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Series Editor: Mike O’Brien, PharmD

Quick evidence-based pearls on all things pharmacology and pharmacy-related in Emergency Medicine

EM Pharm Pearls: Estimated rise in blood glucose concentration with dextrose administration

A common question is how much should we expect the blood glucose concentration to increase after dextrose 50% (D50) administration. Fortunately, there is an answer from 3 studies.

  1. Balentine JR, Gaeta TJ, Kessler D, Bagiella E, Lee T. Effect of 50 milliliters of 50% dextrose in water administration on the blood sugar of euglycemic volunteers. Acad Emerg Med. 1998;5(7):691-694. doi:10.1111/j.1553-2712.1998.tb02487.x PMID 9678393
    • Population: Healthy volunteers in the ED
    • Intervention: 25 gm (1 ampule of D50)
    • Result: Mean increase of 162 mg/dL at 5 min. Glucose concentrations returned to baseline by 30 minutes.
  1. Murthy MS, Duby JJ, Parker PL, Durbin-Johnson BP, Roach DM, Louie EL. Blood glucose response to rescue dextrose in hypoglycemic, critically ill patients receiving an insulin infusion. Ann Pharmacother. 2015;49(8):892-896. doi:10.1177/1060028015585574. PMID 25986006
    • Population: Critically ill patients experiencing hypoglycemia while on insulin infusions
    • Intervention: D50
    • Result: Median increase of 4 mg/dL per gm of D50 administered
  1. Adler PM. Serum glucose changes after administration of 50% dextrose solution: pre- and in-hospital calculations. Am J Emerg Med. 1986;4(6):504-506. doi:10.1016/S0735-6757(86)80004-3. PMID 3778594
    • Population: ED patients with altered mental status (23 with diabetes, 28 without diabetes)
    • Intervention: 25 gm (50 mL of D50)
    • Result: Mean increase of 166 mg/dL

Take Home Points

  • Glucose concentrations increase 4-6 mg/dL per gm of dextrose administered
    • 50 mL of D50 = 25 gm = expected 100-150 mg/dL glucose rise
  • D50 rescue glucose is short-lived (30 minutes)
  • If the blood glucose does not respond as anticipated, investigate further (e.g., IV decannulation)

 

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

By |2022-07-14T18:25:07-07:00Jul 18, 2022|EM Pharmacy Pearls, Endocrine-Metabolic|
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Interpretation and Limitations of Opiate Urine Drug Tests

Background

Urine drug tests are commonly sent for patients in the emergency department, however care should be taken when interpreting the results of these tests given their limitations. The American College of Medical Toxicology published a position statement on the interpretation of urine opiate and opioid tests [1]. In this publication, they outline many of the limitations of opioid urine drug tests and explain why they exist.

Evidence

  • Though often used interchangeably, the terms opiate and opioid are not the same. ‘Opioid’ is the broad category name while ‘opiate’ simply refers to the naturally occurring opioids. The term ‘opioid’ encompasses opiates (e.g., morphine, codeine, opium), semi-synthetic agents (eg, heroin, hydrocodone, hydromorphone, oxycodone), and synthetic agents (eg, methadone, fentanyl, tramadol). Notice the name of the urine drug test next time you order one, it is likely specific for opiates (not opioids). This is because many tests are designed to identify morphine, though they will also detect codeine and heroin as they are both ultimately metabolized to morphine.
  • The standard urine drug tests do not specifically look for oxycodone, hydrocodone, etc. However, they can trigger a positive result due to their structural similarities, but not in every case. Therefore, a negative result doesn’t rule out use of these common drugs.
  • Similarly, synthetic opioids will not reliably cross-react with the opiate urine drug test as they are quite structurally dissimilar. In order to detect some of these agents, a test specific for the compound in question should be used.
  • As there are numerous different manufacturers of urine drug tests, hospitals may not utilize the same tests. In order to further understand the methods and cross-reactivity of a hospital’s specific urine drug test, the hospital’s laboratory should be contacted to request the package insert. Below is an example of the cross reactivity between various opioids with a opiate urine drug test [2].
Cross-reactivity of Various Opioids with Morphine Urine Drug Test [2]
CompoundEquivalent to 300 ng/mL Morphine (ng/mL)Cross-reactivity (%)
Codeine224134
Heroin36682
Hydrocodone1,08628
Hydromorphone1,42521
Oxycodone>75,000<0.4
Meperidine>100,000<0.3

 

Previous ALiEM posts discuss further limitations of urine drug tests, specifically for benzodiazepines and opiates.

Bottom Line

  • The term ‘opioid’ is the broad class of substances, while ‘opiate’ refers to the naturally occurring opioids (e.g., morphine, codeine)
  • Many urine drug tests are designed to identify morphine and will also detect codeine and heroin, as they are ultimately metabolized to morphine
  • Due to structural similarity, some semi-synthetic opioids may cross-react but fully synthetic opioids are unlikely to cross-react

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Stolbach A, Connors N, Nelson L, Kulig K. Acmt position statement: interpretation of urine opiate and opioid tests. J Med Toxicol. 2022;18(2):176-179. doi: 10.1007/s13181-021-00864-1. PMID: 34780053.
  2. Opiates II [package insert]. Indianapolis, IN: Roche Diagnostics; 2006.
By |2022-07-11T19:51:16-07:00Apr 23, 2022|EM Pharmacy Pearls, Tox & Medications|
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Should Diphenhydramine be included in an Acute Agitation Regimen?

Background

Acute agitation in the emergency department is a common issue that frequently requires the use of chemical sedation to preserve safety for patients and healthcare workers. A commonly employed treatment regimen is the combination of haloperidol 5 mg + lorazepam 2 mg + diphenhydramine 50 mg (B-52). Diphenhydramine is included in this treatment regimen primarily to prevent extrapyramidal symptoms [1,2]. However, the incidence of extrapyramidal symptoms (EPS) with haloperidol is quite low when treating agitation in the emergency department (ED) [3,4]. Therefore, the excessive and prolonged sedation from adding prophylactic diphenhydramine may outweigh the intended benefit and should be reserved for treatment of EPS if symptoms occur.

Evidence

Jeffers et al. conducted a multicenter, retrospective, cohort study which compared the efficacy and safety of haloperidol, lorazepam, and diphenhydramine (B-52) (n=200) vs. haloperidol and lorazepam (52) (n=200) in treating patients >18 years old with acute agitation in the ED [5]. Their primary outcome was the administration of additional agitation medication(s) within 2 hours.

Outcomes52 (n=200)B52 (n=200)p-Value
Administration of additional sedative within 2 h, n (%)40 (20)28 (14)0.11
Median ED LOS (hours)13.8170.03
Use of restraints, n (%)53 (26.5)86 (43)0.001
Hypotension, n (%)7 (3.5)32 (16)<0.001
Administration of anticholinergic within 2 days, n (%)15 (7.5%)6 (3%)0.04
    Itching/allergies, n (%)1 (0.5)1 (0.5)1.00
    Home benztropine, n (%)2 (1)4 (2)0.41
    Insomnia, n (%)4 (2)0 (0)0.06
    Unknown, n (%)8 (4)1 (0.5)0.02

 

Overall, the B-52 combination resulted in more oxygen desaturation, hypotension, physical restraint use, and longer length of stay. However, the conclusions from this study may be limited as it was a relatively small study and  it used surrogate markers to assess clinical endpoints.

Further discussion regarding the onset and duration of IM medications for acute agitation may be found in this blog post.

Bottom Line

  • The risk of extrapyramidal symptoms following haloperidol for agitation in the ED is relatively low
  • Diphenhydramine may not be necessary when using haloperidol + lorazepam to treat agitation in the ED
  • ED length of stay is increased with the addition of diphenhydramine to haloperidol + lorazepam

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Mokhtari A, Yip O, Alain J, Berthelot S. Prophylactic administration of diphenhydramine to reduce neuroleptic side effects in the acute care setting: a systematic review and meta-analysis. J Emerg Med. 2021 Feb;60(2):165–74. doi: 10.1016/j.jemermed.2020.09.031. PMID: 33131965.
  2. Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med. 2001 Feb;37(2):125–31. doi: 10.1067/mem.2001.113032. PMID: 11174228. 
  3. Klein LR, Driver BE, Miner JR, Martel ML, Hessel M, Collins JD, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med. 2018 Oct;72(4):374–85. doi: 10.1016/j.annemergmed.2018.04.027. PMID: 29885904.
  4. Schneider A, Mullinax S, Hall N, Acheson A, Oliveto AH, Wilson MP. Intramuscular medication for treatment of agitation in the emergency department: A systematic review of controlled trials. Am J Emerg Med. 2021 Aug;46:193–9. doi: 10.1016/j.ajem.2020.07.013. PMID: 33071100.
  5. Jeffers T, Darling B, Edwards C, Vadiei N. Efficacy of combination haloperidol, lorazepam, and diphenhydramine vs. Combination haloperidol and lorazepam in the treatment of acute agitation: a multicenter retrospective cohort study. J Emerg Med. 2022 Mar 11;S0736-4679(22)00057-9. doi: 10.1016/j.jemermed.2022.01.009. PMID: 35287982.
By |2022-04-09T10:15:43-07:00Apr 16, 2022|EM Pharmacy Pearls, Psychiatry, Tox & Medications|
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Are Thrombolytics Safe for Acute Ischemic Strokes in Patients on DOACs?

Background

Direct-acting oral anticoagulants (DOACs), including apixaban, rivaroxaban, edoxaban, and dabigatran, are widely used for various indications and considered first-line therapy for prevention of acute ischemic stroke in patients with nonvalvular atrial fibrillation [1]. The management of acute ischemic stroke in patients on DOACs presents a difficult clinical scenario in the emergency department due to concern for increased risk of hemorrhage. IV thrombolytics (e.g., alteplase, tenecteplase), a mainstay in acute ischemic stroke management, are not recommended in current guidelines for patients whose last DOAC dose was within the last 48 hours [2, 3]. Therefore, patients with an acute ischemic stroke who are compliant with their DOACs are often excluded from guideline recommended therapy. Additionally, as covered in a previous ALiEM post, it is not recommended to reverse anticoagulation status in order to administer a thrombolytic.

Evidence

The use of IV thrombolytics in patients on DOACs was evaluated by Kam et al in a 2022 study published in JAMA [4]. This retrospective analysis included 163,038 patients from the AHA/ASA Get With The Guidelines-Stroke registry with acute ischemic stroke who received IV alteplase within 4.5 hours of symptom onset. Of the total number of patients, only 2207 had documented use of a DOAC within the last 7 days, with 25 of these patients reporting DOAC use within 48 hours. Patients on warfarin or other anticoagulants were excluded. The primary outcome was symptomatic intracranial hemorrhage (ICH) within 36 hours of IV alteplase administration. After adjusting for clinical factors, the rate of symptomatic ICH was not significantly different between patients taking DOACs and those not on anticoagulation (3.7% vs. 3.2%, adjusted OR 0.88, 95% CI 0.70 to 1.10). However, when stratified based on time from last DOAC dose, patients who took their DOAC 0-48 hours prior had an 8% rate of symptomatic ICH compared to 3.2% among those not on DOACs. Furthermore, the rate of any alteplase complication was 12% vs. 6% in those taking DOACs within 48 hours vs. no DOAC.

Limitations

  • The population at highest risk for bleeding is patients who took a DOAC within the last 48 hours, and this study only included 25 such patients.
    • A similar study tried to answer the same question for warfarin patients with an INR between 1.5-1.7. They also failed to include enough patients to make any definitive conclusions. [5]
  • Timing from the last DOAC dose was given as a range, with the majority of patients reporting use sometime within the last 7 days. It has been established in current AHA/ASA guidelines that receipt of DOACs past 48 hours prior is considered safe for thrombolytic administration, and if the included institutions were following current recommendations, thrombolytics were likely administered mostly to patients outside the 48-hour window.
  • Large potential for selection bias, since it was reported that almost 23,000 patients on DOACs from the original registry (who were otherwise eligible) did not receive thrombolytics.
  • Not clear how patients were determined to be on DOACs or if the authors were able to confirm this in unresponsive/intubated/deceased patients retrospectively. This could have resulted in DOAC patients being included in the non-DOAC group, which could have falsely evened-out the bleeding rates.

Bottom Line

  • The management of acute ischemic stroke in patients receiving prior anticoagulation presents a challenging clinical scenario.
  • Studies to date fail to include enough patients to evaluate the true risk of bleeding.
  • This study supports the current guideline recommendation to avoid alteplase in patients receiving a DOAC within 0-48 hours due to the increased risk of intracranial hemorrhage.

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Published correction appears in Circulation. 2019;140(6):e285. Circulation. 2019;140(2):e125-e151. doi: 10.1161/CIR.0000000000000665. PMID: 30686041.
  2. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. PMID: 31662037.
  3. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021;6(1):I-LXII. doi: 10.1177/2396987321989865. PMID: 33817340.
  4. Kam W, Holmes DN, Hernandez AF, et al. Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase. JAMA. 2022;327(8):760-771. doi:10.1001/jama.2022.0948. doi: 10.1001/jama.2022.0948. PMID: 35143601.
  5. Xian Y, Liang L, Smith EE, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA. 2012;307(24):2600-2608. doi:10.1001/jama.2012.6756. doi: 10.1001/jama.2012.6756. PMID: 22735429.

 

Primary author:

Jessica Mason, PharmD

PGY-2 Emergency Medicine Pharmacy Resident

Massachusetts General Hospital

By |2022-03-18T08:03:52-07:00Apr 2, 2022|EM Pharmacy Pearls, Heme-Oncology, Neurology, Tox & Medications, Uncategorized|
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Blood Pressure Differences in Patients with Acute Aortic Dissections

Background

An acute aortic dissection (AAD) can be a life-threatening emergency which frequently requires rapid and precise control of the patient’s heart rate and blood pressure. The 2010 guidelines for management of patients with thoracic aortic disease suggest a heart rate goal of <60 bpm and a systolic blood pressure between 100-120 mmHg. In order to achieve this, a rapid-acting beta-blocker (i.e., esmolol) may be used in combination with an IV calcium channel blocker (i.e., nicardipine or clevidipine). These medications need to be monitored closely to avoid overshooting these goals and causing hemodynamic compromise. Ideally, an arterial line would be used to monitor the patient’s blood pressure, however this may not always be feasible so a traditional, noninvasive blood pressure cuff can be used. This may be complicated if the patient has the classic, but not universal, finding of unequal systolic blood pressure values between their left and right extremities. This raises the question, in a patient with an AAD and disparate blood pressures in each arm, which arm reading should be used for monitoring?

Evidence

A 2018 study from Um et al. evaluated 111 patients with an AAD and compared them with 111 control patients. This study found that while a systolic blood pressure difference of >20 mmHg between sides was a positive predictor for an AAD, the presence of a pulse deficit had a higher diagnostic accuracy. For the purpose of this study, a pulse deficit was defined as “any recorded difference in volume/force or difference in obvious signs of malperfusion”. The cause of an unequal blood pressure or pulse deficit in the upper extremities in this population is typically due to dissection of the brachiocephalic or subclavian arteries. In order to properly achieve the desired blood pressure reduction in patients with divergent blood pressure values, the higher value should be used for titration of antihypertensives. This is due to the occurrence of pseudohypotension occurring in the limb with the dissected artery.

Bottom-line

  • Aggressive and precise heart rate and blood pressure control are critical for patients with an acute aortic dissection
  • The presence of a pulse deficit may provide better diagnostic accuracy than a difference in systolic blood pressure
  • When titrating blood pressure medications in patients with unequal blood pressure readings between extremities, the higher value should be utilized

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References:

  1. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease Circulation. 2010;121(13):e266-369. doi: 10.1161/CIR.0b013e3181d4739e. PMID: 20233780.
  2. Um SW, Ohle R, Perry JJ. Bilateral blood pressure differential as a clinical marker for acute aortic dissection in the emergency department. Emerg Med J. 2018;35(9):556-558. doi: 10.1136/emermed-2018-207499. PMID: 30021832.
By |2022-03-18T07:53:35-07:00Mar 19, 2022|Cardiovascular, EM Pharmacy Pearls|
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Extracorporeal Treatment Options in Poisoned Patients

Background

Caring for a patient that is critically-ill secondary to a toxic ingestion is complicated and, in severe cases, extracorporeal treatments (ECTRs) may be considered. The most commonly used ECTRs are intermittent hemodialysis (iHD) and continuous renal replacement therapy (CRRT), but ECTRs also include exchange transfusion, hemoperfusion, liver dialysis, and therapeutic plasma exchange. Finding and evaluating the supporting literature for these treatment modalities in a timely manner is not feasible in most situations. In order to assist in this effort, the EXtracorporeal Treatments In Poisoning (EXTRIP) workgroup has reviewed and provided free, evidence-based recommendations regarding the use of ECTRs for many common toxins and toxicants [1]. These recommendations can be found in a summarized format on the EXTRIP website and the links to their comprehensive reviews are published on PubMed with direct links on their website. This international workgroup is made up of experts in toxicology, nephrology, emergency medicine, pediatrics, pharmacology, critical care, and more. An excellent example of this resource is their review and recommendations on ECTRs for poisoning secondary to beta-adrenergic antagonists (BAAs).

Evidence

The EXTRIP workgroup included 76 publications in this comprehensive review on the use of ECTRs in BAA poisoning [2]. They evaluated pharmacokinetic/toxicokinetic data for a total of 334 patients poisoned with various BAAs, of which ~90% of the data was published prior to 1990 and does not necessarily represent the improved clearance of these medications with modern ECTR modalities. Based on this evidence, they deemed atenolol, nadolol, and sotalol as dialyzable BAAs. They also reviewed case reports/series of 37 patients with BAA toxicity and made recommendations for those agents with sufficient evidence. Based on the above data, the EXTRIP group recommends iHD over CRRT in patients severely poisoned with atenolol or sotalol and kidney impairment. They make no recommendation for or against ECTR in patients severely poisoned with atenolol or sotalol with normal kidney function and they recommend against ECTR in patients severely poisoned with propranolol.

 Bottom Line

  • Some toxic ingestions may require invasive treatment strategies (e.g., ECTRs) but a comprehensive review of the literature may not be possible
  • The EXTRIP website is an excellent resource to assess if patients should receive emergent ECTRs due to specific toxins
  • Hemodialysis is recommended in severely symptomatic patients poisoned with atenolol or sotalol and with impaired kidney function

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References:

  1. Ghannoum M, Nolin TD, Lavergne V, Hoffman RS, EXTRIP workgroup. Blood purification in toxicology: nephrology’s ugly duckling. Adv Chronic Kidney Dis. 2011;18(3):160-166. doi: 10.1053/j.ackd.2011.01.008. PMID: 21531321.
  2. Bouchard J, Shepherd G, Hoffman RS, et al. Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup. Crit Care. 2021;25(1):201. doi: 10.1186/s13054-021-03585-7. PMID: 34112223.
By |2022-02-02T13:49:01-08:00Feb 5, 2022|EM Pharmacy Pearls, Tox & Medications|
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Oral Antivirals for Treatment of Mild-Moderate COVID-19 Infection

Background

Two new oral agents were given Emergency Use Authorization to be used in patients with mild-moderate COVID-19 at high risk of progression to severe infection, molnupiravir and nirmatrelvir/ritonavir (Paxlovid) [1,2]. Prior to this authorization, most evidence-based COVID therapies were parenteral and required significant healthcare resources to coordinate and administer.

Comparison

Nirmatrelvir/ritonavir [3]Molnupiravir [4]
Mechanism

Protease inhibitor leadings to interruption of viral replication

Ritonavir has no role in treating COVID-19, it is only included to boost levels of nirmatrelvir via CYP3A4 inhibition

Increased frequency of RNA mutations and impaired replication [5]
Efficacy vs Placebo (Hospitalization or Death)0.8% vs 6.3% (CI -7.21 to -4.03)6.8% vs 9.7% (CI -5.9 to -0.1)
Drug InteractionsCYP3A4 inducers, inhibitors, and substrates

May decrease efficacy of hormonal contraceptives, non-hormonal contraceptives should be considered

Contraindicated medications include: amiodarone, carbamazepine, clozapine, colchicine, dihydroergotamine, dronedarone, flecainide, lovastatin, ranolazine, sildenafil, simvastatin

Many other important interactions exist so care should be taken to assess all medication interactions

N/A
Cost*Patient: $0

US government: $530 [6]

Patient: $0

US Government: $700 [7]

Dose300 mg/100 mg BID for 5 days

Must be started within 5 days of symptom onset

800 mg BID for 5 days

Must be started within 5 days of symptom onset

NotesApproved for patients ≥ 12 years old AND ≥ 40 kg

Not approved for inpatient initiation

If patient is hospitalized, continuation is up to the discretion of the provider

Not used as pre-/post-exposure prophylaxis

Approved for patients ≥ 18 years

Not approved for inpatient initiation

If patient is hospitalized, continuation is up to the discretion of the provider

Not used as pre-/post-exposure prophylaxis

Renal/Hepatic Dose AdjustmentseGFR  ≥30 to <60 mL/min: 150 mg/100 mg BID

eGFR <30 mL/min: Not recommended

Child-Pugh class C: Not recommended

None

*Note: The US federal government has purchased 10 million doses of nirmatrelvir/ritonavir and 3 million doses of molnupiravir [8,9]. These supplies will be allocated to states and territories as needed and will be available to patients at no charge. 

Evidence:

Nirmatrelvir/ritonavir (Paxlovid)

Paxlovid was evaluated in the EPIC-HR trial, which is not fully published at this time [3]. This was a phase 2/3, double-blinded, randomized placebo controlled trial including nonhospitalized, unvaccinated patients adults with mild-moderate COVID-19 within 5 days of symptom onset with at least 1 risk factor† for development of severe illness from COVID-19. Exclusion criteria included patients with a history of COVID-19 infection or COVID vaccination. Patients were given Paxlovid 300 mg/100 mg or placebo BID for 5 days. The primary outcome was hospitalization or death at day 28. The modified intention-to-treat1 (mITT1) group excluded patients who did not receive nor were expected to receive COVID-19 mAb treatment. In the mITT1 group, the primary outcome occurred in 0.8% of patients receiving Paxlovid vs 6.3% of patients in the placebo group (8/1039 vs 66/1046, CI -7.21 to -4.03).

These results appear quite robust with a fragility index of 37. Additionally, in patients with detectable COVID antibodies there was less of an impact of the study medication. However, these patients still appeared to have some benefit (0.2% vs 1.5%, CI -2.45 to -0.23) which suggests that vaccinated patients may still benefit from Paxlovid.

†Risk factors for progression to severe disease: BMI >25, chronic lung disease, asthma, chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or age >60 years

Molnupiravir 

Molnupiravir was evaluated in the MOVe-OUT trial [10]. This was a phase 3, double-blinded, randomized, placebo controlled trial including nonhospitalized, unvaccinated adults with mild-moderate COVID-19 within 5 days of symptom onset with at least 1 risk factor‡ for development of severe illness from COVID-19. Exclusion criteria included anticipated hospitalization within 48 hours, eGFR <30 or dialysis dependent, pregnancy, and COVID vaccination. Patients were able to receive steroids but not monoclonal antibodies (mAbs) nor remdesivir. Patients were given molnupiravir 800 mg or placebo BID for 5 days. The primary outcome was hospitalization or death at 29 days. In the mITT population, the primary outcome occurred in 6.8% of patients in the study group vs 9.7% in the placebo group (48/709 vs 68/699, CI -5.9 to -0.1). Death occurred in 1 patient on molnupiravir and in 9 patients on placebo (0.1% vs 1.3%, RRR 89%, CI 14 to 99).

Despite the above results, this may not be the positive trial it initially appears. First of all, for the primary outcome, the fragility index is 0, meaning that if 1 more patient in the study group experienced the primary outcome then it would have changed the statistical significance. Additionally, when the mITT analysis was adjusted for sex, the absolute risk reduction remained 2.8% but the confidence interval was not significant (-5.7 to 0.1). Lastly, in the subgroup analysis, there was no benefit in patients that had positive COVID antibody tests and there was a slight preference towards placebo over molnupiravir (3.7% vs 1.4%, ARR 2.3, CI -1.7 to 7.1). This suggests that vaccinated patients may not benefit from this therapy as much (or at all) as compared to unvaccinated patients.

‡Risk factors for progression to severe disease: age >60 years, active cancer, chronic kidney disease, COPD, BMI ≥30, heart failure, coronary artery disease, cardiomyopathy, or diabetes mellitus

Note: Both the EPIC-HR and MOVe-OUT studies were funded by their respective pharmaceutical company.

Bottom Line:

  • Nirmatrelvir/ritonavir (Paxlovid) and molnupiravir are approved under FDA EUAs for patients with mild-moderate COVID infection at high risk of severe disease within 5 days of symptom onset
  • Both medications appear to reduce death or hospitalization within a month, with most benefit likely to be experienced by unvaccinated patients
  • Nirmatrelvir/ritonavir (Paxlovid) appears to be more effective but also has many more drug interactions and contraindications

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References:

  1. O’Shaughenessy J. Food and Drug Administration. Molnupiravir Emergency Use Authorization 108. December 23, 2021. https://www.fda.gov/media/155053/download
  2. O’Shaughenessy J. Food and Drug Administration. Nirmatrelvir/ritonavir Emergency Use Authorization 105. December 22, 2021. https://www.fda.gov/media/155049/download
  3. Nirmatrelvir/ritonavir. Package insert. Pfizer, Inc. 2021. https://www.fda.gov/media/155050/download
  4. Molnupiravir. Package insert. Merck Sharp & Dohme Corp. 2021. https://www.merck.com/eua/molnupiravir-hcp-fact-sheet.pdf
  5. Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746. doi: 10.1038/s41594-021-00651-0. PMID: 34381216.
  6. Mishra M. U.S. to buy 10 mln courses of Pfizer’s COVID-19 pill for $5.3 bln. Reuters. Accessed January 12, 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/us-govt-buy-10-mln-courses-pfizers-covid-19-pill-529-bln-2021-11-18/
  7. Willyard C. How antiviral pill molnupiravir shot ahead in the COVID drug hunt. Nature. Published online October 8, 2021. doi: 10.1038/d41586-021-02783-1. PMID: 34625735.
  8. Paxlovid (nirmatrelvir/PF-07321332 and ritonavir). U.S. Department of Health & Human Services: Office of the Assistant Secretary of Preparedness and Response. Updated: January 12, 2022. Accessed January 12, 2022. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Paxlovid/Pages/default.aspx
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By |2022-01-15T19:00:38-08:00Jan 15, 2022|EM Pharmacy Pearls, Infectious Disease, Tox & Medications|
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