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COVID-19 is an emerging, rapidly evolving situation. Get the latest from the CDCNIH, and the Liverpool drug interaction group


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Potential/Off Label Investigational Treatments for Covid-19

(Updated Feb. 2, 2021)


Drug

Caution

Dose Considerations

Adverse Effects and Monitoring

Drug Interactions

Remdesivir

Proposed mechanisms:

Nucleotide prodrug that inhibits RNA-dependent RNA polymerase activity

Exclusion criteria from clinical trials:

  • Evidence of multi-organ failure 
  •  Need of inotropic agents
  • Creatinine clearance < 30 ml/min, dialysis, or hemofiltration 
  • Transaminases > 5X ULN
  • Concomitant use of lopinavir/ritonavir 

    Note that these criteria will likely exclude a great many patients in critical care.

     If the estimated creatinine clearance decreases by more than ≥ 50% from baseline, remdesivir should be held and resumed only when the estimated creatinine clearance returns to baseline. 

    If ALT and/or AST increase to > 3 times ULN remdesivir should be held. Dosing may be resumed when the ALT and/or AST returns to baseline. 

    Remdesivir should be stopped and not restarted if:

    • ALT ≥3 × ULN and bilirubin ≥2 × ULN
    • ALT and/or AST increases to > 5 times ULN

    Transaminase elevations +/- mild, reversible PT prolongation (usually no clinically important change in INR) and infusion related hypotension.

    In clinical trials, participants must abstain from acetaminophen for 14 days after they begin remdesivir. 

    Chloroquine 

    Proposed mechanisms: 

    Inhibition of viral entry, inhibition of viral release into the host cell, reduction of viral infectivity and immune modulation

    • QT >500 msec (Bazett) 
    • Myasthenia gravis 
    • Porphyria 
    • Retinal pathology
    • Epilepsy
    • Hypersensitivity to 4-aminoquinolone compounds

    70% of excretion renal, but no dose adjustments in product monograph. No dose adjustments for hepatic impairment in product monograph.

    Dizziness, headache, nausea, vomiting, diarrhea, dysrhythmias, sudden cardiac death. 

    Perform baseline ECG and regularly monitor if initial QT interval 450-500 msec. Consider daily monitoring, especially when used with azithromycin. 

    Possible additive QT and/or PR interval prolongation with other medications exhibiting these effects

    Possible additive effects with drugs causing hypoglycemia.

    Increased exposure of amiodarone, bepridil, flecainide and mexiletine and digoxin. 

    CYP3A4 and CYP2C8 inhibitors may increase exposure to chloroquine. These include: Trimethoprim, macrolide antibiotics (clarithromycin and erythromycin only), azole antifungals, HIV protease inhibitors, diltiazem, verapamil, amiodarone 

    Hydroxychloroquine

    Proposed mechanism:
    Assumed to be similar to that of chloroquine.

    • QT > 500 msec
    • Myasthenia gravis
    • Porphyria
    • Retinal pathology
    • Epilepsy
    • Hypersensitivity to 4-aminoquinolone compounds

    Product monograph suggests use with caution in patients with hepatic or renal impairment, and that dose reductions may be needed. However, no guidance offered.

    Dizziness, headache, nausea, vomiting, diarrhea, dysrhythmias, sudden cardiac death.

    Perform baseline ECG and regularly monitor if initial QT interval 450-500 msec. Consider daily monitoring, especially when used with azithromycin.

    Possible additive QT and/or PR interval prolongation with other medications exhibiting these effects. 

    Possible additive effects with drugs causing hypoglycemia. 

    Possible additive risk of seizure. 

    May increase levels of CYP2D6-metabolized medications. E.g. metoprolol, trazodone (active anxiogenic metabolite) 

    May increase levels of P-glycoprotein substrates. These include:
    Digoxin, Cyclosporine, Verapamil, Dabigatran (and to a lesser extent apixaban, rivaroxaban), Loperamide 

    Increased exposure of amiodarone, bepridil, flecainide and mexiletine and digoxin; 

    CYP3A4 and CYP2C8 inhibitors may increase exposure to hydroxychloroquine. These include: Trimethoprim, macrolide antibiotics (clarithromycin and erythromycin only), azole antifungals, HIV protease inhibitors, diltiazem, verapamil, amiodarone 

    Lopinavir/
    Ritonavir

    Proposed mechanism:

    SARS-CoV-2 protease inhibition is proposed mechanism.

    Contraindicated in patients taking drugs that are heavily dependent on CYP3A4 for clearance. These include:

    • Alfuzosin
    • Dronedarone
    • Fusidic acid
    • Colchicine
    • Rifampin
    • Lurasidone
    • Pimozide
    • Ergot derivatives
    • elbasvir/grazoprevir
    • lovastatin, simvastatin
    • salmeterol
    • Sildenafil when used for treatment of PAH
    • Vardenafil when used for PAH or ED
    • Midazolam, triazolam

    2 tablets (supplied as 200/50 mg tablets) BID for 14 days.

    Also available as an oral solution containing 400 mg lopinavir/100 mg ritonavir per 5 mL.

    No dose adjustments are likely to be needed for renal impairment. No dose adjustments for  hepatic impairment, but lopinavir exposure increased 30% in patients with mild/moderate hepatic impairment. Use with caution in this population.

    Diarrhea, nausea/vomiting, elevated transaminases. Pancreatitis rare.

     Many interactions. Potent CYP3A4 inhibitor. 

    • >Psychotropics warranting caution and close monitoring, if necessary: Quetiapine, clonazepam, trazodone

    Medications require review prior to prescribing. 

    Azithromycin (COVID studies have used with hydroxychloroquine)

    History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin and in those with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibacterial agent 

    No adjustment for hepatic impairment or mild to moderate renal impairment (GFR GFR 10-80 mL/min). Exposure increases 35% in patients with GFR <10 mL/min compared to patients with normal renal function. Product labelling does not recommend dose adjustment, but exercising caution when azithromycin is administered to subjects with severe renal impairment.

    Nausea, vomiting, diarrhea, adominal pain, rashes and Increase in transaminase and/or alkaline phosphatase levels in patients receiving intravenous azithromycin 

    When used with hydroxychloroquine, baseline ECG. Consider daily monitoring, when used with chloroquine or hydroxychloroquine. 

    Few clinically important interactions. May increase levels of P-glycoprotein substrates. These include: Digoxin, Cyclosporine, Verapamil, Dabigatran (and to a lesser extent apixaban, rivaroxaban), Loperamide 

    While azithromycin’s real-world risk of QT interval prolongation is unclear, monitor patients with risk factors for QT interval prolongation. 

    Loop diuretics which can cause low K, Ca and Mg levels, Amiodarone, haloperidol, quetiapine, olanzapine, risperidone, fluoroquinolones, citalopram/escitalopram. 

    Nonpharmacologic risk factors for QT interval prolongation and Torsade de Pointe include: Low K, Mg, Ca levels, Age ≥65 years, cardiac history, female, baseline QT interval prolongation)

    Tocilizumab

    Serious drug-induced liver injury, in some cases resulting in acute liver failure requiring a transplant, has been reported in patients treated with tocilizumab. The drug is generally not recommended in patients with active liver disease and transaminase levels greater than 3-times the upper limit of normal. However, because most patients with cytokine release syndrome will have elevated transaminases, decision to treat should consider potential benefit versus risk. 

    8 mg/kg as one dose infused over 60 minutes; can be repeated 8 to 12 hours later if continued clinical deterioration or inadequate response to first dose. The total dose should not exceed 800 mg, and the drug should not be administered more than twice. There are no studies to help guide dosing in patients with renal or hepatic insufficiency. However, Health Canada advised withholding in patients with transaminase levels > 3 times the upper limit of normal to minimize the risk of drug-induced liver injury. 

    Increased risk of serious infection including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab for approved indications. Gastrointestinal perforations rare (caution diverticulitis and other symptomatic lower GI conditions). 

    Inhibition of IL-6 may induce the expression of cytochrome P-450 enzymes, increasing the metabolism of CYP substrates. When starting or stopping therapy with tocilizumab, patients taking medications that are metabolised by CYP3A4, 1A2, 2C9 or 2C19 may have to have doses increased to maintain therapeutic effect). Given half-life of 13 days, the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. In patients with rheumatoid arthritis, tocilizumab decreased simvastatin exposure 57%. 

    Colchicine

     Use with care in geriatrics or debilitated patients and those with cardiac, renal (contraindicated CrCl <30cc/min), or gastrointestinal disease or on concomitant medications which inhibit CYP3A4 and/or P-glycoprotein (e.g. amiodarone, macrolides, fluconazole). Dosage reduction may be necessary in these cases and is indicated if weakness, anorexia, nausea, vomiting, or diarrhea appears.

    The ColCORONA phase 3, multicentre, randomized double-blind, placebo-controlled trial stopped early and still undergoing peer-review. Randomized 4488 adult participants, age >40 years (adults), dx SARS-CoV2 within preceding 24 hours (PCR from nasopharyngeal swab OR household member with a POSITIVE nasopharyngeal swab with COVID19 symptoms, OR clinical algorithm in symptomatic patient without obvious alternative cause), outpatients (not hospitalized nor considering hospitalization),
    PLUS one of:
    age >=70 years,
    obesity (BMI >=30),
    diabetes, uncontrolled HTN (SBP >=150 mmHg),
    known respiratory disease,
    known heart failure,
    known CAD,
    fever >38.4C within the last 48 hrs,
    dyspnea at the time of presentation,
    bicytopenia, pancytopenia or neutrophilia AND lymphopenia 
    Exclusions: women of childbearing age NOT practicing adequate contraception, IBD, chronic diarrhea or malabsorption, concomitant progressive neuromuscular disease, GFR<30cc/min/1.73 m2, severe liver disease, current tx with colchicine, chemo for cancer, sensitivity to colchicine. Intervention: colchicine 0.5 mg BID for 3 days and then daily for 27 days. VS Placebo. Trial medications delivered to patient’s house within 4 hours with telephone clinical evaluation at 15 and 30 days.
    What is unknown from the released manuscript: Confirmation of treatment adherence, outcome capture

    Primary endpoint (composite of death or hospitalization for COVID-19) in 4.7% of patients in colchicine vs 5.8% placebo. P=0.08. ARR 1.1% Among patients with PCR confirmed COVID, primary endpoint 4.6% colchicine and 6% placebo p= 0.04 ARR 1.4% NNT 72 patients. 
    SAE 4.9% colchicine vs 6.3% placebo p=0.05 “NNT” 52 patients PE 0.5% colchicine vs 0.1% placebo p = 0.01

    Prespecified subgroup analysis:
    age>=70 years. 18/190 (9.5%) colchicine and 27/213 (12.7%) OR 0.72 (95% CI 0.38 to 1.36) 


    Gastrointestinal (diarrhea, vomiting, nausea); Hematological (leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia, bone marrow depression, disseminated intravascular coagulation) 

    ColCORONA Trial medication-related adverse events 24.2% colchicine vs 15.5% placebo, ARR 8.7% NNH 11.5; at least 1 treatment emergent GI adverse event in 23.9% colchicine group, as compared with 14.8% placebo 

    When used for approved indications, dosage reductions needed when used with CYP3A4 and p-glycoprotein inhibitors. Guidance around dosage adjustments in setting of COVID are unclear. 

    Dexamethasone

     Neuropsychiatric effects are diverse and include insomnia, irritability, depression, mania, psychosis, delirium. Induces CYP3A4 metabolism.

     RECOVERY RCT (UK) found decreased 28 day mortality for inpatients receiving respiratory support (35% decrease in ventilated patients and 20% decrease in patients on oxygen supplementation) among those SARS-CoV2 patients aged <70 years requiring supplemental O2 particularly those requiring greater respiratory support, randomized to dexamethasone 6 mg once daily for up to 10 days compared to placebo (Group, 2020).

    Subgroup analysis:
    Older age:
    aged <70 years receiving dexamethasone, 129/1141 died by day 28 (11.3%) compared to 428/2504 patients receiving standard of care (16.5%; [RR 0.64; 95%CI 0.53-0.78]). ARR 5.2% NNT 20  

    aged ≥70 <80, mortality rate at day 28 was 155/469 (33.0%) for those randomized to dexamethasone, compared to 271/859 for those receiving standard of care alone (31.5%). RR 1.03 (95% CI 0.84−1.25)

    aged ≥80, mortality rate at day 28 was 198/494 (40.1%) for those receiving dexamethasone compared to 411/958 (42.9%) receiving standard of care alone. RR 0.89 (95% CI 0.75 – 1.05)

    Days since symptom onset: Consistent with increased clinical benefit observed for those patients requiring additional oxygen support, dexamethasone treatment had a greater impact at reducing mortality for patients with >7 days since symptom onset at time of trial randomization. 28-day mortality for patients with >7 days since symptom onset: 212/1184 (17.9%; dexamethasone) vs. 604/2507 (24.1%; standard of care) (RR 0.69 [95%CI 0.59-0.80]). 28-day mortality for patients with ≤7 days since symptom onset: 269/916 (29.4%; dexamethasone), vs. 500/1801 (27.8%; standard of care) (RR 1.01 [95% CI 0.87-1.17]). 

    Supplemental O2:
    No reduction in mortality if not receiving supplemental O2. In patients not receiving oxygen, mortality of 17.8% among those received dexamethasone, compared with 14.0% for those who received usual care (rate ratio 1.19, 95% CI 0.91 to 1.55).

     Mood, sleep, cognition, hemoglobin, occult blood loss, blood pressure, serum potassium, glucose, BMD, IOP if systemic use >6 weeks, HPA axis suppression (if chronic)

     CYP3A4 inducers may decreased the concentration of dexamethasone. Avoid this combination in life threatening conditions. CYP3A4 inhibitors may increase the serum concentration of dexamethasone. 

    Concurrent use of dexamethasone with warfarin can increase risk of bleeding. With NSAIDs, it can increase the risk of GI ulceration or bleeding. (1-2)


    *List of substrates, inhibitors and inducers are representative only, and not exhaustive.

    Pharmacokinetic studies among older adults have not been done with the exception of azithromycin which found that older women experienced 30-50% increased AUC. This pharmacokinetic difference was not felt to be clinical relevant.


    References:
    1. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L., Li, C., … Wang, C. (2020). A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. The New England Journal of Medicine, 1–13. https://doi.org/10.1056/NEJMoa2001282
    2. Clinicaltrials.gov. (2020). Remdesivir COVID-19 Clinical Trial Search Results Accessed 03/22/2020. https://clinicaltrials.gov/ct2/results/browse?term=remdesivir&brwse=cond_alpha_all
    3. Eap, C. B., Buclin, T., & Baumann, P. (2002). Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clinical Pharmacokinetics, 41(14), 1153–1193. https://doi.org/10.2165/00003088-200241140-00003
    4. Gomes, T., Mamdani, M. M., & Juurlink, D. N. (2009). Macrolide-induced digoxin toxicity: a population-based study. Clinical Pharmacology and Therapeutics, 86(4), 383–386. https://doi.org/10.1038/clpt.2009.127
    5. Group, R. C. (2020). Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine, 1–11. https://doi.org/10.1056/nejmoa2021436
    6. Leden, I. (1982). Digoxin-hydroxychloroquine interaction? Acta Medica Scandinavica, 211(5), 411–412. https://doi.org/10.1111/j.0954-6820.1982.tb01971.x
    7. Lim, H. S., Im, J. S., Cho, J. Y., Bae, K. S., Klein, T. A., Yeom, J. S., Kim, T. S., Choi, J. S., Jang, I. J., & Park, J. W. (2009). Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by plasmodium vivax. Antimicrobial Agents and Chemotherapy, 53(4), 1468–1475. https://doi.org/10.1128/AAC.00339-08
    8. Malcangi, G., Fraticelli, P., Palmieri, C., Cappelli, M., & Danieli, M. G. (2000). Hydroxychloroquine-induced seizure in a patient with systemic lupus erythematosus. Rheumatology International, 20(1), 31–33. https://doi.org/10.1007/s002960000066
    9. Percodan (Oxycodone and Aspirin Tablets, USP). (n.d.).
    10. Pollack, T. M., McCoy, C., & Stead, W. (2009). Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients. Pharmacotherapy, 29(11), 1386–1391. https://doi.org/10.1592/phco.29.11.1386
    11. Rotzinger, S., Fang, J., & Baker, G. B. (1998). Trazodone Is Metabolized tom-Chlorophenylpiperazine by CYP3A4 from Human Sources. Drug Metabolism and Disposition, 26(6), 572–575. http://www.dmd.org
    12. Sampson, M. R., Cao, K. Y., Gish, P. L., Hyon, K., Mishra, P., Tauber, W., Zhao, P., Zhou, E. H., & Younis, I. R. (2019). Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors. Journal of Clinical Pharmacology, 59(4), 500–509. https://doi.org/10.1002/jcph.1345
    13. Somer, M., Kallio, J., Pesonen, U., Pyykkö, K., Huupponen, R., & Scheinin, M. (2000). Influence of hydroxychloroquine on the bioavailability of oral metoprolol. British Journal of Clinical Pharmacology, 49(6), 549–554. https://doi.org/10.1046/j.1365-2125.2000.00197.x
    14. Stahl, S. M. (2009). Mechanism of Action of Trazodone : a Multifunctional Drug. October.
    15. Trac, M. H., McArthur, E., Jandoc, R., Dixon, S. N., Nash, D. M., Hackam, D. G., & Garg, A. X. (2016). Macrolide antibiotics and the risk of ventricular arrhythmia in older adults. CMAJ : Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 188(7), E120–E129. https://doi.org/10.1503/cmaj.150901
    16. Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, January, 2019–2021. https://doi.org/10.1038/s41422-020-0282-0
    17. Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., Zhao, L., Dong, E., Song, C., Zhan, S., Lu, R., Li, H., Liu, D., Clinical, D., Liu, D., Tan, W., Liu, D., & Clinical, D. (n.d.). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Main point : Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vit. 2, 1–25.
    18. (Cao et al., 2020; Clinicaltrials.gov, 2020; Eap et al., 2002; Gomes et al., 2009; Leden, 1982; Lim et al., 2009; Malcangi et al., 2000; Percodan (Oxycodone and Aspirin Tablets, USP), n.d.; Pollack et al., 2009; Rotzinger et al., 1998; Sampson et al., 2019; Somer et al., 2000; Stahl, 2009; Trac et al., 2016; Wang et al., 2020; Yao et al., n.d.)
    19. Xu X, Han M, Li T et al. Effective treatment of severe COVID-19 patients with Tocilizumab. Available at: file:///C:/Users/owner/Downloads/202003.00026v1.pdf. Accessed March 26, 2019.
    20. Actemra product information. Hoffman La Roche Limited. 2019
    21. Health Canada. Important Safety Information on ACTEMRA® (tocilizumab) - Risk of Hepatotoxicity. Available: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/69991a-eng.php. Accessed March 26, 2019.


    COVID-19 is an emerging, rapidly evolving situation. Get the latest from CDC: https://www.coronavirus.gov and NIH: https://www.nih.gov/coronavirus  and the Liverpool drug interaction group: http://www.covid19-druginteractions.org

    This document is for informational purposes only and is not intended as, and should not be interpreted as, medical advice or other professional advice. Clinical judgement is still required. GeriMedRisk does not endorse the use of any of these therapies for COVID, but offers this information in the hopes of decreasing the risk of harmful drug-drug interactions or adverse drug events. We will do our best to update this information.


    Last updated: Feb. 2, 2021 - 11: 45PM                                                                                                                                                                                                       Back to COVID-19 Resources