dr. Thompson stressed, “We need a 24/7 clinician hotline for Paxlovid.”
—Jason Gallagher, PharmD
Special Dosing Considerations: Renal Function
eGFR 30 to 59 mL/min: Nirmatrelvir 150 mg and ritonavir 100 mg taken together orally twice daily for 5 days.
Severe hepatic impairment (Child-Pugh class C):
Nirmatrelvir-ritonavir is not recommended.
Table. The Ups and Downs of CYP3A4 Drug Interactions
Nirmatrelvir and ritonavir are both CYP3A4 substrates. Thus, the combination is contraindicated in patients taking medications that are: • highly metabolized by CYP3A4, where elevated concentrations can be life-threatening; and • potent CYP3A4 inducers, which may reduce the efficacy of nirmatrelvirritonavir and contribute to the development of drug resistance.
Drugs That Cause Elevated Nirmatrelvir-Ritonavir Concentrations Drugs That Cause Reduced Concentrations
• Alpha1-adrenoreceptor antagonist: alfuzosin • Analgesics: pethidine, propoxyphene • Antianginal: ranolazine • Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine • Anti-gout: colchicine • Antipsychotics: lurasidone, pimozide, clozapine • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine • HMG-CoA reductase inhibitors: lovastatin, simvastatin • PDE5 inhibitor: sildenafil when used for PAH • Sedative/hypnotics: triazolam, oral midazolam • Anticancer drugs: apalutamide • Anticonvulsant: carbamazepine, phenobarbital, phenytoin antimycobacterials: rifampin • Herbal products: St. John’s wort (hypericum perforatum)
CYP3A4, cytochrome P450 3A4; HMG-CoA, hydroxy-methylglutaryl-CoA; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase-5. Source: University of Waterloo School of Pharmacy (bit.ly/3Nfux9C); FDA Fact Sheet (bit.ly/3MgLlf4).
Pediatric COVID-19 Label Mix-Ups
continued from page 1
pharmacists, pediatricians and parents in the fight against the COVID-19 pandemic, which is why the two mRNA vaccines by Pfizer-BioNTech and Moderna are now recommended for children as young as 6 months old.
However, the vial label for the PfizerBioNTech vaccine meant for this age group and the box label for the Moderna vaccine meant for children 6 to 11 could cause confusion—and actually hinder this vaccination mission, according to the experts interviewed.
2 Pfizer-BioNTech Discrepancies
The Pfizer-BioNTech vaccine label has two discrepancies.
The first concerns the age of vaccination. The label says the vaccine should be used for children “2y to <5y,” when it should, in fact, be used for children as young as 6 months old.
What could happen, according to experts, is that clinicians will see that label, believe they have the incorrect product and send the child home without being vaccinated. Parents would have to bring their infants and toddlers back. Many might not.
“I [fear that] people are going to pick up the vial that says it’s for a 2-year through 5-year-old, and they are just going to think, ‘This is not appropriate for a 12-month-old or an 18-month-old, or a 6-month-old.’ They are going to [assume] they got the wrong [vaccine]. It is going to delay vaccination, and it is going to inconvenience people,” said Michael Cohen, RPh, MS, ScD (hon.), DPS (hon.), the founder and president emeritus of the Institute for Safe Medication Practices.
Buddy Creech, MD, MPH, the Edie Carell Johnson Chair and a professor of pediatrics in the Division of Pediatric Infectious Diseases at Vanderbilt University School of Medicine, in Nashville, Tenn., agreed that the labeling is problematic. “Since the dosing is the same for 6 months to under 5 years [as it is for those 5 years and older], thankfully, we shouldn’t run into errors; however, vaccine waste is definitely an issue,” he said. “I can see clinics following the label, drawing up vaccine at 8 a.m. and discarding by 2 p.m., since that is what the label says.”
Dr. Creech’s comment on waste highlights the second label discrepancy.
The label says the vaccine should be discarded after six hours, when it actually can be discarded after 12 hours, according to the CDC (bit.ly/3RmzwI2).
This could be a very expensive error. Although patients are not paying for COVID-19 vaccines or their administration, the government has spent hundreds of billions of dollars to develop, purchase and administer the vaccines, according to a March 29, 2021 congressional report (bit.ly/3R9bCQd-PPN). (As an example, on June 29 Pfizer announced a new vaccine supply agreement with the U.S. government that includes 3-mcg doses valued at $3.2 billion.)
“The labeled six-hour in-use time may lead to waste,” said Michael Ganio, PharmD, MS, the senior director of Pharmacy Practice and Quality at ASHP. “Initially, sites should have no problem using the 10 doses [in each vial] in six hours, but as interest in vaccinating this age group declines, there will be wasted vaccine, even if a 12-hour in-use time is followed.”
Moderna Discrepancy
Moderna’s inconsistency occurs on the purple box for children 6 to 11 years old. The pink box for those 6 months to 5 years is correctly labeled, Moderna said in an email.
The purple box label says the bottle contains “booster” doses, rather than vaccines to be used for the primary series in children 6 to 11 years.
This could lead to someone believing they have the wrong product and not providing people with vaccination, according to Mr. Cohen.
“These discrepancies really bother me,” said Mr. Cohen, who has dedicated his life
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to helping people avoid making errors in the healthcare system. “They [clinicians] are going to think they have the wrong [vaccine], so it is going to delay [vaccination] and inconvenience people,” he said.
Experts told Pharmacy Practice News that the labeling isn’t likely to cause an administration error or safety issue, but instead cited the potential for missed vaccinations and waste.
“We would not expect the labeling to cause an administration error, since no other vaccine can be used for children under 2 years old,” Dr. Ganio said. “However, as noted, it may lead to confusion and possibly delay vaccination. Agerelated vaccine mix-ups have been the most common vaccination errors, so it will be important for vaccinators to be aware of this discrepancy.”
Jason G. Newland, MD, MEd, a professor of pediatrics at Washington University in St. Louis, agreed that these labeling discrepancies “obviously will result in [vaccine] not being used for all ages. I hope this label is being corrected as soon as possible.”
However, it does not appear as if the label is being corrected—at least not immediately, according to the CDC, which said it was also concerned about the discrepancies. “This mislabeled product may cause confusion,” said Elisha Hall, PhD, the clinical guidelines lead at CDC. Dr. Hall was scheduled to present the label information at a June Advisory Committee on Immunization Practices (ACIP) meeting, but could not, so CDC’s Sara Oliver, MD, MPH, presented it.
The CDC “is working diligently to communicate information about the label to vaccine providers to avoid and correct any confusion,” Dr. Hall told Pharmacy Practice News. (See box.)
The correct label will appear on vaccine vials manufactured after the EUA was granted for this age group, Pfizer stated in an email.
Labeling Fix Suggested
At the ACIP meeting, ACIP member Sarah S. Long, MD, a professor of pediatrics at Drexel University College of Medicine, in Philadelphia, suggested the company print new labels with an adhesive back that could be placed over the incorrect information, but there was no indication that that would be done.
The FDA, which did not respond to multiple requests for comment, also has provided information about this label discrepancy on the first page of the emergency use authorization (EUA) fact sheet for healthcare providers in bold print (bit.ly/3nD52nk).
Mr. Cohen said the Pfizer-BioNTech label for 2-year-olds has been available and discussed since December 2021, so he is unsure why that label is being used. “I never thought the 2-year label would be used as a label for those vials [for 6-month-olds].”
Dr. Creech said good communication, such as the CDC is doing, as well as training should improve the situation and ensure that children are vaccinated. “Realistically, I think these are preventable issues.”
However, both Drs. Newland and Long said the complicated logistics involved in getting a vaccine from the
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The Moderna box for its COVID-19 vaccine says the bottle contains “booster” doses, rather than telling clinicians it should be used for the primary series in children 6 to 11 years.
manufacturer to the physician’s office, pharmacy or vaccination center into a patient’s arm could be a hindrance to any type of communication.
“It is a challenge to reach every practice/other site where vaccinations may be given,” said Dr. Long, who added that she has received several missives from the producers to be aware of these issues.
EUA Versus Approval
The FDA would never have let these types of packaging inconsistencies fly with an approved product, according to Mr. Cohen. “Absolutely, for an approved product, this would never be allowed,” he said, “but the product is not an FDA-approved product; it is an EUA product.”
Pfizer also cited the EUA process as a partial explanation for the label discrepancies. “In order to ensure rapid access to the Pfizer-BioNTech COVID-19 vaccine for ages 6 months to less than 5 years as soon as possible following the FDA granting an [EUA], the companies manufactured and labelled doses at-risk—as has been the case with all previous formulations of the vaccine,” the company said in the email. “Given the at-risk manufacturing, labels on the doses initially shipped after the EUA may not reflect the final age group authorized by the FDA or the final authorized storage conditions.”
Pfizer also stressed that the vaccine doses “meet all the appropriate standards and authorizations,” and reiterated that “the updated labels have been applied to all doses manufactured since the EUA was granted.”
Mr. Cohen said throughout the pandemic, information about the EUA products has changed, and the FDA has updated fact sheets and sent announcements highlighting the changes. These steps were taken repeatedly for the monoclonal antibodies as their efficacy changed against different variants. “So, changes in some of the information is not unusual,” he said. “But I have not seen a label discrepancy like this before.”
3 CDC Action Steps
1. Highlighted the COVID-19 vaccine labeling discrepancies on multiple webinars and calls that have been “highly attended,” and distributed written information to attendees; 2. Posted its Interim Clinical
Considerations for Use of
COVID-19 Vaccines, which includes information about the label error (bit.ly/3NF6qAl). 3. Provided printable products that include a storage and handling label (bit.ly/3R9NPj0) with the correct age and beyonduse time that can be put on the vaccine carton, as well as a printable infographic (bit. ly/3IdYPaW) providers can hang in their designated vaccine preparation area to reminder vaccinators about the label discrepancy.
Dr. Creech is a principal investigator for the KidCOVE study by Moderna, with NIH funding. The other sources reported no relevant financial disclosures.
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