Nirmatrelvir/Ritonavir (PaxlovidTM) - Tip Sheet for Drug-Interactions

Last revision 1/12/2022

Nirmatrelvir/Ritonavir (Paxlovid

) - Tip Sheet for Drug-Interactions

***Tables are NOT Exhaustive and Represent SHC/National Most Commonly Prescribed Drugs***

For drugs not listed, check DDIs using resources below, particularly the Liverpool tool, for more information.

Consider consulting specialist and/or clinical pharmacist.

Background and Basis for Potential Drug Interactions

Paxlovid

received an emergency use authorization (EUA) from the US Food and Drug Administration (FDA)

on December 22, 2021.

This medication is comprised of nirmatrelvir, a SARS-CoV-2 protease inhibitor and

CYP3A4 substrate, and ritonavir, a strong CYP3A4 and P-gp inhibitor, weak CYP2D6 inhibitor, moderate

CYP2B6 inducer, and weak CYP1A2, CYP2C19, and CYP2C9 inducer. The EUA allows Paxlovid

to be used

in adults and pediatric patients (12 years and older weighing at least 40 kg) with positive SARS-CoV-2 viral

testing and a high risk of progression to severe COVID-19 infection.

Paxlovid

is an oral medication and is dosed 300 mg of nirmatrelvir (two 150 mg tablets) and 100 mg of

ritonavir (one 100 mg tablet). For patients without kidney dysfunction (eGFR ≥ 60) all three tablets are taken

together twice daily for 5 days.

While ritonavir has no activity against SARS-CoV-2, it is used to boost nirmatrelvir levels.

Because of

ritonavir’s potent CYP3A and P-gp inhibition, it carries significant drug-drug interactions (DDIs) with many other

medications. The anticipated onset of CYP3A inhibition by ritonavir is approximately 48 hours with an offset of

2 to 5 days after discontinuation.

3-5

Because of the short course of Paxlovid

, the induction properties of

ritonavir are less likely to be clinically relevant. Read more on metabolism and DDIs here (link).

Recommended Resources for Providers to Assess Potential DDIs:

• American Society of Transplantation Statement on Oral COVID-19 Antivirals

• FDA Paxlovid

Fact Sheet for Healthcare Providers

• Liverpool COVID-19 Drug Interactions Checker

• Liverpool HIV Drug Interactions Checker

• Liverpool Protease Inhibitors Interaction Summary Table

• NIH Statement on Paxlovid Drug-Drug Interactions

Table 1. Commonly Prescribed Drugs Contraindicated with Nirmaltrelvir/Ritonavir

***Tables are NOT Exhaustive and Represent SHC/National Most Commonly Prescribed Drugs***

Prescribe Alternative COVID-19 Therapy

Withhold or Use Alternative Therapy

†

Use Alternative COVID-19 Therapy

Amiodarone (X)

Apixaban (X)

Carbamazepine (X)

Clopidogrel (X)

Colchicine (X)

Phenobarbital (X)

Phenytoin (X)

Rifampin (X)

Rivaroxaban (X)

Sildenafil (X†)*

Tadalafil (X†)*

Ticagrelor (X)

Alprazolam (†)

Antineoplastics (X†)

Atorvastatin (†)

Everolimus (X)

Fentanyl (†)

Isavuconazole (†)

Oral contraceptives (†)

Quetiapine (†)

Rosuvastatin (†)

Simvastatin (X)

Sirolimus (X)

Voriconazole (X)

Key: X = absolute contraindication, † Consider using “Look for alternatives” functionality of Liverpool HIV Drug

Interactions Checker searching under drug name “ritonavir”.

*Absolute contraindication for pulmonary hypertension, if used for erectile dysfunction withhold medication

Last revision 1/12/2022

Table 2. Top SHC/Nationally-Prescribed Non-Contraindicated Drug Interactions with

Nirmatrelvir/Ritonavir

***Tables are NOT Exhaustive and Represent SHC/National Most Commonly Prescribed Drugs***

Concomitant Drug Class:

Drug Name

Effect on

Concentration

Clinical Comments from FDA EUA HCP Fact Sheet

and/or Liverpool

Amlodipine

↑ Amlodipine

Based on DDI studies with amlodipine and

indinavir/ritonavir or paritaprevir/ritonavir, amlodipine

exposure is expected to increase by ~2-fold. Reduce

amlodipine dose by 50% when coadministered with

nirmatrelvir/ritonavir and for a further 2 days after the

last dose of nirmatrelvir/ritonavir.

Bupropion

↓ Bupropion

Concurrent administration of bupropion with repeated

doses of ritonavir 100mg is expected to decrease

bupropion level to a limited extent. Since duration of

treatment for nirmatrelvir/ritonavir is short and maximal

reduction effect expected after several days of

concomitant therapy, no empiric dose adjustment is

recommended. Monitor for decreased bupropion

efficacy.

Clonazepam

↑ Clonazepam

Inhibition of CYP3A4 by ritonavir may increase

clonazepam concentrations and a decrease in dose

may be necessary. Monitor therapy for adverse drug

effects due to increased serum concentrations of

clonazepam.

Cyclosporine

↑ Cyclosporine

Cyclosporine is metabolized by CYP3A4 and plasma

concentrations of cyclosporine are expected to increase

when administered with nirmatrelvir/ritonavir.

In a statement from the American Society of

Transplantation, they recommend to significantly reduce

the dose to 20% of the current dose.

For solid organ

transplant recipients, reach out to the solid organ

transplant provider for guidance. Therapeutic monitoring

is recommended for immunosuppressants.

For all other indications, consultation with an expert

(e.g. clinical pharmacist, HIV specialist, and/or patient’s

specialist provider) should be considered. Avoid use of

nirmatrelvir/ritonavir when close monitoring of

immunosuppressant serum concentrations is not

feasible.

Hydrocodone

↑ Hydrocodone

↓ Active metabolites

Hydrocodone is metabolized by CYP2D6 to

hydromorphone and by CYP3A4 to norhydrocodone.

Inhibition of CYP3A4 and CYP2D6 by

nirmatrelvir/ritonavir may increase hydrocodone

concentrations but decrease concentrations of

norhydrocodone and hydromorphone. Monitor the

analgesic effect and signs of opiate toxicity.

Last revision 1/12/2022

Itraconazole

↑ Paxlovid

Itraconazole is metabolized by CYP3A4 and is a strong

inhibitor of CYP3A4. Coadministration of itraconazole

(200 mg once daily) and nirmatrelvir/ritonavir (300/100

mg twice daily) increased nirmatrelvir AUC and Cmax

by 39% and 19%. High doses of itraconazole (>200

mg/day) are not recommended.

Levothyroxine

↓ Levothyroxine

The induction of glucuronidation by ritonavir increases

the elimination of levothyroxine. However, no significant

interaction is expected given the short treatment course

of nirmatrelvir/ritonavir. Monitor therapy for signs and

symptoms of hypothyroidism.

Mirtazapine

↑ Mirtazapine

Mirtazapine is metabolized by CYP3A4 and

coadministration could increase mirtazapine

concentrations. Use with caution as mirtazapine has

been shown to prolong the QT interval, clinical

monitoring including ECG assessment should be

considered.

Oxycodone

↑ Oxycodone

↓ Active metabolites

Oxycodone is metabolized to noroxycodone via

CYP3A4 and oxymorphone via CYP2D6.

Concentrations of oxycodone may increase due to

CYP3A4 inhibition by ritonavir. A dose reduction of

oxycodone may be required to prevent opioid-related

adverse effects with clinical monitoring. Monitor the

analgesic effect and signs of opiate toxicity.

Posaconazole

↑ Paxlovid

Coadministration has not been studied. Posaconazole

is not significantly metabolized and eliminated mainly as

unchanged drug in the feces. Approximately 17% of

posaconazole undergo non-CYP mediated metabolism

(hepatic glucuronidation by UGT1A4). Posaconazole is

a strong inhibitor of CYP3A4 and could potentially

increase nirmatrelvir/ritonavir exposure, although to a

limited extent.

Prednisone

↑ Active metabolite

Prednisolone, the active metabolite of prednisone, is

metabolized by CYP3A4. Coadministration with

nirmatrelvir/ritonavir is expected to increase exposure of

the prednisolone. Given the 5-day duration of

nirmatrelvir/ritonavir this is unlikely to be clinically

significant. Monitor therapy for adverse drug effects

such as Cushing’s syndrome and adrenal suppression.

Quetiapine

↑ Quetiapine

Consider therapy modification or dose reduction of

quetiapine when combined with a strong CYP3A4

inhibitor. If initiating therapy start at the lowest dose and

up-titrate cautiously.

Last revision 1/12/2022

Risperidone

↑ Risperidone

Risperidone is partly metabolized by CYP3A4 and

substrate of P-gp. Nirmatrelvir/ritonavir could increase

risperidone exposure. Use with caution and monitor

closely for adverse effects such as malignant syndrome,

extrapyramidal syndrome, and angioedema.

Tacrolimus

↑ Tacrolimus

Tacrolimus is metabolized by CYP3A4 and is a

substrate of P-gp. Consider alternative COVID-19

therapies, if coadministration is unavoidable expect

profoundly increased plasma concentrations of

tacrolimus. Micelli et al, Mertz et al, and Lange et al,

suggest intense dose reduction and/or withholding

tacrolimus during all or part of duration while receiving

concomitant ritonavir, alongside close therapeutic

monitoring to guide dosing.

11,12

In a statement from the

American Society of Transplantation, they recommend

to hold or substantially reduce the dose, for HIV patients

on ritonavir, doses of tacrolimus 0.5 mg per week have

been used.

Some have proposed holding tacrolimus

and to measure a level on day 3 to assess whether a

one-time tacrolimus dose is needed during

nirmatrelvir/ritonavir treatment.

For solid organ

transplant recipients, reach out to the solid organ

transplant provider for guidance. For all other

indications, consultation with an expert (e.g. clinical

pharmacist, HIV specialist, and/or patient’s specialist

provider) should be considered, any decision to hold

tacrolimus should be made in discussion with the

transplant provider or clinical specialist. Avoid use of

nirmatrelvir/ritonavir when close monitoring of

immunosuppressant serum concentrations is not

feasible. TAT for tacrolimus levels at the SHC lab is

24hr (routine); 1 hr (STAT).

Tamsulosin

↑ Tamsulosin

Tamsulosin is metabolized mainly by CYP3A4 and

coadministration may increase tamsulosin exposure.

Given tamsulosin’s higher affinity for prostatic smooth

muscle and its demonstrated tolerability when combined

with other CYP3A4/CYP2D6 inhibitors, consider using

tamsulosin at 0.4 mg/day if coadministered. Monitor

blood pressure.

Tramadol

↑↓ Tramadol

Nirmatrelvir/ritonavir may increase tramadol exposure

but also reduce the conversion to the more potent

active metabolite. Monitor the analgesic effect and signs

of opiate toxicity.

Trazodone

↑ Trazodone

Combination therapy should be used with caution and a

dose reduction of trazodone should be considered. In

healthy volunteers, ritonavir 200 mg twice daily

increased trazodone concentrations by more than two-

fold. Monitor for adverse reactions such as nausea,

dizziness, hypotension, syncope, and QTc prolongation.

Last revision 1/12/2022

Warfarin

↑↓ Warfarin

Warfarin is a mixture of enantiomers which are

metabolized by different cytochromes. Co-

administration may increase or decrease warfarin

concentrations. Closely monitor INR if co-administration

with warfarin is necessary. TAT for tacrolimus levels at

the SHC lab is 4hr (routine); 1 hr (STAT).

Zolpidem Tartrate

↑ Zolpidem Tartrate

Coadministration with ritonavir increased zolpidem AUC

and Cmax by 28% and 22%. However, a dosage

adjustment may not be necessary based on drug-drug

interaction data with ketoconazole (a strong inhibitor).

Patients should be informed that they may experience

enhanced sedative effects.

Last revision 1/12/2022

References

1. U.S. Food and Drug Administration. 2022. Coronavirus (COVID-19) Update: FDA Authorizes First Oral

Antiviral for Treatment of COVID-19. [online] Available at: <https://www.fda.gov/news-events/press-

announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19>

[Accessed 3 January 2022].

2. Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid. Pfizer Inc; 2021.

3. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome p450 3A

function after single doses of grapefruit juice. Clin Pharmacol Ther. 2003;74(2):121-129.

doi:10.1016/S0009-9236(03)00118-8

4. Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the

drug interacting effect. J Antimicrob Chemother. 2020;75(10):3084-3086. doi:10.1093/jac/dkaa253

5. Katzenmaier S, Markert C, Riedel KD, Burhenne J, Haefeli WE, Mikus G. Determining the time course

of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using A limited sampling

strategy. Clin Pharmacol Ther. 2011;90(5):666-673. doi:10.1038/clpt.2011.164

6. National Institutes of Health. 2021. The COVID-19 Treatment Guidelines Panel's Statement on

Potential Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant

Medications [online] Available at: <https://www.covid19treatmentguidelines.nih.gov/therapies/

statement-on-paxlovid-drug-drug-interactions/> [Accessed 3 January 2022].

7. Centers for Medicare & Medicaid Services. 2019. Medicare Provider Utilization and Payment Data: Part

D Prescriber. [online] Available at: < https://www.cms.gov/Research-Statistics-Data-and-

Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/Part-D-Prescriber> [Accessed

3 January 2022].

8. American Society of Transplantation. 2021. AST Statement on Oral Antiviral Therapy for COVID-19 for

Organ Transplant Recipients. [online] Available at: < https://www.myast.org/sites/default/files/

AST%20Statement %20on%20Oral%20Antiviral% 20Therapy %20for%20COVID%20Jan%204%

20%282%29.pdf> [Accessed 11 January 2022].

9. Liverpool COVID-19 DDI checker, accessed 1/3/2022

10. Liverpool HIV DDI checker, accessed 1/3/2022

11. Miceli M, Cronin S, Ayash L, Alangaden G, Chandrasekar PH. Significant interaction of tacrolimus with

ritonavir during allogeneic hematopoietic SCT in an HIV-infected patient. Bone Marrow Transplant.

2012 Aug;47(8):1140-2. doi: 10.1038/bmt.2011.230. Epub 2011 Nov 28. PMID: 22120984.

12. Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a kidney transplant recipient

receiving HIV salvage therapy and tacrolimus. Am J Kidney Dis. 2009 Jul;54(1):e1-4. doi:

10.1053/j.ajkd.2009.01.268. Epub 2009 Apr 5. PMID: 19346040.

13. Lange NW, Salerno DM, Jennings DL, et al. Nirmatrelvir/ritonavir use: Managing clinically significant

drug-drug interactions with transplant immunosuppressants [published online ahead of print, 2022 Jan

11]. Am J Transplant. 2022;10.1111/ajt.16955. doi:10.1111/ajt.16955

14. Stanford Anatomic Pathology & Clinical Laboratories Test Directory https://stanfordlab.com/test-

directory.html, accessed 1/5/2022