PHARMACY NEWSLETTER Q1 – Q2 2021

CONTENT COVID-19 TREATMENT UPDATES COVID-19 TREATMENT Vaccine-Induced Thrombotic Thrombocytopenia UPDATES Shortly after widespread administration of cHaDOx1 nCoV-19 (Astra Zeneca), MEDICATION SAFETY an adenovirus vectored vaccine, case reports of severe thrombosis with thrombocytopenia emerged. In April 2021, the FDA briefly paused continued

ANTIMICROBIAL distribution of AD26.COV2.S (Johnson & Johnson), similarly an adenovirus vectored vaccine, due to observation of several cases of thrombosis with STEWARDSHIP thrombocytopenia syndrome post-vaccination.

FORMULARY Vaccine-Induced Thrombotic Thrombocytopenia (VITT) resembles the well known immune-mediated adverse effect, Heparin Induced Thrombocytopenia POLICY UPDATES (HIT). Like HIT, VITT is characterized by a positive PF4-heparin ELISA indicating platelet activating antibodies, mild to severe thrombocytopenia, and venous or arterial thrombosis. The syndrome can result in cerebral venous sinus DRUG SHORTAGES thrombosis (CVST), portal vein thrombosis (PVT), and has progressed to disseminated intravascular coagulation (DIC). Although extremely rare, health care professionals should be knowledgeable in the recognition and treatment of this life-threatening adverse effect.

Prepared by Presentation and diagnosis of VITT are detailed elsewhere.1-4 Once VITT is suspected, treatment is similar to HIT. Several societal guidelines and expert Kaitlyn Moorehead, recommendations for management have been released and are summarized PharmD in the table below. Renu Bajwa, PharmD Ollie Liu, PharmD, Due to the ongoing research of the syndrome, treatment recommendations BCPS are subject to rapid change. Consultation with hematology is recommended. It should be emphasized that complications such as VITT following COVID-19 vaccination are exceptionally rare. Based on risk-benefit analysis, the Advisory Committee on Immunization Practices (ACIP) continue to recommend the use of all FDA authorized COVID-19 vaccines. Reports of VITT or any other serious adverse effects after COVID-19 vaccination should be submitted to the Vaccine Adverse Event Reporting System (VAERS) for continued surveillance of vaccine safety. Table 1. Summary of VITT Management Recommendations in patients with positive or pending ELISA1-4 Treatment Rationale IVIG 0.5-1g/kg q24h x 2 days Inhibits platelet activation. Resulted in rapid increases in platelet count and de-escalation of hypercoagulability in severe HIT treatment. Corticosteroids (e.g., prednisone 1-2 mg/) if May be helpful in suppression of immune reactivity. platelet count <50 x109/L Plasma Exchange q24h x 5 days if platelet Removes anti-PF4 antibodies. count remains <30 x109/L or fibrinogen<1 g/L Non-heparin therapeutic anticoagulation x Treatment of thrombosis avoids potential heparin- ≥3 months. dependent platelet activation. Analogous to HIT treatment although no direct evidence that heparin - Direct Thrombin Inhibitor products worsen VITT. (e.g. argatroban) - Direct Oral Anticoagulant Choice of agent depends on severity (e.g. rivaroxaban, apixaban) - Fondaparinux Avoid Rationale Platelet Transfusions Theoretical prothrombotic risk. Unknown whether platelet transfusion will exacerbate the condition. Higher mortality in HIT.

Assess risk/benefit in setting of acute hemorrhage or emergent surgical procedure following IVIG. Heparin products Unknown whether heparin products (including heparin flushed) will exacerbate the condition. Could trigger further platelet activation. Warfarin Results in early protein C depletion which can lead to further thrombosis. Aspirin Does not block platelet activation in VITT.

Monoclonal Antibody Recommendation Changes

Regeneron’s investigational monoclonal anti-viral antibody cocktail, casirivimab and imdevimab (REGEN-COV) has emerged as the NIH’s recommended monoclonal antibody regimen for non-hospitalized patients with COVID-19 at high risk for progression. Previously authorized mABs, such as bamlanivimab and bamlanivimab plus etesevimab are no longer recommended due to decreased efficacy versus circulating SARS-CoV-2 variants of concern including Delta, Beta, and Gamma. Several changes to the REGEN-COV EUA in recent weeks should be noted.5

Based on results from a Phase 3 study of REGEN-COV2 in outpatients, the FDA updated the authorized dose of casirivimab and imdevimab from 1200 mg of each component to 600 mg each. Furthermore, casirivimab 600 mg and imdevimab 600 mg doses can be administered subcutaneously when IV administration is not feasible. Administration of the 10 mL total volume must be divided into four 2.5 mL doses given in four different quadrants of the abdomen, upper thighs, or back of upper arms. Patients still must be observed for at least 1 hour following subQ administration.

The current REGEN-COV EUA continues to limit authorized use to nonhospitalized patients however recent news releases indicate Regeneron will seek expansion to include hospitalized patients. This is based on positive data from the Phase 3 RECOVERY trial which found hospitalized patients treated with REGEN-COV had a 20% reduced risk of death. We may see the EUA expansion as soon as this summer. MEDICATION SAFETY

Verbal & Telephone Orders Prone To Error DOSE OF 15 OR 50? Medication Error Report:

After consulting an endocrinologist, a medical resident ordered 50 units of insulin glargine for a pediatric patient. A pharmacist confirmed the high dose with the resident, who mentioned that the endocrinologist seemed tired when they spoke. Upon investigation, the endocrinologist stated he ordered 15, not 50, units during the phone consultation.

Strategies for Safer Communication:

When verbalizing medication orders, state the dose the way pilots state numbers (e.g., “15 units” stated as “one-five units”). Always follow through with read-back, where the listener documents what is heard and then reads it back to the speaker to ensure the order was heard and transcribed correctly. When possible, remove a mask and face shield when speaking by phone.

Following a verbal read-back to the prescriber, recipients of verbal orders should request confirmation from the prescriber that the read-back matches the intended order.

STAR Reporting

Medication event reporting is critical to medication safety. CMHS utilizes STAR for event reports. Every medication event is investigated and presented to the Medication Error Reduction Program (MERP) committee. MERP analyzes the errors and develops improved medication processes to enhance patient safety.

The more information collected from initial STAR report, promotes a more robust analysis and response. Providing contributing factors allows the MERP to identify patterns and direct improvements. The STAR event submission form includes an optional field for Contributing Factors. Pre-existing factors for selection include Administration, Drug Information, Labelling, Drug Storage or Delivery, Environment, Lack of Quality Control, Lack of Staff Education, Miscommunication of Drug Order, Monitoring, Organization, Patient Education, Patient Info Missing, Preparation, Prescribing, and Staff-specific factors.

When entering events into STAR, please report contributing factors in the General information about the event. lPharmaceutical Waste Reminder

Table 2. Excerpt from CMHS Pharmaceutical Waste Disposal Gudelines

Recyclable waste Drain Disposal Pharmaceutical Waste -Empty, intact glass or plastic -Liquid dextrose, saline, sterile water, -Partially used or wasted prescription bottles/vials that are not and/or lactated ringers solutions or OTC medication associated with medications -Potassium salts -Syringes, needles, and/or carpujects with -Nonconfidential/Non PHI paper -Magnesium salts pourable medication -Newspapers, Magazines -Calcium salts -IV bags and tubing with pourable medication -Plastic bottles or containers -Other electrolytes to which no other drug -Epinephrine, Nitroglycerin, Insulins -Aluminum cans has been added -Empty medication containers, e.g.,syringes, -Small, empty cardboard boxes IV bags, tubing, bottle vials, insulin (e.g, glove boxes) containers, inhalers, epinephrine syringes

Standardized Vaccine Abbreviations

The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) provides a list (Table 1) of standardized abbreviations or acronyms for FDA-approved vaccines. The list includes most single and combination vaccines but not all. CDC believes this list will promote accuracy, consistency, and convenience, and will reduce errors and ambiguity in vaccine labelling, medical practice and scientific publications.

ANTIMICROBIAL STEWARDSHIP

Surgical Prophylaxis Guideline Update

Surgical site infections (SSI) are a source of significant morbidity and mortality post-operatively. SSIs are estimated to occur in up to 4% of all patients undergoing inpatient surgical procedures5 and can cost over $25,000 per case.6 Surgical teams utilize several measures to prevent SSIs such as hand hygiene, PPE, patient skin prep, hair removal, and when indicated, preoperative antibiotics. Appropriate selection, dose, timing, and duration of antimicrobial prophylaxis can prevent SSIs without excess harm commonly associated antibiotics.

As reportable health care associated infections (HAI), SSIs are closely monitored by institutional Infection Prevention teams. Recent audits and literature reviews performed by Main OR Nursing, Infection Prevention, and Antimicrobial Stewardship identified procedures in which routine preoperative prophylaxis may not be necessary. These low-risk of infection procedures include but are not limited to: D&C for non-pregnancy indications, hysteroscopy,7 dermatologic procedures without breech of oral mucosa,8 tonsillectomy, clean-contaminated head and neck surgery,9 laparoscopic cholecystectomy in patients without increased risk for infectious complications.10

Clinicians may refer to specialty guidelines for more detailed lists of procedures and prophylactic regimen recommendations. Decisions to follow the updated CMHS recommendations must be based on the clinical judgement and patient-specific factors.

Antibiotic Indications

Pharmacists at CMHS have performed pharmacokinetic dosing and monitoring of narrow Table 3. Proposed Antibiotic Indication List therapeutic index antibiotics such as vancomycin Indication or Presumed source and aminoglycosides for decades. Our dosing Bloodstream responsibilities were expanded with the approval of Bone and/or Joint a Renal Dose Adjustment per Pharmacy Policy and C. difficile Protocol in early 2021. To optimize dosing, an Central Nervous System indication for antimicrobial use is crucial. For example, the therapeutic targets and therefore dose Community Acquired Pneumonia (including Community of vancomycin can vary considerably when treating Acquired Aspiration Pneumonia) cellulitis versus meningitis. Consulting pharmacists Diabetic Foot infection without indication information available may select Empiric therapy for unclear source an inappropriate dosing regimen that impacts Febrile neutropenia patient outcomes in achieving pharmacokinetic and Hospital or ventilator associated pneumonia (including clinical goals. Healthcare-Associated Aspiration Pneumonia) Intra-abdominal Additionally, documentation of antibiotic indications Pelvic can facilitate other stewardship interventions, like Prophylaxis- medical/surgical prospective audit and feedback and optimizing post- discharge durations of therapy, and, in and of itself, Skin and soft tissue can improve antibiotic use.11 Finally, including a Urinary tract infection or Prostatitis suspected or definitive indication upon antibiotic Other- please specify in comments prescribing minimizes the clarifying phone calls and texts from pharmacy to physicians, NPs, and PAs.

Vanco Dosing Reminders

 Loading doses for vancomycin are utilized to rapidly achieve target concentrations in the first 24 hours in the critically ill or patients with serious infections. A loading dose of 20-25 mg/kg based on actual body weight is recommended, with our institutional max of 2 g. A recent update to our therapeutic substitution policy allows pharmacists to adjust doses ordered in the Emergency Department to the appropriate weight-based loading dose. These dose adjustments by pharmacists will be entered directly in Picis.

 Dosing vancomycin in Acute Kidney Injury requires intensive pharmacy monitoring. A loading dose followed by a level 24 hours post-dose is an effective strategy to attain therapeutic levels when renal function is rapidly fluctuating. When the post dose level is below 20 mg/L, re-dose the vanco. This process can be repeated until renal function stabilizes.

FORMULARY

Non-Formulary Psychotropics

CMHS has multiple antipsychotics, antidepressants, and mood stabilizers on formulary for continuation or initiation in hospitalized patients. However if a patient is maintained on a regimen prior to admission that is not consistent with our formulary options, missed doses may occur. Abrupt discontinuation of therapy for psychotropic and antipsychotic medications may withdrawal symptoms such as hyperarousal, sensory disturbances, and insomnia, all of which may emerge within the first few days after stopping the medication. There is a large body of literature which shows the negative impact of acute drug withdrawal on acute care admissions – oftentimes new-start antipsychotics used to treat ICU delirium, use of restraints, and increased length of stay. As we are working on measures to address anxiety and aggression in patients to increase both patient and staff safety, this could be an item to keep in mind.

The patient’s own non-formulary medication policy and procedure can be applied to avoid interruption in therapy. Cefotaxime Removed from Formulary

In late 2015, Baxter discontinued Cefotaxime (Claforan) injection production. In the following years, Hospira, Sanofi- Aventis, and Hikma similarly discontinued the product. This resulted in persistent, critical Cefotaxime shortages in the United States. The FDA even allowed temporary importation of the injectable from Canada.

However, cefotaxime’s primary role in the management of neonatal and pediatric infections has been filled by alternative, although broader ceftazidime. With neonatologist approval, P&T removed Cefotaxime from formulary in March 2021.

POLICY UPDATES

Patient’s Own Prostacyclin Pump Policy

A new policy, “Use of Patient Owned Prostacyclin Pumps in the Hospital” was approved by Nursing Directors in February 2021. Its purpose is to provide guidelines for patients admitted on a prostacyclin pumps. Serious and even fatal errors can occur with this therapy.

Prostacyclins are a class of drugs used to treat Pulmonary Arterial Hypertension. Continuous infusions of epoprostenol (Flolan, Veletri) and treprostanil (Remodulin) are life sustaining for patients with advanced PAH. Patients of caregivers self-manage ambulatory infusion pumps outside of the hospital. Due to the short half-life of these agents, even a brief interruption can lead to rapid decompensation and cardiovascular collapse.

To ensure safe, timely, and accurate patient self-administration of prostacyclin infusions, this policy outlines procedures for both pharmacists and nurses to follow. Pharmacists should be aware of the risks of disruption of prostacyclin infusions and be able to educate nurses who may not have experience in caring for a patient on a prostacyclin pump.

Look out for the final version in Intelex soon!

Medication Administration Policy Addition

To ensure the complete dose of a small IVPB is infused into the patient, CMHS is standardizing infusion practices for administering intermittent small volume IVs of 100 mL or less. The following procedure was added to HS- NUR140 Administering intermittent small volume IVs :

i. For IVPB volumes of 100 mL or less, the recommendation is to run the medication as a secondary infusion. Reminder to open the secondary clamp to allow infusion. ii. Per policy, a pharmacist may add a 50 mL carrier fluid as a PRN entry onto the patient eMAR profile. This carrier fluid is used to flush the tubing at the same rate as the previous infusion to ensure the patient receives the full medication dose.

DRUG SHORTAGES Ongoing Shortages  Protamine  Conjugated Estrogens Vaginal Cream  Lidocaine + Epinephrine  Bupivacaine + Epinephine  Refresh Celluvisc  Lidocaine 4% Ampules

Resolved Shortages  IV Hydralazine  Enalaprilat

*not an all-inclusive list

References

1. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Jun 3;384(22):2092-2101. 2. International Society on Thrombosis and Haemostasis (ISTH). ISTH Interim Guidance for the Diagnosis and Treatment on VaccineInduced Immune Thrombotic Thrombocytopenia. Updated April 20, 2021. https://cdn.ymaws.com/www.isth.org/resource/resmgr/ISTH_VITT_Guidance_2.pdf. Accessed: June 21, 2021. 3. Pavord S, Lester W, Makris M, et al. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Updated May 28, 2021. https://b-s-h.org.uk/media/19718/guidance-v20-20210528- 002.pdf. Accessed: June 21, 2021. 4. American Society of Hematology (ASH). Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia). Updated: April 29, 2021. https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic- thrombocytopenia. Accessed: June 21, 2021. 5. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surgery. 2017;152(8). doi:10.1001/jamasurg.2017.0904. 6. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect Dis. 2018 Jan 18;66(3):329-336. 7. ACOG Practice Bulletin No. 195: Prevention of Infection After Gynecologic Procedures. Obstet Gynecol. 2018 Jun;131(6):e172-e189. doi: 10.1097/AOG.0000000000002670. PMID: 29794678. 8. Wright TI, Baddour LM, Berbari EF, Roenigk RK, Phillips PK, Jacobs MA, Otley CC. Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. J Am Acad Dermatol. 2008 Sep;59(3):464-73. doi: 10.1016/j.jaad.2008.04.031. PMID: 18694679. 9. Patel PN, Jayawardena ADL, Walden RL, Penn EB, Francis DO. Evidence-Based Use of Perioperative Antibiotics in Otolaryngology. Otolaryngol Head Neck Surg. 2018 May;158(5):783-800. doi: 10.1177/0194599817753610. Epub 2018 Feb 6. PMID: 29405833. 10. Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, Fish DN, Napolitano LM, Sawyer RG, Slain D, Steinberg JP, Weinstein RA; American Society of Health-System Pharmacists (ASHP); Infectious Diseases Society of America (IDSA); Surgical Infection Society (SIS); Society for Healthcare Epidemiology of America (SHEA). Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). 2013 Feb;14(1):73-156. doi: 10.1089/sur.2013.9999. Epub 2013 Mar 5. PMID: 23461695. 11. CDC. Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. Available at https://www.cdc.gov/antibiotic-use/core-elements/hospital.html.