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Lopinavir/ritonavir for COVID-19

HIV Protease Inhibitor; Antiviral

(Updated April 6, 2020)



  1. Lopinavir/ritonavir remains off label use for COVID-19.
  2. There are no well conducted studies of the pharmacokinetics of lopinavir/ritonavir in older adults. Dosage adjustments based on age are therefore not recommended.
  3. Lopinavir/ritonavir is a potent inhibitor of CYP3A4, producing clinically relevant interactions with many drugs. Screening for potential drug interactions prior to use is therefore required.
  4. The main side effects of lopinavir/ritonavir are diarrhea, abdominal pain and nausea and vomiting. Elevated hepatic transaminases can occur, and pancreatitis is a rare side effect.
  5. Post-marketing reports of second- or third-degree heart block in patients with underlying structural heart disease, pre-existing conduction abnormalities and patients receiving drugs which prolong the PR interval. Should be used with caution in these patients.


Mechanism of Action:  Antiviral: inhibits protease enzyme of coronavirus. As of March 24, 2020, there have been no reported in vitro data for SARS-COV-2. The 50% effective concentrations (EC50) of lopinavir in vitro for SARS-CoV-1 have ranged from 4.0 to 10.7 g per milliliter, depending on the cell type used.¹,² Although the mean peak (9.6 g/mL) and trough (5.5 g/mL) concentrations of lopinavir are within this range,³ other in vitro studies have reported little to no activity of lopinavir against SARS-CoV-1. In a randomized, controlled, open-label trial of hospitalized patients with confirmed SARS-CoV-2 infection, treatment with lopinavir–ritonavir was not associated with a difference in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72) relative to usual care. In the intention-to-treat population, lopinavir–ritonavir treatment within 12 days after the onset of symptoms was not found to be associated with a shorter time to clinical improvement (hazard ratio, 1.25; 95% CI, 0.77 to 2.05); similar results were found regarding later treatment with lopinavir–ritonavir (hazard ratio, 1.30; 95% CI, 0.84 to 1.99). Although 28-day mortality did not differ statistically between the two groups, 28-day mortality was lower in the lopinavir/ritonavir treated patients (19.2% vs. 25.0%; difference, 5.8 percentage points; 95% CI, 17.3 to 5.7). This difference was driven largely by patients treated within 12 days of symptom onset (19.0% vs. 27.1%; difference -8.0 percentage points; 95% CI -25.3 to 9.3). The authors concluded that the question of whether earlier lopinavir–ritonavir treatment in Covid-19 could have clinical benefit requires further study. Other outcomes favouring lopinavir/ritonavir included stay in the intensive care unit (median, 6 days vs. 11 days; difference, 5 days; 95% CI, 9 to 0), and the duration from randomization to hospital discharge (median, 12 days vs. 14 days).

Dosage:  COVID (off label; current clinical trial data): 400/100 mg (supplied as 2 tablets of 200/50 mg tablets) twice a day for 14 days. Also available as an oral solution containing 400 mg lopinavir/100 mg ritonavir per 5 mL.


Drug Interactions:³ Pharmacodynamic: Other agents that result in PR prolongation (e.g. verapamil, calcium channel blockers, beta-adrenergic blockers, digoxin, cholinesterase inhibitors). Although post-marketing reports describe possible QT-interval prolongation with lopinavir/ritonavir, causality has not been demonstrated. However, consider ECG monitoring in patients receiving with other QT prolonging agents.


Pharmacokinetic: Potent inhibitor of CYP3A4. The following drugs are contraindicated with lopinavir/ritonavir: Pimozide, ergot derivatives, elbasvir/grazoprevir, lovastatin, simvastatin, salmeterol, sildenafil when used for treatment of PAH, vardenafil when used for PAH or ED, midazolam, triazolam, alfuzosin, dronedarone, fusidic acid, neratinib, venetoclax, colchicine and lurasidone. The natural health product, st. john’s wart, is also contraindicated.


Interactions with other psychotropic agents (e.g. trazodone, quetiapine, clonazepam), calcium channel blockers and statins (e.g. atorvastatin) can occur. A full medication history is required before prescribing lopinavir/ritonavir so that interactions can be flagged and managed. Rifampin is also contraindicated because it can reduce levels of lopinavir/ritonavir, possibly compromising effectiveness. Complicating matters is that lopinavir/ritonavir Induces glucuronyl transferases and possibly CYP1A2, CYP2C19 and 2C9. Apalutamide, another moderate to strong CYP3A4 inducer, is also contraindicated.


Adverse effects :³  Diarrhea, nausea, vomiting, abdominal pain. Elevations in hepatic transaminases less common. Pancreatitis rare.


Monitoring:  Liver function tests, consider baseline and follow ECG in patients at risk for heart block and/or QT interval prolongation


Absorption:      Absolute bioavailability not known; Tmax 4 hours. Tablets can be taken without regard to meals.

Distribution:    protein binding 98% to 99%;

Metabolism:    CYP3A4 substrate

Elimination:    After multiple dosing, <3% lopinavir excreted unchanged in urine.

Half-life:            5 to 6 hours


  1. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-256.
  2. Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004;31:69-75.
  3. Kaletra product monograph. Abbvie. September 2019.
  4. Yamamoto N, Yang R, Yoshinaka Y, et al. HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus. Biochem Biophys Res Commun 2004;318:719-725.
  5. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282. [Epub ahead of print]


Last updated: April 6, 2020 - 12:37 PM                                                                                                                                                                                                        Back to COVID-19 Resources