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Patients taking the oral combination antiviral drug PAXLOVID (nirmatrelvir and ritonavir) should be aware that it has clinically important and potentially dangerous interactions with many other prescription medications.
In December 2021, the Food and Drug Administration (FDA) issued an emergency use authorization for Paxlovid for the treatment of mild-to-moderate COVID-19 in adults and children (age 12 years or older and weighing at least 88 pounds) who test positive for the COVID-19 virus...
Patients taking the oral combination antiviral drug PAXLOVID (nirmatrelvir and ritonavir) should be aware that it has clinically important and potentially dangerous interactions with many other prescription medications.
In December 2021, the Food and Drug Administration (FDA) issued an emergency use authorization for Paxlovid for the treatment of mild-to-moderate COVID-19 in adults and children (age 12 years or older and weighing at least 88 pounds) who test positive for the COVID-19 virus and are at high risk of progression to severe COVID-19, including hospitalization and death.[1] The drug is available by prescription only and must be started within five days of onset of COVID-19 symptoms.
Paxlovid consists of two active ingredients that are dispensed in separate tablets.[2] The first is nirmatrelvir, which prevents the COVID-19 virus from making copies of itself after it infects a person’s cells. The second is ritonavir — a drug that was originally approved by the FDA in 1996 for use in combination with other drugs to treat HIV infection.[3]
Notably, ritonavir does not have any antiviral activity against the COVID-19 virus. Instead, it slows the breakdown of nirmatrelvir by enzymes in the liver and thus helps nirmatrelvir to remain in the body for a longer period at higher concentrations.[4]
Paxlovid is administered as three tablets (two nirmatrelvir tablets and one ritonavir tablet packaged together) taken twice daily for five days.[5]
Contraindicated interacting drugs
The FDA issued a patient eligibility screening checklist for patients being considered for Paxlovid treatment.[6]
The checklist identified 25 drugs currently marketed in the U.S. that are contraindicated in patients taking Paxlovid, meaning the interacting drugs should never be used concomitantly (at the same time) with Paxlovid (see Table 1, below). The list includes certain drugs for gout, heart-rhythm disorders, high blood cholesterol, infections, migraine headaches, prostate disease, psychosis and seizures.
For some of these drugs, Paxlovid inhibits the liver enzymes that break down the interacting drug.[7] Thus, concomitant use of Paxlovid with these interacting drugs can increase blood concentrations of the interacting drugs to toxic levels, potentially resulting in serious or life-threatening adverse effects. To avoid such toxicity, the interacting drug should be discontinued prior to Paxlovid treatment and not restarted until the effect of the antiviral drug on liver enzymes has subsided.[8] For example, patients who are taking either lovastatin (ALTOPREV) or simvastatin (FLOLIPID, VYTORIN, ZOCOR) should stop the cholesterollowering statin drug 12 hours prior to the first dose of Paxlovid and wait until five days after Paxlovid treatment has ended before restarting the statin.
Other drugs can accelerate the breakdown of Paxlovid by liver enzymes.[9] Thus, their concomitant use with Paxlovid can lead to reduced blood levels of Paxlovid, which may result in COVID-19 treatment failure and potentially promote the development of COVID-19 virus variants that are resistant to Paxlovid. For the same reason, use of the herbal supplement St. John’s wort also is contraindicated in patients taking Paxlovid.[10] Importantly, Paxlovid cannot be initiated immediately after discontinuation of any of these interacting drugs (or St. John’s wort) because it takes time for their effect on liver enzymes to resolve.[11]
Table 1: Drugs That Are Contraindicated in Patients Taking Paxlovid
| Generic Name | Brand Name(s) | Drug Class |
|---|---|---|
| Concomitant use of Paxlovid with the following drugs can cause dangerously high levels of the interacting drug | ||
| alfuzosin* | UROXATRAL | Alpha blocker for benign prostate enlargement |
| amiodarone* | PACERONE | Heart-rhythm disorder drug |
| clozapine* | CLOZARIL, VERSACLOZ | Antipsychotic |
| colchicine | COLCRYS, GLOPERBA, MITIGARE | Gout drug |
| dihydroergotamine | D.H.E. 45, MIGRANAL, TRUDHESA | Migraine headache drug |
| dronedarone** | MULTAQ | Heart-rhythm disorder drug |
| ergotamine | CAFERGOT,† ERGOMAR, MIGERGOT,† WIGRAINE† | Migraine headache drug |
| flecainide | generic only | Heart-rhythm disorder drug |
| lovastatin | ALTOPREV | Cholesterol-lowering statin |
| lurasidone | LATUDA | Antipsychotic |
| meperidine* | DEMEROL | Opioid analgesic |
| methylergonovine | METHERGINE | Drug for uterine bleeding |
| midazolam (oral) | generic only | Benzodiazepine sedative |
| pimozide | generic only | Tourette’s syndrome drug |
| propafenone | RYTHMOL SR | Heart-rhythm disorder drug |
| quinidine* | NUEDEXTA† | Heart-rhythm disorder/malaria/pseudobulbar affect drug |
| ranolazine | RANEXA, ASPRUZYO SPRINKLE | Angina drug |
| sildenafil (only products used for pulmonary arterial hypertension) | REVATIO | Drug for pulmonary hypertension |
| simvastatin | FLOLIPID, VYTORIN,† ZOCOR | Cholesterol-lowering statin |
| triazolam** | HALCION | Benzodiazepine sedative |
| Concomitant use of Paxlovid with the following drugs can cause reduced Paxlovid levels | ||
| apalutamide | ERLEADA | Prostate cancer drug |
| carbamazepine | CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL | Seizure drug |
| phenobarbital* | LUMINAL, SOLFOTON | Seizure drug |
| phenytoin | DILANTIN, PHENYTEK | Seizure drug |
| rifampin | RIFADIN, RIMACTANE | Antibiotic |
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News
†Brand-name combination product that contains one or more additional active ingredients not listed
Other interacting drugs
The FDA’s patient eligibility screening checklist for patients being considered for Paxlovid treatment identifies 56 other drugs that have potentially dangerous interactions with Paxlovid (see Table 2, below, for a list of examples; the complete list is available at https://www.fda.gov/media/158165/ download).[12] The list includes certain antibiotics, anticoagulants (blood thinners), antidepressants, antifungal drugs, calcium channel blockers for treating hypertension, cancer drugs, glucocorticoids (also called corticosteroids) administered orally or by injection, immunosuppressants used in organ transplant patients and opioids.
For these drugs, the FDA advises that concomitant use of Paxlovid with the interacting drug should be avoided, the dose of the interacting drug should be adjusted or special monitoring of the interacting drug is needed during concomitant use.[13]
For patients taking a hormonal contraceptive containing ethinyl estradiol (AFIRMELLE, BEKYREE, CYCLESSA, GILDAGIA, KURVELO, NORTREL and many others) who need treatment with Paxlovid, an additional nonhormonal method of contraception should be used during the five days of Paxlovid therapy and until one menstrual cycle after stopping Paxlovid.[14]
Table 2: Examples of Other Drugs That Interact With Paxlovid
| Generic Name | Brand Name(s)† | Drug Class |
|---|---|---|
| amlodipine* | AZOR,† CADUET,† EXFORGE,† EXFORGE HCT,† KATERZIA, LOTREL,† NORLIQVA, NORVASC, PRESTALIA,† TRIBENZOR† | Calcium channel blocker, hypertension drug |
| bupropion** | APLENZIN, CONTRAVE,† FORFIVO XL, WELLBUTRIN | Antidepressant, weight-loss drug |
| ceritinib | ZYKADIA | Cancer drug |
| clarithromycin* | generic only | Antibiotic |
| cyclosporine | GENGRAF, NEORAL, SANDIMMUNE | Immunosuppressant/organ-transplant drug |
| dabigatran** | PRADAXA | Anticoagulant |
| dexamethasone | HEMADY | Glucocorticoid |
| digoxin | LANOXIN | Heart disease drug |
| diltiazem* | CARDIZEM, CARTIA XT, TAZTIA XT, TIAZAC | Calcium channel blocker, hypertension drug |
| erythromycin | E.E.S., E.E.S. 400, ERYC, ERYPED, ERY-TAB, ERYTHROCIN | Antibiotic |
| felodipine | generic only | Calcium channel blocker, hypertension drug |
| fentanyl* | ACTIQ, FENTORA, LAZANDA, SUBSYS | Opioid analgesic |
| ibrutinib | IMBRUVICA | Cancer drug |
| itraconazole*** | SPORANOX, TOLSURA | Antifungal drug |
| ketoconazole (oral)** | generic only | Antifungal drug |
| methadone* | METHADOSE | Opioid for pain, opioid-use disorder |
| methylprednisolone | DEPO-MEDROL, MEDROL, SOLU-MEDROL | Glucocorticoid |
| nicardipine* | generic only | Calcium channel blocker, hypertension drug |
| prednisone | RAYOS | Glucocorticoid |
| quetiapine* | SEROQUEL | Antipsychotic |
| rifabutin | MYCOBUTIN, TALICIA† | Antibiotic |
| rivaroxaban** | XARELTO | Anticoagulant |
| sirolimus | FYARRO, RAPAMUNE | Immunosuppressant/organ-transplant drug |
| tacrolimus | ASTAGRAF XL, ENVARSUS XR, PROGRAF | Immunosuppressant/organ-transplant drug |
| trazodone** | generic only | Antidepressant |
| vincristine | generic only | Cancer drug |
| voriconazole | VFEND | Antifungal drug |
| warfarin | JANTOVEN | Anticoagulant |
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News
***Designated as Do Not Use except for serious fungal infection by Worst Pills, Best Pills News
†Brand-name combination product that contains one or more additional active ingredients not listed
What You Can Do
If you need treatment with Paxlovid, review all your other medications with your doctor to assess for potentially significant drug interactions. If you are taking a medication that interacts with Paxlovid, you may need to stop or adjust the dosage of the interacting drug, undergo more frequent monitoring of the blood levels of the interacting drug or your doctor may advise you to take a different drug than Paxlovid for treating your COVID-19 infection. Be aware that other drugs not listed in this article also may have dangerous interactions with Paxlovid.
References
[1] Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. December 22, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed May 31, 2022.
[2] Ibid.
[3] Abbvie, Inc. Label: ritonavir (NORVIR). October 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020659s072,022417s024,209512s007lbl.pdf. Accessed May 31, 2022.
[4] Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. December 22, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed May 31, 2022.
[5] Ibid.
[6] Food and Drug Administration. PAXLOVID patient eligibility screening checklist tool for prescribers. May 4, 2022. https://www.fda.gov/media/158165/download. Accessed May 31, 2022.
[7] Pfizer. Fact sheet for healthcare providers: Emergency use authorization for Paxlovid. April 14, 2022. https://www.fda.gov/media/155050/download. Accessed May 31, 2022.
[8] Food and Drug Administration. PAXLOVID patient eligibility screening checklist tool for prescribers. May 4, 2022. https://www.fda.gov/media/158165/download. Accessed May 31, 2022.
[9] Pfizer. Fact sheet for healthcare providers: Emergency use authorization for Paxlovid. April 14, 2022. https://www.fda.gov/media/155050/download. Accessed May 31, 2022.
[10] Ibid.
[11] Ibid.
[12] Ibid.
[13] Ibid.
[14] Ibid.
