Coronavirus Disease 2019 (COVID-19) is severe acute respiratory syndrome due to the coronavirus 2 (SARS-CoV-2). It’s origins have been traced to an outbreak in Wuhan China in December 2019 that quickly spread internationally causing a global pandemic.1 Common symptoms include fever, dry cough, shortness of breath or difficulty breathing, chills, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell.2 Patients with COVID-19 often have other comorbidities that can increase the risk of fatality. These comorbidities include cardiovascular disease (OR=13.64), diabetes mellitus (OR=9.07), chronic lung disease (OR=7.74), hypertension (OR=7.39), and cancer (OR=6.88).1 At present time, there is no known effective therapy and treatment has to be individualized case by case. To date, remdesivir is the only FDA approved medication for COVID-19 treatment. However, many other medications have also been used off-label to treat patients with COVID-19. According to the survey of 203 physicians with frontline care roles was conducted April 14-15, 2020, the leading treatments prescribed to patients with COVID-19 are acetaminophen approximately (82%), antibiotics (41%), bronchodilators (40%), plasma from recovered patients (21%), hydroxychloroquine (21%), ibuprofen (20%), remdesivir (17%) and antiviral agents (10%).3 Many of these medications are associated with serious adverse reactions. Clinicians should be aware of possible drug-drug interactions that warrant careful monitoring.
Acetaminophen is a commonly prescribed and over the counter use medication. It is a preferred analgesic agent for patients receiving anticoagulation treatment.4 Although it can increase the risk of bleeding in this population it is considered a safer alternative to non-steroidal anti-inflamatory drugs (NSAIDs). A systematic review and meta-analysis of 7 randomized-controlled trials (225 patients) comparing acetaminophen versus placebo or no treatment in patients treated with vitamin K antagonists found that the use of acetaminophen was associated with an increase mean INR of 0.62 (95% CI: 0.42-0.78) compared to placebo; and each daily gram of acetaminophen increased mean INR of 0.17 (95% CI: 0.004-0.33).4 In a double-blind, crossover study, 20 patients on stable doses of warfarin were randomized to receive the maximum recommended dose of acetaminophen (4 gram/day) or placebo for 14 days. The maximum INR increase from baseline was found to be 2 times larger following acetaminophen.5
Azithromycin is a macrolide antibiotic commonly prescribed for a respiratory infection.6 The evidence on the effect of azithromycin on QTc have been inconsistent. A study reported an increased risk of death (HR=1.48, 95% CI, 1.05-2.09) and serious arrhythmia (HR=1.77, 95% CI, 1.20-2.62) in patients receiving azithromycin compared with patients receiving amoxicillin.6 Several cases reported azithromycin was associated with QTc prolongation.7,8 However, another study of 56 patients with cystic fibrosis who received long-term treatment with azithromycin reported the change in QTc was only 1.0 ± 18 milliseconds and no patient had a clinically prolonged QTc interval with azithromycin therapy.9 A study of 90 healthy adults reported the use of azithromycin alone (500 mg x 1 dose then 250 mg/day x 4 days), desloratadine alone (5 mg x 7 days) and combination of azithromycin and desloratadine found the change in QTc by -0.1, 6.3, and 4.2 milliseconds, respectively.10
Chloroquine is an antimalaria agent, which has been used off-label to treat COVID-19. Chloroquine has been associated with many drug-drug interactions especially QTc prolongation. A study reported that in healthy adults who received chloroquine 600 mg, the QTc increased by 15 milliseconds by day 1, but decreased by 3 milliseconds on day 14.11 In another study, a 600 mg single dose of chloroquine in 16 healthy adults increased QTc by 6.32 milliseconds (95%CI, -1.45-12.3)12 but was not statistically significant possibly due to small sample size. Chloroquine 1,500 mg has been shown to increase QTc by 16-21 milliseconds.11 Moreover, QTc prolongation was found to be longer with the combination of chloroquine and azithromycin (19.9±16.3 milliseconds) compared to chloroquine alone (13.7 ± 7.4 milliseconds).13Chloroquine has also been reported to interact with other medications such as antacids14 and cimetidine.15
Colchicine, an antigout agent, has been used to treat COVID-19 due to its ability to suppress interleukins (IL-1b, IL-18, and IL-6) through inhibition of Inflammasome NLRP3. Inflammasome NLRP3 is thought to be a major factor in the pathophysiology of acute respiratory distress syndrome (ARDS) that occurs frequently in patients with COVID-19.16 However, when given with CYP3A4/P-glycoprotein inhibitors, colchicine can induce life-threatening toxicity such as pancytopenia, multiple organ failure, and myopathy .17 For example, clarithromycin, a strong CYP3A4 and P-glycoprotein inhibitor increased colchicine AUC approximately 282%.18 Concurrent use of clarithromycin and colchicine for more than two days could lead to death.18
Hydroxychloroquine (HCQ), is an antimalaria agent commonly used for long-term treatment of connective tissue diseases (CTDs). It is relatively safe but may occasionally cause severe side effects including retinopathy, neuropathy, vascular myopathy, and cardiotoxicity.19 A study of 85 patients with CTDs who received 200 mg of HCQ either twice or once daily for an average of 8 years had a normal QTc interval with an average of 410 milliseconds (range 349-464).19 Another study of 127 patients with CTD treating with either chloroquine (mean cumulative dose of 803 grams) or hydroxychloroquine (mean cumulative dose of 1235 grams) for an average of 7 years (3-35 years) did not find an increase in QTc.20 However, an increase in QTc has been reported when HCQ was used in combination with other medications. A cohort study reported that patients receiving concomitant HCQ and azithromycin had a greater median (interquartile range) change in QT interval of 23 milliseconds (10-40) compared to those receiving HCQ alone of 5.5 milliseconds (-15.5-34.25); P=0.03.21 Hydroxychloroquine can also interact with other medications such as metoprolol22 and tamoxifen.23
We will provide a summary soon.
We will provide a summary soon.
Webinar on 05/13/20
- Kang Y, Chen T, Mui D, et al. Cardiovascular manifestations and treatment considerations in covid-19. Heart. 2020.
- Prevention CfDCa. Coronavirus Disease 2019 (COVID-19). 2020.
- Which Drugs Are Used Most for COVID-19 in Hospitals?
- Caldeira D, Costa J, Barra M, Pinto FJ, Ferreira JJ. How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis. Thromb Res. 2015;135(1):58-61.
- Mahe I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica. 2006;91(12):1621-1627.
- Rao GA, Mann JR, Shoaibi A, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam Med. 2014;12(2):121-127.
- Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol. 2007;18(3):243-246.
- Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT prolongation in elderly patient. Acta Biomed. 2006;77(1):30-32.
- Lenehan PJ, Schramm CM, Collins MS. An evaluation strategy for potential QTc prolongation with chronic azithromycin therapy in cystic fibrosis. J Cyst Fibros. 2016;15(2):192-195.
- Gupta S, Banfield C, Kantesaria B, et al. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther. 2001;23(3):451-466.
- Mzayek F, Deng H, Mather FJ, et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials. 2007;2(1):e6.
- Pukrittayakamee S, Tarning J, Jittamala P, et al. Pharmacokinetic interactions between primaquine and chloroquine. Antimicrob Agents Chemother. 2014;58(6):3354-3359.
- Cook JA, Randinitis EJ, Bramson CR, Wesche DL. Lack of a pharmacokinetic interaction between azithromycin and chloroquine. Am J Trop Med Hyg. 2006;74(3):407-412.
- McElnay JC, Mukhtar HA, D’Arcy PF, Temple DJ, Collier PS. The effect of magnesium trisilicate and kaolin on the in vivo absorption of chloroquine. J Trop Med Hyg. 1982;85(4):159-163.
- Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans: effect of low-dose cimetidine. J Clin Pharmacol. 1987;27(10):813-816.
- Deftereos SG, Siasos G, Giannopoulos G, et al. The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design. Hellenic J Cardiol. 2020.
- Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C. Acute fatal colchicine intoxication in a patient on continuous ambulatory peritoneal dialysis (CAPD). Possible role of clarithromycin administration. Clin Nephrol. 2001;55(2):181-182.
- Villa Zapata L, Hansten PD, Horn JR, et al. Evidence of Clinically Meaningful Drug–Drug Interaction With Concomitant Use of Colchicine and Clarithromycin. Drug Safety. 2020.
- Costedoat-Chalumeau N, Hulot J-S, Amoura Z, et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology. 2007;46(5):808-810.
- Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018;41(10):919-931.
- Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020.
- Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol. 2000;49(6):549-554.
- Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453-1460.
Last revision: 5/12/2020