In this article an infectious diseases pharmacist compares Paxlovid versus molnupiravir – the first oral COVID-19 antivirals with FDA Emergency Use Authorization.
Authored By: Timothy P. Gauthier, Pharm.D., BCPS, BCIDP
Article Posted 24 December 2021
The FDA has released emergency use authorizations for Pfizer’s COVID-19 pill Paxlovid (generic name nirmatrelvir/ ritonavir) as well as Merck’s COVID-19 pill molnupiravir (UK brand name Lagevrio). There are a lot of questions about these two new oral COVID-19 therapies. This article provides an overview comparing the two.
Note that things are evolving rapidly and the content presented here may be rendered inaccurate or incorrect as things change. To prepare this post I have utilized the following resources, which are subject to future updates:
- Paxlovid
- Paxlovid (nirmatrelvir/ ritonavir) Fact Sheet for Healthcare Providers
- Paxlovid (nirmatrelvir/ ritonavir) Fact Sheet for Patients and Caregivers
- FDA’s Frequently Asked Questions on the Emergency Use Authorization for Paxlovid for Treatment of COVID-19
- US HHS Public Health Emergency Webpage on Paxlovid (nirmatrelvir/PF-07321332 and ritonavir)
- US HHS ASPR Frequently Asked Questions – Paxlovid (nirmatrelvir/PF-07321332 and ritonavir)
- FDA Letter of Emergency Use Authorization for Paxlovid (nirmatrelvir/ ritonavir)
- Molnupiravir
- Molnupiravir Fact Sheet for Healthcare Providers
- Molnupiravir Fact Sheet for Patients and Caregivers
- FDA’s Frequently Asked Questions on the Emergency Use Authorization for Molnupiravir for Treatment of COVID-19
- US HHS Public Health Emergency Webpage on Molnupiravir
- US HHS ASPR Frequently Asked Questions – Molnupiravir
- FDA Letter of Emergency Use Authorization for Molnupiravir
Of note, nirmatrelvir is the active component in Paxlovid. Ritonavir has some antiviral properties (not against the SARS-CoV-2 virus though) and works as a booster to increase nirmatrelvir concentrations. Ritonavir (RTV, Norvir) has long been used as a booster in HIV therapy regimens.
LEARN ANTIBIOTICS
Here is a table providing a comparison of Paxlovid to molnupiravir…
| Generic Name |
Nirmatrelvir/ritonavir |
Molnupiravir |
| Branded Names |
Paxlovid |
Lagevrio |
| Manufacturer |
Pfizer |
Merck |
|
FDA EUA Date |
12/22/2021 |
12/23/2021 |
| Drug Class |
SARS-CoV-2 main protease inhibitor (nirmatrelvir) HIV-1 protease inhibitor & CYP3A inhibitor (ritonavir) |
Nucleoside analogue |
| Drug Type |
Antiviral |
Antiviral |
| Mechanism of Action versus SARS-CoV-2 |
Inhibits mPRO, preventing viral replication |
Viral lethal mutagenesis |
| Cross-Resistance with Anti-SARS-CoV-2 Monoclonal Antibodies |
Not expected |
Not Expected |
| Cross-Resistance with Remdesivir |
Not Expected |
Not Expected |
|
Delta Variant Activity |
Yes |
Yes |
| Omicron Variant Activity |
Expected |
Expected |
| Indication |
At risk patients with mild-moderate COVID-19 |
At risk patients with mild-moderate COVID-19 |
| Age Limit |
Must be 12 years or older |
Must be 18 years or older |
| Weight Limit |
Must be 40 kg or more |
None stated |
| Need Positive Direct SARS-CoV-2 Test? |
Yes |
Yes |
| Can Initiate if Hospitalized for COVID-19? |
No |
No |
| Can Continue if Hospitalized During Therapy? |
Yes |
Yes |
| Authorized for Pre or Post Exposure Prophylaxis? |
No |
No |
| Must Provide Patient/ Caregiver Fact Sheet? |
Yes |
Yes |
| MedWatch Med Errors/ Severe Adverse Event Reporting Required? |
Yes |
Yes |
| When to Start |
Within 5 days symptom onset |
Within 5 days symptom onset |
| Route |
Oral |
Oral |
| Dose |
300 mg nirmatrelvir with 100 mg ritonavir every 12 hours |
800 mg every 12 hours |
| Pills per Dose |
3 |
4 |
| Duration of Therapy |
5 days |
5 days |
| Pill Imprint |
“PFE” and “3CL” for nirmatrelvir “a” and “NK” for ritonavir |
“82” |
| How Supplied |
5 daily dose blister cards |
40 count bottles |
| Storage |
Room Temperature |
Room Temperature |
| NDC |
NDC-0069-1085-30 NDC-0069-1085-06 |
NDC-0006-5055-06 NDC-0006-5055-07 |
| Take with Food? |
With or without, but high fat meal increases absorption ~15% |
With or without |
| Okay to Crush? |
No |
No |
| Renal Dose Adjustment |
For eGFR 30 to below 60 Avoid if eGFR below 30 |
None |
| Hepatic Dose Adjustment |
Avoid in severe hepatic impairment (Child-Pugh Class C) |
None |
| Contraindications |
Hypersensitivity to ingredients Use with certain drugs that have CYP3A4 interactions |
None listed |
| Warnings |
Beware drug interactions Hepatotoxicity HIV-1 drug resistance in patients with HIV-1 infection |
Embryo-fetal toxicity Bone and cartilage toxicity |
| Most Common Adverse Reactions |
Dysguesia, diarrhea, hypertension, myalgia |
Diarrhea, nausea, dizziness |
| Special Populations |
No human data on use in pregnancy or breastfeeding |
Not recommended in pregnancy Not recommended if breastfeeding (Has pregnancy surveillance program) |
| Drug Interactions |
Many, see below |
None identified to date |
| HCP Fact Sheet Length |
29 pages |
18 pages |
| Courses Available in First US Allocation |
64,970 courses |
300,620 courses |
| Prescription Needed? |
Yes |
Yes |
| Cost to US Gov’t | ||
| Cost to Patient |
$0 |
$0 |
Brief Summary of Clinical Study Data – Molnupiravir
MOVe-OUT Trial randomized 1,433 high-risk non-hospitalized adult subjects with mild-moderate COVID-19. 709 patients received molnupiravir and 699 patients received placebo. All-cause hospitalization 24 hours or more for acute care or death at day 29 was 6.8% for molnupiravir (n=48) and 9.7% for placebo (n=68). Mortality at day 29 was 0.1% for molnupiravir (n=1) and 1.3% for placebo (n=9).
Brief Summary of Clinical Study – Paxlovid
EPIC-HR Trial randomized 2,246 high-risk non-hospitalized symptomatic adults with COVID-19. 1,039 patients received Paxlovid and 1,046 received placebo. In the modified intent to treat analysis, COVID-19 related hospitalization or death from any cause through day 28 was 0.8% in the Paxlovid arm (n=8) and 6.3% in the placebo arm (n=66). All cause mortality through day 28 was 0% in the Paxlovid arm and 1.1% in the placebo arm (n=12).
Paxlovid versus molnupiravir – Figure 1 provided in HCP Fact Sheet
Paxlovid HCP Fact Sheet Details
Molnupiravir HCP Fact Sheet Details
Paxlovid drug-drug interactions listed as contraindications
CYP3A inducers will speed up the metabolism (i.e. decrease concentrations) of drugs that use the CYP3A4 pathway. CYP3A inhibitors will slow the metabolism (i.e., increase concentrations) of drugs that use the CYP3A4 pathway. CYP3A4 substrates use the CYP3A4 pathway.
- Contraindicated drugs highly dependent on CYP3A for clearance:
- Alpha1-adrenoreceptor antagonist: alfuzosin
- Analgesics: pethidine, piroxicam, propoxyphene
- Antianginal: ranolazine
- Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
- Anti-gout: colchicine
- Antipsychotics: lurasidone, pimozide, clozapine
- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: lovastatin, simvastatin
- PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH)
- Sedative/hypnotics: triazolam, oral midazolam
- Contraindicated drugs or herbals that are potent CYP3A4 inducers:
- Anticancer drugs: apalutamide
- Anticonvulsant: carbamazepine, phenobarbital, phenytoin
- Antimycobacterials: rifampin
- Herbal products: St. John’s Wort (hypericum perforatum)
Of note, ritonavir in Paxlovid may reduce the efficacy of combined hormonal contraceptives. This is not a contraindication to Paxlovid use, but should be included in patient counseling when relevant. There are many drug interactions not listed here, refer to HCP Fact Sheet for more, the resources may also be helpful:
- University of Liverpool Interaction Checker
- University of Liverpool HIV Drug Interaction Checker
- HIV.gov Adult ARV Guideline (with information on ritonavir drug-drug interactions)
Closing comments
I hope that you have found this helpful. Please access the resources cited at the beginning of this article for the most up to date information on these new oral COVID medications.
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